Technical situation

Summary

Introduction

• Health care IT is health care information technology.  The AHRQ argues HCIT consists of a complex set of technologies, policies, standards and user sets.  Technically they represent it as a set of layers: Application: CPOE, CDS, e-prescribing, eMAR, Results reporting, Electronic documentation, Interface engines, etc.; Communication: Messaging standards (HL7, ADT, NCPDP, X12, DICOM, ASTM, etc,) Coding standards (LOINC, ICD10, CPT, NDC, RxNorm, SNOMED CT, etc.), Process: HIE, MPI, HIPAA security & privacy, etc.; Device: Tablet and PC, ASP, PDAs, Bar Coding, etc.; 
  offers to: Enhance the quality/process, extend the intelligence, increase the transparency, reduce the cost, improve RCM is either:
  
  • Restrictive cardiomyopathy, a rare disease where scar tissue makes the heart muscle rigid and reduces the efficiency.  Or
    
  • Revenue Cycle Management aligns treatment with reimbursement.  Customer service will be involved.  IT will architect the core billing, decision support and ad-hoc services, constructed by RCM vendors, into systems to support RCM.  The Hospital's central business office will aim to maximize cash recoveries.  As per Deming, mistakes in the RCM pipeline result in rework and lost cash flow and revenue of between 4 - 12%.  The staff must be trained and fully engaged in the design and operation of the pipeline.  The front end processes are best placed to capture all the information needed to make the cycle successful.  The activities include:
  • Scheduling and Appointments - where visits and procedures are booked and demographic and insurance information is collected.  If this information is incorrect it is likely the claims will not forward to third party payers.  When resources and their states are accurately known an optimal set of plans can be constructed to efficiently and effectively flow patients through the system.  But that is difficult to guarantee because of a number of interrelated problems:
  • Scale - as the number of resources increases the ability of a central scheduling system to represent all of them accurately and reliably becomes impossible. 
    
  • Ubiquity - a CAS strategy for ensuring availability is to have an over-abundance of equivalent resource that can be used for schedule allocation.  But often these resource levels are set by local decision makers who all respond at about the same time to imposed funding changes.  The effect is to suddenly and unpredictably undermine the guarantee of over-abundance.  Sometimes the assumption of equivalence also fails as in the desire of a patient to see only a specific surgeon. 
    
  • Changes can ripple through the plans requiring coordination meetings and notifications or guaranteed receipt of status updates. 
    
  • Verification checks for:
    
  • Referral - Is there PCP authorization?  Is the PCP referred service covered by the patient's plan,
    
  • Authorization - obtain Insurance authorization if required, and
    
  • Pre-certification - is there 'need' for inpatient care or other care before admission by the MCO.  Otherwise could introduce problems including not obtaining/verifying the insurance name, number and eligibility, not securing pre-certification and pre-authorization with time limits, not copying the insurance card, not checking for secondary coverage, not detecting expired referral or authorization,
    
  • Pre-registration - provide advice about their financial obligations and what documents to bring to the procedure.  If there is a copay or an outstanding payment to be paid these should be processed,
    
  • Registration - some patients are scheduled outside of the main admitting process (by OP clinic or E.D.) and this must be detected and the scheduling verification and pre-registration process be performed,
    
  • Time of service payments - co pays and self pays,
    
  • Coding - identify diagnosis (ICD 9 -> ICD-10 codes) and treatment (CPT) activities and charges for the episode.  More than 80% of hospital cases are coded in error. 
    
  • Demographics and billing data entry - enter charges and adjust capitated charges,
    
  • Patient statements - submit primary and secondary claims (following HIPAA formats) with or without involvement of a clearinghouse, produce patient statements including time of service, outstanding balance, charged amount with codes, insurance details, forms used (UB 92/04 and HCFA 1500).  A paper based claims filing has a rejection rate of 30%.  Duplicate claim payment rates of 1 - 2% of medical expenses are common.  Duplicate claims detection is often not part of the process.  Payer's goals are in conflict with Provider goals.  
    
  • Collections and payment posting - Post all payments and adjustments and deposit money into the bank,
    
  • Denials and appeals - resubmission and appeal of claims, denial analysis and bad debts and write offs.  To reduce denial rates and appeals the reimbursement contracts payer processes and actual denials must be analyzed and understood. 
    
  • Account follow up - Patient inquiries, resubmission of claims and issue refunds. 
    
  • Financial counseling;
  and extend the reach of health care;
• Central banks look at bitcoin is a set of open-source software, used to provide infrastructure that supports a distributed cryptocurrency and payment system, based on the blockchain.   All transaction inputs are unspent outputs from previous transactions.  All transaction inputs are signed.  Change is provided in an additional output to the transaction. 
  's blockchain is a bitcoin distributed database technology that allows several bitcoin operators to keep a shared, cryptographically verified, ledger and consensus mechanism to allow agreement on what transactions have happened and in what order.  It implements a Merkle tree.  Six times an hour on average, a new group of validated transactions, a block, is created, added to the local block chain and published to all nodes.  Paraphrasing breadwallet's Aaron Voisine, publishing is robust because: Each operator has connected via references from its initial peers to a random subset of all the other operators; and the new block is offered to the connected peers who can both ask for it if they have not seen it previously from some other source and pass it on to their other peers in a cascade (a gossip network).  To build new blocks an operator must have all the prior blocks in the chain.  All unspent bitcoins are represented [only] in the blockchain.  Miners keep the blockchain consistent by verifying that a new block has a proof-of-work.  This requires that miners find a nonce that multiplied by the block hash is smaller than the network's difficulty target.   to develop a distributed ledger (Oct 2016)
• Security:
• Internet increasingly impacted (Oct 2016)
• Prosecutor Haun and TSRI's Topol review the problem and a blockchain is a bitcoin distributed database technology that allows several bitcoin operators to keep a shared, cryptographically verified, ledger and consensus mechanism to allow agreement on what transactions have happened and in what order.  It implements a Merkle tree.  Six times an hour on average, a new group of validated transactions, a block, is created, added to the local block chain and published to all nodes.  Paraphrasing breadwallet's Aaron Voisine, publishing is robust because: Each operator has connected via references from its initial peers to a random subset of all the other operators; and the new block is offered to the connected peers who can both ask for it if they have not seen it previously from some other source and pass it on to their other peers in a cascade (a gossip network).  To build new blocks an operator must have all the prior blocks in the chain.  All unspent bitcoins are represented [only] in the blockchain.  Miners keep the blockchain consistent by verifying that a new block has a proof-of-work.  This requires that miners find a nonce that multiplied by the block hash is smaller than the network's difficulty target.   solution for Health Data breaches (Jan 2017)
• Congress concludes Chinese distributors ship fentanyl is a synthetic opioid pain medication that acts on micro-opioid receptors in the brain.  It is 50 times more potent than morphine.  It was originally manufactured by Janssen Pharmaceutica in 1959 which was acquired by Johnson & Johnson.  It is branded as: Sublimaze, Actiq, Durogesic, Duragesic, Fentora, Matrifen, Subsys, Instanyl, Abstral, Lazanda; with a variety of deployment formulations.  It is often used, in a transdermal patch such as durogesic, to treat severe ongoing pain which can be induced by cancer.  It has followed heroin into the back-street opioid epidemic (Jun 2017). 
  via e-commerce: UPS, FEDEX, USPS; via third countries, to buyers in US is the United States of America.  : Ohio, Pennsylvania, Florida; who pay with Bitcoins is a set of open-source software, used to provide infrastructure that supports a distributed cryptocurrency and payment system, based on the blockchain.   All transaction inputs are unspent outputs from previous transactions.  All transaction inputs are signed.  Change is provided in an additional output to the transaction. 
  (Jan 2018)
• Imaging: CT is computerized tomography in which a series of X-ray views taken from many angles are combined by computer processing to create 3-D images.  It is very useful for examining people who have been subject to trauma such as car accidents.  The high dose of radiation is a cause for concern with over use of CT scanning (Jan 2014).  The Banyan Brain Trauma Indicator blood test should help here. 
  , fMRI is functional magnetic resonance imaging.  Seiji Ogawa leveraged the coupling of neuronal circuit activity and blood flow through the associated glial cells to build a 3 dimensional picture of brain cell activity.  As haemoglobin gives up its oxygen to support the neural activity it becomes magnetic and acts as a signal detected by the fMRI.  fMRI easily visualizes the state of activity in the living human brain at millimeter resolution, up to several times a second but it cannot track the time course of neural firing so it is augmented with EEG.  , molecular imaging allows the visualization of cellular function and molecular processes, allowing more precise and earlier diagnosis of disease.  It extends traditional imaging by:
  
  • Using biomarkers, including Nano sensors, which interact chemically with their surroundings, to image particular targets and pathways
    
  • Leveraging deep learning to reduce the required imaging, and target it more effectively
    
  • Providing quantitative data on the imaged process or function enabling Nano medicine.  
  • Extending mass spectrometry with MALDI to allow rapid (relative to sequencing or x-ray crystallography), low cost analysis of proteins, bacteria and viruses.  
  : MALDI is matrix-assisted laser desorption/ionization mass spectrometry.  It generates ions in the gas phase from large molecules.  The sample (a protein, DNA, sugar) is: 1. Mixed with an appropriate matrix material and is deployed to a metal plate.  2. Irradiated with a pulsed laser.  3. Ionized with an ablated gas; and then flowed to an appropriate mass spectrometer.  MALDI is low cost and rapid to perform but it is hard to make quantitatively repeatable. 
  ; sensors,
  
• Genomics combines recombinant DNA editing with tools: CRISPR; DNA next generation sequencing and bioinformatics  to sequence, assemble and analyse genomes.   and proteomics may: transform screening, testing uses genomic analysis to diagnose genetic disorders - for example Genomic Health's Oncotype DX & Agendia's MammaPrint.  The desire to see the genetic risk factors identified by such tests should depend on the risk * burden * Possibility of intervention.  Early tests look at only single gene mutations, but big data research tools are showing promise with large gene algorithms (Aug 2018).  Genomic testing can be performed direct-to-consumer.  Data is being collated on the genetic components of most diseases to enable more sophisticated diagnosis in the future such as the OPHG (EGAPP initiative), USPSTF recommendations and NCBI (Genetic test registry).  While there is only limited identification of the significant mutations and limited patient bases misdiagnosis is a problem (Aug 2016). 
  , and drug delivery studies how genes affect a person's response to drugs so as to develop personalized drug treatment plans, tailored to a person's specific phenotype.  The process optimizes the treatment process but there are barriers to its deployment:
  • Large scale clinical trials may test 20,000 individuals, but if a toxic response impacts only 0.1% of them there would only be 20 cases found which is often too few to identify the cause of the response.  Instead a process for capturing adverse drug reactions after approval and marketing must be used along with the ability to take a blood sample in these cases.  
  • Simplified studies on a subset of individuals that have the target allele should be cheaper but are unattractive to pharmaceutical companies which typically want to maximize their target market (Aug 2016).  
  • F.D.A. has not required genomic testing for most drug developments.  
  • Health care providers are being slow to use pharmacogenomics.  Often third-party payers are unwilling to reimburse the tests. 
    
  • Transportation to centralized laboratories for genomic testing causes delays which makes some drug therapy applications impractical.  An alternative solution would be to have a patient's EHR contain their genome sequence for immediate genomic implications.  
  . 
  
• Can the key mutations be identified? Can the control systems be understood? 
  
• Precision/Personalized medicines is a medical strategy where decisions, practices, and products are tailored to the individual patient.  Research is looking at the impact of providing potentially deleterious genomic testing information to people: The REVEAL study found no increased anxiety induced by hearing that one's genome implied increased risk of developing late onset Alzheimer's disease.  The take-up of personalized medicine benefits from the focus on genomics, enabled by next generation sequencing of DNA, and detailed by the NIH director Francis Collins and includes:
  • NCCN intensive cell therapies
    
  • Direct to consumer genomic testing
    
  • Direct to consumer diagnostics
    
  • Pharmacogenomics tailored drug treatments reducing the risk and cost of adverse drug reactions.   
  : Obesity is an addictive disorder where the brain is induced to require more eating, often because of limits to the number of fat cells available to report satiation (Jul 2016).  Brain images of drug-addicted people and obese people have found similar changes in the brain.  Obese people's reward network tends to be less responsive to dopamine and have a lower density of dopamine receptors.  Obesity spreads like a virus through a social network with a 171% likelihood that a friend of someone who becomes obese will also become so.  Obesity is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes, asthma and heart disease.  It is suspected that this is contributing to the increase in maternal deaths in the US (Sep 2016).  Obesity is a complex condition best viewed as representing many different diseases, which is affected by the: Amount of brown adipose tissue (Oct 2016), Asprosin signalling by white adipose tissue (Nov 2016), Genetic alleles including 25 which guarantee an obese outcome, side effects of some pharmaceuticals for: Psychiatric disorders, Diabetes, Seizure, Hypertension, Auto-immunity; Acute diseases: Hypothyroidism, Cushing's syndrome, Hypothalamus disorders; State of the gut microbiome.  Infections, but not antibiotics, appear associated with childhood obesity (Nov 2016). 
  mechanism, Immuno-oncology uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
  • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
    
  • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
    
  • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
    
  • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
    
  and direct-to-consumer genetic and diagnostic testing.  
• New: Trial process, Pharmaceutical & biotech business model
  
• Can discrete signals be induced that differentiate every cell?  Why would a cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016). 
  cooperate anyway?
  
• Nanomedicine is the application of nanotechnology to medicine (May 2016, Feb 2019).  Commercial applications are focused on research and clinical tools for drug delivery, therapies, safer and more effective in vivo imaging, neuro-electronic interfaces, other Nano-sensors, and eventually cell repair machines!!  There are issues with determining toxicology etc. 
  will: Reduce the invasiveness of surgery, enhance screening, testing and drug delivery.  
• Expanded scientific conception of the patient: Awareness of the individual is a medical strategy where decisions, practices, and products are tailored to the individual patient.  Research is looking at the impact of providing potentially deleterious genomic testing information to people: The REVEAL study found no increased anxiety induced by hearing that one's genome implied increased risk of developing late onset Alzheimer's disease.  The take-up of personalized medicine benefits from the focus on genomics, enabled by next generation sequencing of DNA, and detailed by the NIH director Francis Collins and includes:
  • NCCN intensive cell therapies
    
  • Direct to consumer genomic testing
    
  • Direct to consumer diagnostics
    
  • Pharmacogenomics tailored drug treatments reducing the risk and cost of adverse drug reactions.   
  , neuroscience deals with the structure, development, chemistry, pharmacology, function and pathology of networks of biological neurons. 
  : Dementia is a classification of memory impairment, constrained feelings and enfeebled or extinct intellect.  The most common form for people under 60 is FTD.  Dementia has multiple causes including: vascular disease (inducing VCI) including strokes, head trauma, syphilis and mercury poisoning for treating syphilis, alcoholism, B12 deficiency (Sep 2016), privation, Androgen deprivation therapy (Oct 2016), stress, Parkinson's disease, Alzheimer's disease, and prion infections such as CJD and kuru.  The condition is typically chronic and treatment long term (Laguna Honda ward) and is predicted by Stanley Prusiner to become a major burden on the health system.  It may be possible to constrain the development some forms of dementia by: physical activity, hypertension management, and ongoing cognitive training.  Dementia appears to develop faster in women than men.   research (Alzheimer's is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and declarative memory and thinking problems (MCI).  Specific cells within the hippocampal circuitry and its gateway, the entorhinal cortex, are damaged.  The amygdala, cerebelum and other areas supporting implicit memory are not impacted during the early stages of the disease.  Grid cell destruction results in a sense of being lost.  The default mode network is disrupted.  Variants include: late-onset sporadic; with risk factors - ApoE4 for late onset Alzheimer's, presenilin, androgen deprivation therapy (Dec 2015), type 2 diabetes.  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation, Neurons of sporadic Alzheimer's sufferers show greater APP gene diversity due to somatic recombination; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form.  These are seen in fMRIs 10 to 15 years prior to detecting memory and thinking changes.  APP deployed in the cell membrane is cut into three parts.  The external part becomes amyloid-beta peptide which aggregates into Amyloid plaques, external to the neurons, if too much is generated or it is not removed fast enough. 
    
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016). 
    
  • Encouraging the garbage collection of amyloid and tau with gamma rhythms stimulation retards Alzheimer's in mice studies (Mar 2019)
    
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • Mutation driven misfolded Tau proteins can form tangles within the cytoplasm of neurons.  The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    
  • The brain becomes inflamed resulting in the killing of many more nerve cells.  The hippocampus disintegrates and the brain loses critical functions and memory loss becomes noticeable. 
    
  ), Memory (sleep facilitates salient memory formation and removal of non-salient memories.  The five different stages of the nightly sleep cycles support different aspects of memory formation.  The sleep stages follow Pre-sleep and include: Stage one characterized by light sleep and lasting 10 minutes, Stage two where theta waves and sleep spindles occur, Stage three and Stage four together represent deep slow-wave sleep (SWS) with delta waves, Stage five is REM sleep; sleep cycles last between 90-110 minutes each and as the night progresses SWS times reduce and REM times increase.   Sleep includes the operation of synapse synthesis and maintenance through DNA based activity including membrane trafficking, synaptic vesicle recycling, myelin structural protein formation and cholesterol and protein synthesis.  Sleep also controls inflammation (Jan 2019)  Sleep deprivation undermines the thalamus & nucleus accumbens management of pain. 
  ); microbiome, the trillions of bacteria and viruses that live inside higher animals' guts, on their skin etc.  These bacteria and viruses seem to play a role in: immune responses, digesting food, making nutrients, controlling mental health and maintaining a healthy weight.  The signals from the gut microbiota are relayed by major nerve fibers: vagus; to the central nervous system.  The symbiotic relationship must be actively managed.  Human armpits include glands which provide food favoring certain symbionts who build a defensive shield above the skin.  In the human gut: Barriers are setup: Mucus secretions form a physical constraint and provide sites for bacteriophages to anchor and attack pathogenic bacteria; Symbiont tailored nourishment: Plant-heavy food creates opportunities for fibre specialists like Bacteroides thetaiotaomicron; is provided, Selective binding sites are provided, Poisons are deployed against the unwelcome, and Temperature, acidity and oxygenation are managed.    High throughput sequencing allows the characterization of bacterial populations inside guts.  Beginning at birth, as they pass down the birth canal infants are supplied with a microbiome from their mothers.  If they are borne via cesarean they never receive some of the key bacteria: Bifidobaterium infantis which is also dependent on oligosaccharides in breast milk; from their mothers.  A variety of diseases may be caused by changes in the microbiome:
  • Eczema can be related to changes in the skin microbiome. 
    
  • Obesity can be induced by changes to the gut microbiome.  
  • Chronic inflammation
    
  • Allergies
    
  • Type 1 diabetes
    
  , Immune system has to support and protect an inventory of host cell types, detect and respond to invaders and maintain the symbiont equilibrium within the microbiome.  It detects microbes which have breached the secreted mucus barrier, driving them back and fortifying the barrier.  It culls species within the microbiome that are expanding beyond requirements.  It destroys invaders who make it into the internal transport networks.  As part of its initialization it has immune cells which suppress the main system to allow the microbiome to bootstrap.  The initial microbiome is tailored by the antibodies supplied from the mother's milk while breastfeeding.  The immune system consists of two main parts the older non-adaptive part and the newer adaptive part.  The adaptive part achieves this property by being schematically specified by DNA which is highly variable.  By rapid reproduction the system recombines the DNA variable regions in vast numbers of offspring cells which once they have been shown not to attack the host cell lines are used as templates for interacting with any foreign body (antigen).  When the immune cell's DNA hyper-variable regions are expressed as y-shaped antibody proteins they typically include some receptor like structures which match the surfaces of the typical antigen.  Once the antibody becomes bound to the antigen the immune system cells can destroy the invader. 
  : development is a phase during the operation of a CAS agent.  It allows for schematic strategies to be iteratively blended with environmental signals to solve the logistical issues of migrating newly built and transformed sub-agents.  That is needed to achieve the adult configuration of the agent and optimize it for the proximate environment.  Smiley includes examples of the developmental phase agents required in an emergent CAS.  In situations where parents invest in the growth and memetic learning of their offspring the schematic grab bag can support optimizations to develop models, structures and actions to construct an adept adult.  In humans, adolescence leverages neural plasticity, elder sibling advice and adult coaching to help prepare the deploying neuronal network and body to successfully compete. 
  , operation, extension uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
  • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
    
  • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
    
  • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
    
  • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
    
  and disease; Technological extensions: Overtreatment is the application of unnecessary health care.  It is a complex problem:
  • Overtreatment needs to be adaptive.  As people age their medicine levels typically need to be changed.  Often, as in the case of blood pressure, and blood sugar reduction, they should be reduced to avoid inducing falls (Nov 2015).  
  • Patients with chronic diseases, such as type 2 diabetes, often require different treatment settings.  And again these vary with age. 
    
  • Patients who have learned a regime, and been told it was successful, may resist instructions to change it.  Some worry that they will impact their health care provider's treatment performance measures. 
    
  , Mis-treatment, Medication adherence is focused on improving how effectively patients take their medicines.  In the US in 2017 the problem is huge and costly (Apr 2017).  Chronic diseases such as Malaria illustrate the complexity of the task.  A coherent medical network with shared access to EHR should help.  So do blister packs with the days of the week marked.  M-health glow caps with a wireless transmitter that lights up if medication has not been taken as expected.  An improved prescription label is less open to confusion.  Codes on drugs can be scanned by smartphones to initiate download of an informational video.  Smart pillboxes control when pills are dispensed.  Measuring the contents of a medication bottle can alert for intervention if too much or too little is in the bottle.  Drug manufacturers see ways to get closer to the patient: Sanofi Toujeo deployment; Pharmacies are implementing VDS to support medication adherence: Connected Care;
  , Brain computer interfaces; Double blind research and sham procedures: Stents is a small wire cage that can be inserted into an artery to prop it open.  They were introduced as an alternative to bypass surgery in the 1990s.  Stents are expensive.  Medicare payments vary depending on what kind of stent is used and how many, but are generally in the range $10,000 to $17,000 in 2015.   Double blind trials show that stents have no effect on chest pain relief (Nov 2017)
  ;
  
• Systemic understanding of antibiotics are compounds which kill bacteria, molds, etc.  Sulfur dye stuffs were found to be effective antibiotics.  The first evolved antibiotic discovered was penicillin.  Antibiotics are central to modern health care supporting the processes of: Surgery, Wound management, Infection control; which makes the development of antibiotic resistance worrying.  Antibiotics are:
  • Economically problematic to develop and sell. 
    
  • Congress enacted GAIN to encourage development of new antibiotics.  But it has not developed any market-entry award scheme, which seems necessary to encourage new antibiotic R&D. 
    
  • Medicare has required hospitals and SNFs to execute plans to ensure correct use of antibiotics & prevent the spread of drug-resistant infections.  
  • C.D.C. is acting to stop the spread of resistant infections and reduce unnecessary use of antibiotics.  
    
  • F.D.A. has simplified approval standards.  It is working with industry to limit use of antibiotics in livestock. 
    
  • BARDA is promoting public-private partnerships to support promising research.
    
  • Impacting the microbiome of the recipient.  Stool banking is a solution  (Sloan-Kettering stool banking).  
  • Associated with obesity, although evidence suggests childhood obesity relates to the infections not the antibiotic treatments (Nov 2016). 
    
  • Monitored globally by W.H.O.
    
  • Regulated in the US by the F.D.A. who promote voluntary labeling by industry to discourage livestock fattening (Dec 2013).  
  • Customer demands have more effect - Perdue shifts to no antibiotics in premier chickens (Aug 2015). 
    
  .
  
• Robotics: Robots & sensors, Virtual Reality is the full immersion of a human user into a virtually generated world.  Hence the user is not able to interact or think about the real world at the same time.  The use of sensors detecting the user's skin, eyes, ears, and other state and signal generators for touch, hearing, visuals etc. supports the transportation of the brain into an alternate situation where the user can interact.  As long as the sensors are broadly detecting the state of the user's body and the signals are generated at greater than 60 per second it is a truly real experience.  Unfortunately it is hard to fool gravity so these systems can induce motion sickness.  Virtual reality is likely to be significant in medicine in:
  • Training with new tools including surgical instruments. 
    
  • Remote treatment including surgery where the feedback allows the surgeon to operate robotic instruments experiencing the remote OR. 
    
  , Mind computer interfaces;  
• Pharmaceutical research on NME is a new molecular entity, including: biologics, biosimilars and some other specialty medications. 
  s:
  

• Technology change provides the potential to destabilize!  As ever an enterprise dashboard bringing together an overview of process and population analytics is desired.  Christensen, Grossman and Huang argue that EMR refers to electronic medical records which are a synonym of EHR.  EMRs have strengths and weaknesses:
  • The EHR provides an integrated record of the health systems notes on a patient including: Diagnosis and Treatment plans and protocols followed, Prescribed drugs with doses, Adverse drug reactions;
  • The EHR does not necessarily reflect the patient's situation accurately. 
    
  • The EHR often acts as a catch-all.  There is often little time for a doctor, newly attending the patient, to review and validate the historic details. 
    
  • The meaningful use requirements of HITECH and Medicare/Medicaid specify compliance of an EHR system or EHR module for specific environments such as an ambulatory or hospital in-patient setting. 
    
  • As of 2016 interfacing with the EHR is cumbersome and undermines face-to-face time between doctor and patient.  Doctors are allocated 12 minutes to interact with a patient of which less than five minutes was used for recording hand written notes.  With the EHR 12 minutes may be required to update the record!
    
  , Imaging and Molecular diagnostics (nano-materials in medicine May 2016, Feb 2019) will enable disruption of the whole US health care network. 
  
• Big data -
  
• Big data encompasses the IT systems and processes necessary to do population based data collection, management and analysis.  The very low cost, robust, data storage organized by infrastructure: HADOOP; allows digital data to be stored en mass.  Data scientists then apply assumptions about the world to the data, analogous to evolved mechanisms in vision, in the form of algorithms: Precision medicine, Protein folding modeling (Feb 2019) assumes coevolutionary methods can be applied to identify contact points in a protein's tertiary structure.  Rather than depending on averages, analysis at Verisk drills down to specifics and then highlights modeling problems by identifying the underlying CAS.  For the analysis to be useful it requires a hierarchy of supporting BI infrastructure:
  • Analytics utilization and integration delivered via SaaS and the Cloud to cope with the silos and data intensive nature. 
    
  • Analytics tools (BI) for PHM will be hard to develop.  
  • Complex data models must include clinical aspects of the patient specific data, including disease state population wide.  
  • A key aspect is providing clear signals about the nature of the data using data visualization. 
    
  • Data communication with the ability to exchange and transact.  HIEs and EMPI alliance approaches are all struggling to provide effective exchange. 
    
  • Data labeling and secure access and retreival.  While HIPAA was initially drafted as a secure MPI the index was removed from the legislation leaving the US without such a tool.  Silos imply that the security architecture will need to be robust. 
    
  • Raw data scrubbing, restructuring and standardization.  Even financial data is having to be restandarized shifting from ICD-9 to -10.  The intent is to transform the unstructured data via OCR and NLP to structured records to support the analytics process. 
    
  • Raw data warehousing is distributed across silos including PCP, Hospital system and network, cloud and SaaS for process, clinical and financial data. 
    
  • Data collection from the patient's proximate environment as well as provider CPOE, EHRs, workflow and process infrastructure.  The integration of the EHR into a big data collection tool is key. 
    
  patterns captured from the Internet are competitive control points for Alphabet, Amazon, Apple, IBM Watson, Microsoft (Jan 2017)
• Could integrate cell phone data with health records refers to electronic medical records which are a synonym of EHR.  EMRs have strengths and weaknesses:
  • The EHR provides an integrated record of the health systems notes on a patient including: Diagnosis and Treatment plans and protocols followed, Prescribed drugs with doses, Adverse drug reactions;
  • The EHR does not necessarily reflect the patient's situation accurately. 
    
  • The EHR often acts as a catch-all.  There is often little time for a doctor, newly attending the patient, to review and validate the historic details. 
    
  • The meaningful use requirements of HITECH and Medicare/Medicaid specify compliance of an EHR system or EHR module for specific environments such as an ambulatory or hospital in-patient setting. 
    
  • As of 2016 interfacing with the EHR is cumbersome and undermines face-to-face time between doctor and patient.  Doctors are allocated 12 minutes to interact with a patient of which less than five minutes was used for recording hand written notes.  With the EHR 12 minutes may be required to update the record!
    
  and tele-health is the use of remote health care.  It includes telepharmacy and clinical telehealth for stroke and psychiatry.  It also includes sessions between primary care providers and patients and assisted caregiving such as medication reminders and DME usage monitors. 
  to capture problematic chronic activities.  Verisk Health's use of payment data to detect costly 'hot spot' patients aligns with CAS principles.  
  
• CMS is the centers for Medicare and Medicaid services.   implements CHRONIC care act of 2017 is Ron Wyden & Orrin Hatch's Creating High-Quality Results and Outcomes Necessary to Improve Chronic Care Act signed into law by President Trump as title III of the BBA of 2018. 
  through Medicare Advantage (MA) is a private provider administered health insurance plan providing access to Medicare benefits.  It was originally enacted as part of BBA Medicare + Choice or Part C plans.  The government funded the plan with an annual fee, based on age and severity of the subscriber's medical conditions, rather than FFS.  When a Medicare eligible person enrolls in a MA plan the government pays the private provider a set amount each month.  The participant pays the Medicare part B premium and if required a part C premium each month.  The MA plans offer a PCP who coordinates care.  And the plans have an annual limit on out-of-pocket expenses unlike traditional Medicare.  When they obtain treatment they will have to pay a copayment which may be quite high for some specialists.  It is the health plan's responsibility to contract the physician network that will provide the care, leaving the risk with the insurer.  About 36% of Medicare beneficiaries are enrolled with Medicare Advantage by 2019.  The ACA introduced quality outcome and patient satisfaction based differential payments into MA.  To measure the performance it added a five-star quality rating scheme.  MA plans report their quality and patient satisfaction data to CMS annually and based on the results are awarded one to five stars.  The highest rated plans are provided with large additional payments.  It was assumed that subscribers would shift to the highest rated plans and the other plans would improve or drop out of MA.  And the ACA eliminated subsidies which the federal government used to establish Medicare Advantage.  However, the Obama administration has used a $8.5 Billion demonstration project to maintain this funding.  It is intended that it will eventually taper off so that the cost of Medicare Advantage coverage will be equivalent to standard Medicare. 
  changes, affecting the costly half of Medicare is a social insurance program that guarantees access to health insurance for Americans aged 65 and over, and younger people with disabilities and end stage renal disease or ALS.  Medicare is currently missing a cap on out-of-pocket costs and direct prescription drug coverage.  It includes:
  
  • Benefits
  • Part A: Hospital inpatient insurance.  As of Dec 2013 Medicare pays for home care in only limited circumstances, such as when a person needs temporary nursing care after a hospitalization.  Part A covers 20 days of inpatient rehabilitation at a SNF after discharge from inpatient care at a hospital. 
    
  • Part B: Medical insurance for non-hospital services including: doctor visits, tests, injectable drugs, ambulances, physical therapy;
    
  • Part C: Medicare Advantage 
  • Part D: indirect prescription drug coverage The MMA prohibits Medicare from directly negotiating drug prices. 
    
  • Eligibility
    
  • All persons 65 years of age or older who are legal residents for at least 5 years.  If they or a spouse have paid Medicare taxes for 10 years the Medicare part A payments are waived.  Medicare is legislated to become the primary health plan. 
    
  • Persons under 65 with disabilities who receive SSDI. 
    
  • Persons with specific medical conditions:
  • Have end stage renal disease or need a kidney transplant. 
    
  • They have ALS. 
    
  • Some beneficiaries are dual eligible. 
    
  • Part A requires the person has been admitted as an inpatient at a hospital.  This is constrained by a rule that they stay for three days after admission.  
    
  • Sign-up
  • Part A has automatic sign-up if the person is drawing social security.  Otherwise the person must sign-up for Part A and Part B. 
    
  • Should sign-up for Part B during the Initial Enrollment Period, of seven months centered around 65th birthday, online or at a social security office.  But if still covered by spouse's insurance or not yet retired then may only join during the 3 month general enrollment period (January to March) each year, with coverage initiated the following July.  Incremental yearly 10% penalties apply for not signing up at 65.  These penalties apply to all subsequent premiums. 
    
  • Premiums
  • Part A premium
  • Part B insurance premium
    
  • Part C & D premiums are set by the commercial insurer.  
  's patients with multiple chronic conditions.  The act offers additional benefits for people suffering from chronic diseases including: diabetes includes type 1 and type 2.  Common side effects include: increased heart disease, hypertension, kidney disease, vision loss, nerve damage, and infections. 
  , Alzheimer's is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and declarative memory and thinking problems (MCI).  Specific cells within the hippocampal circuitry and its gateway, the entorhinal cortex, are damaged.  The amygdala, cerebelum and other areas supporting implicit memory are not impacted during the early stages of the disease.  Grid cell destruction results in a sense of being lost.  The default mode network is disrupted.  Variants include: late-onset sporadic; with risk factors - ApoE4 for late onset Alzheimer's, presenilin, androgen deprivation therapy (Dec 2015), type 2 diabetes.  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation, Neurons of sporadic Alzheimer's sufferers show greater APP gene diversity due to somatic recombination; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form.  These are seen in fMRIs 10 to 15 years prior to detecting memory and thinking changes.  APP deployed in the cell membrane is cut into three parts.  The external part becomes amyloid-beta peptide which aggregates into Amyloid plaques, external to the neurons, if too much is generated or it is not removed fast enough. 
    
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016). 
    
  • Encouraging the garbage collection of amyloid and tau with gamma rhythms stimulation retards Alzheimer's in mice studies (Mar 2019)
    
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • Mutation driven misfolded Tau proteins can form tangles within the cytoplasm of neurons.  The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    
  • The brain becomes inflamed resulting in the killing of many more nerve cells.  The hippocampus disintegrates and the brain loses critical functions and memory loss becomes noticeable. 
    
  , Parkinson's corresponds to the breakdown of certain interneurons in the brain.  It is not fully understood why this occurs.  Dopamine system neuron breakdown generates the classical symptoms of tremors and rigidity.  In some instances an uncommon LRRK2 gene mutation confers a high risk of Parkinson's disease.  In rare cases Italian and Greek families are impacted in their early forties and fifties resulting from a single letter mutation in alpha-synuclein which alters the alpha-synuclein protein causing degeneration in the substantia nigra, after a build up of Lewy bodies in the neurons.  But poisoning from MPTP has also been shown to destroy dopamine system neurons.  DeLong showed that MPTP poisoning results in overactivity in the subthalamic nucleus.  People who have an appendectomy in their 20s are at lower risk of developing Parkinson's disease.  The Alpha-synuclein protein is known to build up in the appendix in association with changes in the gut microbiome.  This buildup may support the 'flow' of alpha-synuclein from the gut along neurons that route to the brain.  Paraquat has also been linked to Parkinson's disease.  Parkinson's disease does not directly kill many sufferers.  But it impacts swallowing which encourages development of pneumonia through inhaling or aspirating food.  And it undermines balance which can increase the possibility of falls.  Dememtia can also develop.  Treatment with deep-brain stimulation, after surgical implantation of electrodes in the subthalamic nucleus removes the symptoms of Parkinson's disease in some patients. 
  , CHF is congestive heart failure which occurs when the heart is unable to generate enough blood flow to meet the body's demands.  There are two main types: failure due to left ventricular dysfunction and abnormal diastolic function increasing the stiffness of the left ventricle and decreasing its relaxation.  Heart expansion in CHF distorts the mitral valve which exacerbates the problems.  MitraClip surgery trials found effective in correcting the mitral valve damage (Sep 2018).  Treatments include: digoxin; , rheumatoid Arthritis is an autoimmune disorder where the immune system attacks the joints and can generate inflammation around the lungs and heart.  It can be treated with: Enbrel, Humira, Ilaris, Xeljanz;
  , and some cancers is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016). 
  .  Combinations of social and medical services are funded.  The act will encourage high tech remote capabilities to be deployed (Jun 2018)
• Web search is showing early promise of detecting diseases (Pancreatic cancer is most often an exocrine tumor.  Islet cell tumors are less common.  These are rare cancers: less than 200,000 US cases per year, but the five year survival rates are extremely low 3%.  They all have KRAS mutations.  They are associated with obesity.  Diagnostics are starting to leverage genomics and big databases (23 and me).  Treatments include:
  • Avastin
    
  • Tarceva 
  Jun 2016). 
  
• Watson supported genomics combines recombinant DNA editing with tools: CRISPR; DNA next generation sequencing and bioinformatics  to sequence, assemble and analyse genomes.   for oncologists with: Quest (Oct 2016), MS-KCC, Broad Institute;
• MIT is Massachusetts Institute of Technology.   Whitehead Institute for biomedical ethics: risk of bias with Big Data encompasses the IT systems and processes necessary to do population based data collection, management and analysis.  The very low cost, robust, data storage organized by infrastructure: HADOOP; allows digital data to be stored en mass.  Data scientists then apply assumptions about the world to the data, analogous to evolved mechanisms in vision, in the form of algorithms: Precision medicine, Protein folding modeling (Feb 2019) assumes coevolutionary methods can be applied to identify contact points in a protein's tertiary structure.  Rather than depending on averages, analysis at Verisk drills down to specifics and then highlights modeling problems by identifying the underlying CAS.  For the analysis to be useful it requires a hierarchy of supporting BI infrastructure:
  • Analytics utilization and integration delivered via SaaS and the Cloud to cope with the silos and data intensive nature. 
    
  • Analytics tools (BI) for PHM will be hard to develop.  
  • Complex data models must include clinical aspects of the patient specific data, including disease state population wide.  
  • A key aspect is providing clear signals about the nature of the data using data visualization. 
    
  • Data communication with the ability to exchange and transact.  HIEs and EMPI alliance approaches are all struggling to provide effective exchange. 
    
  • Data labeling and secure access and retreival.  While HIPAA was initially drafted as a secure MPI the index was removed from the legislation leaving the US without such a tool.  Silos imply that the security architecture will need to be robust. 
    
  • Raw data scrubbing, restructuring and standardization.  Even financial data is having to be restandarized shifting from ICD-9 to -10.  The intent is to transform the unstructured data via OCR and NLP to structured records to support the analytics process. 
    
  • Raw data warehousing is distributed across silos including PCP, Hospital system and network, cloud and SaaS for process, clinical and financial data. 
    
  • Data collection from the patient's proximate environment as well as provider CPOE, EHRs, workflow and process infrastructure.  The integration of the EHR into a big data collection tool is key. 
    
  . 
• CHIP is:
  
  • The Children's Health Insurance Program started in 1997 as part of the BBA as SCHIP.  It provides health insurance coverage for children in families with income below 200 percent of the poverty line.  The coverage is focused on care specialized for children including: developmental delays, chronic conditions including asthma and obesity.  CHIP's funding must be iteratively re-authorized by Congress.  CHIP is financed federally, but states must enroll eligible children.  In many states one agency administers CHIP and Medicaid.  CHIP is leveraged by families that have employer based insurance with costly premiums, so the families only cover the adults.  
  • Clonal Hematopoiesis of Indeterminate Potential, where stem cells develop a somatic mutation cluster pair often found in leukemia, which is expressed in white blood cells they produce.  The mutation clusters give these stem cells a competitive advantage and they accumulate over time.  The white blood cells form inflammatory plaques.  CHIP increases with age, increasing the risk of dying, of clot fragment induced heart attacks and stroke, over the subsequent 10 years by 54%
  mechanism identified: somatic, Schematic structures which are used to support the operation of the agent.  They are modified as the agent's state changes unlike the germ-line schemata.   mutated stem cells is a biological cell which is partly or wholly undifferentiated.  A totipotent cell can generate a complete embryo and placenta.  Embryos include pluripotent cells which can generate any tissue in the body.  Adult humans' cells have turned off this ability but still include multipotent stem cells that differentiate into multiple cell types.   Typically a cell's local environment will have the signals required for it to obtain context and differentiate appropriately.  This will include both the external environment and the internal state of the cell which has replicated from a parent and obtained its epi-genetic state.   So introduction of undifferentiated stem cells into an injured area is not likely to have either aspect of the environment suitable.  Consequently development is aiming to encourage differentiation to progenitor cells for the damaged region.  This requires delivering the cells to the appropriate part of the body.  To avoid rejection by the immune system techniques aim to use cell lines developed from the patient's cells.  The techniques to generate these cell lines include: SCNT, iPS.  Possible mechanisms of stem cell therapy are: Generation of new differentiated cells, Stimulation of growth of new blood vessels to repopulate damaged regions, Secretion of growth factors, Treatment of diabetes (1 and 2) with addition of pancreatic cells, Assistance of other mechanisms;, with certain leukemia is a group of cancers of blood forming tissues: bone marrow, lymphatic network; where abnormal white blood cells are generated.  One type of leukemia is induced when TAD boundaries near the TAL1 gene fail allowing promotors from across the TAD border to distort the operation of the TAL transcription factor.  Mutation clusters common in leukemia have been identified in CHIP. 
  mutations, accumulate in bone marrow and generate white blood cells that are highly inflammatory; encouraging: arthritis, clot formation or coagulation is formation of a clot:
  • Platlets become activated, adhere and aggregate supported by
  • Fibrin polymerization, deposition and maturation.  
  and collapse resulting in high incidence of heart attack is an AMI. It can induce cardiac arrest.  Blocking the formation of clots with platelet aggregation inhibitors, can help with treating and avoiding AMI.  Risk factors include: taking NSAID pain killers (May 2017).  There is uncertainty about why AMI occur.  Alternative hypotheses include:
  
  • Plaques started to gather in the coronary arteries and grew until no blood flow was possible.  If this is true it makes sense to preventatively treat the buildup with angioplasty. 
    
  • Plaques form anywhere in the body due to atherosclerosis and then break up and get lodged in the coronary artery and start to clot.  If this is true it makes sense to preventatively limit the buildup of plaques with drugs like statins or PCSK9 inhibitors. 
    
  and stroke is when brain cells are deprived of oxygen and begin to die.  750,000 patients a year suffer strokes in the US.  85% of those strokes are caused by clots.  There are two structural types: Ischemic and hemorrhagic.  Thrombectomy has been found to be a highly effective treatment for some stroke situations (Jan 2018). 
  ; Dana-Farber's Ebert, Broad Institute/Massachusetts General's Kathiresan conclude from Big Data encompasses the IT systems and processes necessary to do population based data collection, management and analysis.  The very low cost, robust, data storage organized by infrastructure: HADOOP; allows digital data to be stored en mass.  Data scientists then apply assumptions about the world to the data, analogous to evolved mechanisms in vision, in the form of algorithms: Precision medicine, Protein folding modeling (Feb 2019) assumes coevolutionary methods can be applied to identify contact points in a protein's tertiary structure.  Rather than depending on averages, analysis at Verisk drills down to specifics and then highlights modeling problems by identifying the underlying CAS.  For the analysis to be useful it requires a hierarchy of supporting BI infrastructure:
  • Analytics utilization and integration delivered via SaaS and the Cloud to cope with the silos and data intensive nature. 
    
  • Analytics tools (BI) for PHM will be hard to develop.  
  • Complex data models must include clinical aspects of the patient specific data, including disease state population wide.  
  • A key aspect is providing clear signals about the nature of the data using data visualization. 
    
  • Data communication with the ability to exchange and transact.  HIEs and EMPI alliance approaches are all struggling to provide effective exchange. 
    
  • Data labeling and secure access and retreival.  While HIPAA was initially drafted as a secure MPI the index was removed from the legislation leaving the US without such a tool.  Silos imply that the security architecture will need to be robust. 
    
  • Raw data scrubbing, restructuring and standardization.  Even financial data is having to be restandarized shifting from ICD-9 to -10.  The intent is to transform the unstructured data via OCR and NLP to structured records to support the analytics process. 
    
  • Raw data warehousing is distributed across silos including PCP, Hospital system and network, cloud and SaaS for process, clinical and financial data. 
    
  • Data collection from the patient's proximate environment as well as provider CPOE, EHRs, workflow and process infrastructure.  The integration of the EHR into a big data collection tool is key. 
    
  genomics combines recombinant DNA editing with tools: CRISPR; DNA next generation sequencing and bioinformatics  to sequence, assemble and analyse genomes.   (Jan 2018) 
• Mount Sinai Icahn SOM's Dr. Joel Dudley's precision medicine is the integration of molecular research: genomics, proteomics, transcriptomics, metabolomics, cell signalling; and clinical data through a taxonomy based on CAS modeling overlaid on an information commons.  It aims to support treatment of disease and remove the organ and symptom based methodological flaws in the ICD.  Supporters of the D.S.M. note the aggressive shift to precision medicine at the NIMH under Dr. Insel, constrained useful clinical research (Nov 2015). 
  (Big Data encompasses the IT systems and processes necessary to do population based data collection, management and analysis.  The very low cost, robust, data storage organized by infrastructure: HADOOP; allows digital data to be stored en mass.  Data scientists then apply assumptions about the world to the data, analogous to evolved mechanisms in vision, in the form of algorithms: Precision medicine, Protein folding modeling (Feb 2019) assumes coevolutionary methods can be applied to identify contact points in a protein's tertiary structure.  Rather than depending on averages, analysis at Verisk drills down to specifics and then highlights modeling problems by identifying the underlying CAS.  For the analysis to be useful it requires a hierarchy of supporting BI infrastructure:
  • Analytics utilization and integration delivered via SaaS and the Cloud to cope with the silos and data intensive nature. 
    
  • Analytics tools (BI) for PHM will be hard to develop.  
  • Complex data models must include clinical aspects of the patient specific data, including disease state population wide.  
  • A key aspect is providing clear signals about the nature of the data using data visualization. 
    
  • Data communication with the ability to exchange and transact.  HIEs and EMPI alliance approaches are all struggling to provide effective exchange. 
    
  • Data labeling and secure access and retreival.  While HIPAA was initially drafted as a secure MPI the index was removed from the legislation leaving the US without such a tool.  Silos imply that the security architecture will need to be robust. 
    
  • Raw data scrubbing, restructuring and standardization.  Even financial data is having to be restandarized shifting from ICD-9 to -10.  The intent is to transform the unstructured data via OCR and NLP to structured records to support the analytics process. 
    
  • Raw data warehousing is distributed across silos including PCP, Hospital system and network, cloud and SaaS for process, clinical and financial data. 
    
  • Data collection from the patient's proximate environment as well as provider CPOE, EHRs, workflow and process infrastructure.  The integration of the EHR into a big data collection tool is key. 
    
  ) study associates Roseoloviruses is a subset: HHV6 (HHV-6A, HHV-6B), HHV7; of Herpes viruses.  HHV6 typically infects human infants before age two, with symptoms of fever, diarrhea, and a rash known as roseola. 
  : HHV-6A is a double stranded DNA Roseolovirus.  It infects all tested humans and is neuroinflammatory, being seen in diseases such as MS. 
  , HHV7 is a double stranded DNA Roseolovirus. 
  ; with Alzheimer's disease is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and declarative memory and thinking problems (MCI).  Specific cells within the hippocampal circuitry and its gateway, the entorhinal cortex, are damaged.  The amygdala, cerebelum and other areas supporting implicit memory are not impacted during the early stages of the disease.  Grid cell destruction results in a sense of being lost.  The default mode network is disrupted.  Variants include: late-onset sporadic; with risk factors - ApoE4 for late onset Alzheimer's, presenilin, androgen deprivation therapy (Dec 2015), type 2 diabetes.  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation, Neurons of sporadic Alzheimer's sufferers show greater APP gene diversity due to somatic recombination; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form.  These are seen in fMRIs 10 to 15 years prior to detecting memory and thinking changes.  APP deployed in the cell membrane is cut into three parts.  The external part becomes amyloid-beta peptide which aggregates into Amyloid plaques, external to the neurons, if too much is generated or it is not removed fast enough. 
    
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016). 
    
  • Encouraging the garbage collection of amyloid and tau with gamma rhythms stimulation retards Alzheimer's in mice studies (Mar 2019)
    
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • Mutation driven misfolded Tau proteins can form tangles within the cytoplasm of neurons.  The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    
  • The brain becomes inflamed resulting in the killing of many more nerve cells.  The hippocampus disintegrates and the brain loses critical functions and memory loss becomes noticeable. 
    
  , judged by changes in the entorinal cortex is a main limbic association area between the hippocampus and the neocortex, in the medial temporal lobe.  It is a hub for memory and navigation: location awareness is supported by grid cells.  It is the first brain area impacted in Alzheimer's disease. 
  , hippocampus is a part of the medial temporal lobe of the brain involved in the temporary storage or coding of long-term episodic memory.  It includes the dentate gyrus.  Memory formation in the cells of the hippocampus uses the MAP kinase signalling network which is impacted by sleep deprivation.  The hippocampus dependent memory system is directly affected by cholinergic changes throughout the wake-sleep cycle.  Increased acetylcholine during REM sleep promotes information attained during wakefulness to be stored in the hippocampus by suppressing previous excitatory connections while facilitating encoding without interference from previously stored information.  During slow-wave sleep low levels of acetylcholine cause the release of the suppression and allow for spontaneous recovery of hippocampal neurons resulting in memory consolidation.  It was initially associated with memory formation by McGill University's Dr. Brenda Milner, via studies of 'HM' Henry Molaison, whose medial temporal lobes had been surgically destroyed leaving him unable to create new explicit memories.  The size of neurons' dendritic trees expands and contracts over a female rat's ovulatory cycle, with the peak in size and cognitive skills at the estrogen high point.  Adult neurogenesis occurs in the hippocampus (3% of neurons are replaced each month) where the new neurons integrate into preexisting circuits.  It is enhanced by learning, exercise, estrogen, antidepressants, environmental enrichment, and brain injury and inhibited by various stressors explains Sapolsky.  Prolonged stress makes the hippocampus atrophy.  He notes the new neurons are essential for integrating new information into preexisting schemas -- learning that two things you thought were the same are actually different.  Specific cells within the hippocampus and its gateway, the entorhinal cortex, are compromised by Alzheimer's disease.  It directly signals area 25. 
  , promoter enrichments for C2H2 zink finger is a large set of finger like binding domains in mammalian transcription factors with a Cys2-His2 (C2H2) fold group, which can bind in the major groove of DNA. 
  transcription factor are enzymes which associate with a transcription complex to bind to the DNA and control its transcription and hence translation into proteins.  The regulation of DNA transcription and protein synthesis are reviewed by Tsonis.  Transcription factors allow environmental state to become reflected in the control of DNA transcription.  Transcription factors can regulate multiple genes, allowing network effects & multiple transcription factors can regulate a gene allowing sophisticated control processes.  In AWF the transcription, translation and deployment infrastructure of the eukaryotic cell has been abstracted in a codelet based implementation. 
  binding motifs and signalling, is an emergent capability which is used by cooperating agents to support coordination & rival agents to support control and dominance.  In eukaryotic cells signalling is used extensively.  A signal interacts with the exposed region of a receptor molecule inducing it to change shape to an activated form.  Chains of enzymes interact with the activated receptor relaying, amplifying and responding to the signal to change the state of the cell.  Many of the signalling pathways pass through the nuclear membrane and interact with the DNA to change its state.  Enzymes sensitive to the changes induced in the DNA then start to operate generating actions including sending further signals.  Cell signalling is reviewed by Helmreich.  Signalling is a fundamental aspect of CAS theory and is discussed from the abstract CAS perspective in signals and sensors.  In AWF the eukaryotic signalling architecture has been abstracted in a codelet based implementation.  To be credible signals must be hard to fake.  To be effective they must be easily detected by the target recipient.  To be efficient they are low cost to produce and destroy. 
  links with ApoE4 is a gene variant which produces the E4 variant of APOE.  It is a risk-factor for late-onset sporadic Alzheimer's disease.  Being homozygote for E4 does not imply getting Alzheimer's but does increase the risk 20 fold.  ApoE2 may reduce the risk of Alzheimer's.  It appears that ApoE4 differentially affects women.  Apoe4 is known to be broken down into fragments which impare mitochondrial operation.  It also promotes amyloid plaque buildup.  Therapies are being developed based on small molecules which reshape ApoE4 to be more like ApoE3 reducing the breakdown.   
  . It seems likely that after remaining dormant for years the virus is a relatively small capsule containing genetic material which utilizes the cellular infrastructure of its target host to replicate its genetic material and operational proteins.  The relationship with the host is short term, relative to parasites, with the virus entering the host cell, leveraging the host infrastructure to replicate its self massively and then exiting the host cell by rupturing it. 
  activates (stressor is a multi-faceted condition reflecting high cortisol levels.  Dr. Robert Sapolsky's studies of baboons indicate that stress helps build readiness for fight or flight.  As these actions occur the levels of cortisol return to the baseline rate.  A stressor is anything that disrupts the regular homeostatic balance.  The stress response is the array of neural and endocrine changes that occur to respond effectively to the crisis and reestablish homeostasis. 
  
  • The short term response to the stressor
    
  • activates the amygdala which: Stimulates the brain stem resulting in inhibition of the parasympathetic nervous system and activation of the sympathetic nervous system with the hormones epinephrine and norepinephrine deployed around the body, Activates the PVN which generates a cascade resulting in glucocorticoid secretion to: get energy to the muscles with increased blood pressure for a powerful response.  The brain's acuity and cognition are stimulated.  The immune system is stimulated with beta-endorphin and repair activities curtail.  In order for the body to destroy bacteria in wounds, pro-inflammatory cytokines increase blood flow to the area.  The induced inflammation signals the brain to activate the insula and through it the ACC.  But when the stressor is
    
  • long term: loneliness, debt; and no action is necessary, or possible, long term damage ensues.  Damage from such stress may only occur in specific situations: Nuclear families coping with parents moving in.  Sustained stress provides an evolved amplifier of a position of dominance and status.  It is a strategy in female aggression used to limit reproductive competition.  Sustained stress:
    
  • Stops the frontal cortex from ensuring we do the harder thing, instead substituting amplification of the individual's propensity for risk-taking and impairing risk assessment! 
    
  • Activates the integration between the thalamus and amygdala. 
    
  • Acts differently on the amygdala in comparison to the frontal cortex and hippocampus: Stress strengthens the integration between the Amygdala and the hippocampus, making the hippocampus fearful. 
    
  • BLA & BNST respond with increased BDNF levels and expanded dendrites persistently increasing anxiety and fear conditioning. 
    
  • Makes it easier to learn a fear association and to consolidate it into long-term memory.  Sustained stress makes it harder to unlearn fear by making the prefrontal cortex inhibit the BLA from learning to break the fear association and weakening the prefrontal cortex's hold over the amygdala.  And glucocorticoids decrease activation of the medial prefrontal cortex during processing of emotional faces.  Accuracy of assessing emotions from faces suffers.  A terrified rat generating lots of glucocorticoids will cause dendrites in the hippocampus to atrophy but when it generates the same amount from excitement of running on a wheel the dendrites expand.  The activation of the amygdala seems to determine how the hippocampus responds. 
    
  • Depletes the nucleus accumbens of dopamine biasing rats toward social subordination and biasing humans toward depression. 
    
  • Disrupts working memory by amplifying norepinephrine signalling in the prefrontal cortex and amygdala to prefrontal cortex signalling until they become destructive.  It also desynchronizes activation in different frontal lobe regions impacting shifting of attention.  
  • Increases the risk of autoimmune disease (Jan 2017) 
  • During depression, stress inhibits dopamine signalling.  
  • Strategies for stress reduction include: Mindfulness. 
    
  ) & generates an immune has to support and protect an inventory of host cell types, detect and respond to invaders and maintain the symbiont equilibrium within the microbiome.  It detects microbes which have breached the secreted mucus barrier, driving them back and fortifying the barrier.  It culls species within the microbiome that are expanding beyond requirements.  It destroys invaders who make it into the internal transport networks.  As part of its initialization it has immune cells which suppress the main system to allow the microbiome to bootstrap.  The initial microbiome is tailored by the antibodies supplied from the mother's milk while breastfeeding.  The immune system consists of two main parts the older non-adaptive part and the newer adaptive part.  The adaptive part achieves this property by being schematically specified by DNA which is highly variable.  By rapid reproduction the system recombines the DNA variable regions in vast numbers of offspring cells which once they have been shown not to attack the host cell lines are used as templates for interacting with any foreign body (antigen).  When the immune cell's DNA hyper-variable regions are expressed as y-shaped antibody proteins they typically include some receptor like structures which match the surfaces of the typical antigen.  Once the antibody becomes bound to the antigen the immune system cells can destroy the invader. 
  response that stimulates plaques which kill neurons, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
  • Receptive element - dendrites
    
  • Transmitting element - axon and synaptic terminals.  The axon may be myelinated, focusing the signals through synaptic transmission, or unmyelinated - where crosstalk is leveraged. 
  • Highly variable DNA schema using transposons. 
    
  (Jun 2018)
• Bolt on Analytics - will put pressure on installed transactional accounting systems.  Value based care will require broad analysis of the data collected by the accounting systems. 
  
• Proposed statistical aggregation of diverse complex adaptive system (CAS) network operations to develop bundled payment is where the purchaser disburses a single predefined payment to cover certain combinations of hospital, physician, post-acute, or other services performed during an episode of care relating to a particular condition (unlike capitation).  This bundling is assumed (Sep 2018) to allow the value delivery system to optimize around low cost high quality long term health care.  With one bundled payment physicians & hospitals must coordinate care and reduce the unit costs to remain profitable.  And to avoid taking on risk of expensive complications physicians & hospitals are incented to standardize and focus on quality.  This optimization is dependent on quantifying the value of the outcome of the episode of care.  Previously FFS payments induced excessive treatment activity.  Bundled payment is included in CMS ACE demonstrations and BPCI initiatives.  There are significant impacts on IT. 
  
  1. It is argued that effective pricing of the bundle requires marketing data which must be extracted from the historic transaction base.  
  2. Billing and payment systems must be updated to handle the receipt and distribution of the bundled payments. 
     
  3. Care delivery must be re-architected to reduce costs and improve quality. 
     
  4. Monitoring sensors can be used to feed reports to ensure re-architected operations conform.  
  benchmarks (Developing episode pricing successfully demonstrated in Geisinger's "ProvenCare" program with a focus on reengineering the business and VDS is value delivery system.  ) obscures (2) the need to define and reduce the upper and lower limits of key process variables of the network flows.  
• Is there a conflict between Christensen's disruption of CABG by Angioplasty and ProvenCare's bundled pricing for CABG refers to Coronary artery bypass grafting, a treatment provided by cardiac surgeons.  Lower cost angioplasty has disrupted this business but both have been provided by general hospitals.  Christensen argues angioplasty should be part of a radically lower cost business which should disrupt the solution business of the general hospital.  .  
• Can historic data describing pre-disruption processes and associated VDS analyzed with additional IT infrastructure help effectively model the future price of bundled offers?  It didn't help much in high tech.  So these arguments are assuming no disruption.  
• Payers include four types:
  • From the 1930s the insurers Blue Cross and Blue Shield catalyzed health care activity by paying a daily per diem to hospitals for the diagnoses and treatments the hospital's dispensed.  At their inception in 1966 Medicare and Medicaid followed this reimbursement model. 
  • From 1983 Medicare and Medicaid switched to the PPS reimbursement mechanism.  This forced alignment of the supplier, diagnosis, treatment, billing and reimbursement processes.  The health care network is still structurally aligned around PPS.  Under scrutiny of ProPAC and its successor MedPAC,  as well as pressure of the BBA after 1997, the payments per DRG have been steadily reduced until it was below the cost of care, forcing hospitals to seek margin from their other payers.  Medicare outlier payments benefited hospitals that inflated charges and thus became eligible. 
    
  • Employers as they experienced cost shifting from the hospital's increased product charges moved their employees over to managed care based payment. 
  • Private payers pay hospitals directly for their diagnosis and treatment.  Typically this group has little power.  There are default rates for private payers - typically 40% of billed charges that are not covered by a fixed payment or a fee schedule.  For the uninsured poor until 2004 they obtained little discount on the hospital's chargemaster list price, because insurers and CMS required to be charged the lowest value offered to any patients.  Medicare has now relaxed this constraint. 
  are buying up bundled payment analytics companies.  They need to look across their environment to understand trends.  This could leave health systems (providers) dependent on payers for developing effective marketing and bundling strategies!
  
• Algorithms
• Helping sustain Moore's exponential growth (Oct 2016)
  
• Email
  
• Failing but ubiquitous (Oct 2016)
• Security
  
• Internet increasingly impacted (Oct 2016)
• Prosecutor Haun and TSRI's Topol review the problem and a blockchain is a bitcoin distributed database technology that allows several bitcoin operators to keep a shared, cryptographically verified, ledger and consensus mechanism to allow agreement on what transactions have happened and in what order.  It implements a Merkle tree.  Six times an hour on average, a new group of validated transactions, a block, is created, added to the local block chain and published to all nodes.  Paraphrasing breadwallet's Aaron Voisine, publishing is robust because: Each operator has connected via references from its initial peers to a random subset of all the other operators; and the new block is offered to the connected peers who can both ask for it if they have not seen it previously from some other source and pass it on to their other peers in a cascade (a gossip network).  To build new blocks an operator must have all the prior blocks in the chain.  All unspent bitcoins are represented [only] in the blockchain.  Miners keep the blockchain consistent by verifying that a new block has a proof-of-work.  This requires that miners find a nonce that multiplied by the block hash is smaller than the network's difficulty target.   solution for Health Data breaches (Jan 2017)
• Congress concludes Chinese distributors ship fentanyl is a synthetic opioid pain medication that acts on micro-opioid receptors in the brain.  It is 50 times more potent than morphine.  It was originally manufactured by Janssen Pharmaceutica in 1959 which was acquired by Johnson & Johnson.  It is branded as: Sublimaze, Actiq, Durogesic, Duragesic, Fentora, Matrifen, Subsys, Instanyl, Abstral, Lazanda; with a variety of deployment formulations.  It is often used, in a transdermal patch such as durogesic, to treat severe ongoing pain which can be induced by cancer.  It has followed heroin into the back-street opioid epidemic (Jun 2017). 
  via e-commerce: UPS, FEDEX, USPS; via third countries, to buyers in US is the United States of America.  : Ohio, Pennsylvania, Florida; who pay with Bitcoins is a set of open-source software, used to provide infrastructure that supports a distributed cryptocurrency and payment system, based on the blockchain.   All transaction inputs are unspent outputs from previous transactions.  All transaction inputs are signed.  Change is provided in an additional output to the transaction. 
  (Jan 2018)
• Bundled payments is where the purchaser disburses a single predefined payment to cover certain combinations of hospital, physician, post-acute, or other services performed during an episode of care relating to a particular condition (unlike capitation).  This bundling is assumed (Sep 2018) to allow the value delivery system to optimize around low cost high quality long term health care.  With one bundled payment physicians & hospitals must coordinate care and reduce the unit costs to remain profitable.  And to avoid taking on risk of expensive complications physicians & hospitals are incented to standardize and focus on quality.  This optimization is dependent on quantifying the value of the outcome of the episode of care.  Previously FFS payments induced excessive treatment activity.  Bundled payment is included in CMS ACE demonstrations and BPCI initiatives.  There are significant impacts on IT. 
  
  1. It is argued that effective pricing of the bundle requires marketing data which must be extracted from the historic transaction base.  
  2. Billing and payment systems must be updated to handle the receipt and distribution of the bundled payments. 
     
  3. Care delivery must be re-architected to reduce costs and improve quality. 
     
  4. Monitoring sensors can be used to feed reports to ensure re-architected operations conform.  
  enhanced IT requirements will drive new technology deployments but uses a ONC planning and advocacy mechanism is the Office of the National Coordinator for Health Information Technology of the US Department of Health and Human Services.  It was required to support the President's 10 year goal of interoperable EHR, and lead the nation in the strategic planning for nationwide interoperable HIT.  It develops the US HIT strategic plan.  It specifies the standards, implementation specifications and certification criteria used to certify meaningful use.  It develops key programs: RECs, HITRC, State HIE Cooperative Agreements, Beacon Communities, Health IT Workforce Development, SHARP, National Health Information Network, FHA, CONNECT.  It must encourage the development of RHIOs to facilitate community and regional clinical data exchange.   reminiscent of early Telecoms standardization under CCITT and OSI supporting AT&T and the telecom equipment provider oligopoly rather than the subsequent IETF style emergent and disruptive process.  
• Proposed Flags of success of the strategy will include: 2011 The presence of formal process reengineering strategies with leadership aims to develop plans and strategies which ensure effective coordination to improve the common good of the in-group.  John Adair developed a leadership methodology based on the three-circles model. 
  sponsors. 
  
• Pricing startups are increasing visibility of generic drug prices (Feb 2016). 
  
• Cloud computing
  
• Central banks look at bitcoin is a set of open-source software, used to provide infrastructure that supports a distributed cryptocurrency and payment system, based on the blockchain.   All transaction inputs are unspent outputs from previous transactions.  All transaction inputs are signed.  Change is provided in an additional output to the transaction. 
  's blockchain is a bitcoin distributed database technology that allows several bitcoin operators to keep a shared, cryptographically verified, ledger and consensus mechanism to allow agreement on what transactions have happened and in what order.  It implements a Merkle tree.  Six times an hour on average, a new group of validated transactions, a block, is created, added to the local block chain and published to all nodes.  Paraphrasing breadwallet's Aaron Voisine, publishing is robust because: Each operator has connected via references from its initial peers to a random subset of all the other operators; and the new block is offered to the connected peers who can both ask for it if they have not seen it previously from some other source and pass it on to their other peers in a cascade (a gossip network).  To build new blocks an operator must have all the prior blocks in the chain.  All unspent bitcoins are represented [only] in the blockchain.  Miners keep the blockchain consistent by verifying that a new block has a proof-of-work.  This requires that miners find a nonce that multiplied by the block hash is smaller than the network's difficulty target.   to develop a distributed ledger (Oct 2016)
• Proliferation of device types (iPad, Android * n, Microsoft, smart phones). 
• Internet of things is encouraging the development of smart fabrics (Mar 2016). 
  
• Electronic medical records (EMR refers to electronic medical records which are a synonym of EHR.  EMRs have strengths and weaknesses:
  • The EHR provides an integrated record of the health systems notes on a patient including: Diagnosis and Treatment plans and protocols followed, Prescribed drugs with doses, Adverse drug reactions;
  • The EHR does not necessarily reflect the patient's situation accurately. 
    
  • The EHR often acts as a catch-all.  There is often little time for a doctor, newly attending the patient, to review and validate the historic details. 
    
  • The meaningful use requirements of HITECH and Medicare/Medicaid specify compliance of an EHR system or EHR module for specific environments such as an ambulatory or hospital in-patient setting. 
    
  • As of 2016 interfacing with the EHR is cumbersome and undermines face-to-face time between doctor and patient.  Doctors are allocated 12 minutes to interact with a patient of which less than five minutes was used for recording hand written notes.  With the EHR 12 minutes may be required to update the record!
    
  ) are being adopted by:
  
• National government health ministries:
• US VA - Department of Veterans Affairs.  Includes the Veterans Health Administration. 
  has deployed the largest enterprise-wide HIS Health care information systems.  There were traditionally four backbone services:
  • ADT,
  • Financial,
    
  • Scheduling,
  • Acuity (EDIS);
    
  that includes an EMR, called VistA is the veterans' health information systems and technology architecture.  It includes: VistA imaging system; and a GUI CPRS.  It is composed of over 150 applications built using a MUMPS accessed data store.  It was originally called decentralized hospital computer program (DHCP).  It had three core aspects:
  1. System/database management
  2. Administrative management - supporting normal hospital admin (scheduling, etc)
     
  3. Clinical management - information provision in the lab, pharmacy etc.  The EHR facilities were built via the clinical records project with support for order entry/results reporting, health summary, problem index, allergies/adverse reactions, progress notes, crisis warnings, consults, clinical observations and clinical measurements. 
     
  .  
• US VA - Department of Veterans Affairs.  Includes the Veterans Health Administration. 
  and Kaiser Permanente have connected VistA is the veterans' health information systems and technology architecture.  It includes: VistA imaging system; and a GUI CPRS.  It is composed of over 150 applications built using a MUMPS accessed data store.  It was originally called decentralized hospital computer program (DHCP).  It had three core aspects:
  1. System/database management
  2. Administrative management - supporting normal hospital admin (scheduling, etc)
     
  3. Clinical management - information provision in the lab, pharmacy etc.  The EHR facilities were built via the clinical records project with support for order entry/results reporting, health summary, problem index, allergies/adverse reactions, progress notes, crisis warnings, consults, clinical observations and clinical measurements. 
     
  and HealthConnect using the connect project uses open source Java to implement the architectures of eHealth Exchange.  It was sponsored by a variety of federal agencies which wanted one implementation of eHealth Exchange to operate across.  The agencies now use the connect gateway for at least demonstrations.  The architecture includes a gateway and adapter.  These use lower level core components to perform operations:
  • Gateway - Network orchestration components, gateway processes responsible for accepting messages from the NHIN and processing them or passing them through to the adapter. 
    
  • Adapter - uses entity orchestration components which orchestrate the request and send the message and SAML assertion through the message proxy component. 
    
  • Message proxy components must properly handle the SAML security layer.  Once it has constructed a valid SAML message it submits it to the NHIN and waits for the SAML response.  
  • Adapter services: adapter, adapter document query, adapter document retrieve, adapter document submission, Adapter master patient index, Adapter notification processing, Adapter policy, Adapter re-identification, Adapter subscription management
    
  • NHIN orchestration, Entity orchestration, Message Proxy all contain,
    
  • Audit reporting component
  • Document query component
  • Document retrieve component
  • Document submission component
  • Notification processing component
  • Patient discovery component
  • Core components:
  • Aggregator
  • Audit
  • Audit log data transfer engine
  • Audit recorder facade
  • Audit repository
  • Connection manager
  • Patient correlation
  • Patient correlation facade
  • Property accessor
  • Subscription repository
  .  
• Jordan has deployed VistA is the veterans' health information systems and technology architecture.  It includes: VistA imaging system; and a GUI CPRS.  It is composed of over 150 applications built using a MUMPS accessed data store.  It was originally called decentralized hospital computer program (DHCP).  It had three core aspects:
  1. System/database management
  2. Administrative management - supporting normal hospital admin (scheduling, etc)
     
  3. Clinical management - information provision in the lab, pharmacy etc.  The EHR facilities were built via the clinical records project with support for order entry/results reporting, health summary, problem index, allergies/adverse reactions, progress notes, crisis warnings, consults, clinical observations and clinical measurements. 
     
  .  The UK National Health Service having written off a $24 billion centralized EHR project is looking to follow Jordan with open source VistA EHR infrastructure. 
  
• Accountable Care Organizations (ACO is an Accountable Care Organization. These are accredited bundles of companies which together try to offer Dartmouth-Hitchcock like business models (Dec 2015, Sep 2016) focused on wellness, improving the provision of primary care to a large group of Medicare patients, and rewarding doctors for preventing problems.  Advocate health illustrates the idea.  Robert Pearl notes that the transition is difficult: hospitals that find their efficiency improving should reduce the number of doctors they utilize.  But any doctors that are pushed out of the ACO will likely take their patients with them, undermining the revenues that support the FFV business.  The ACA regulates qualification to be a Medicare ACO.  Individual organizations within a Medicare shared savings ACO continue to submit their own claims and are paid by Medicare for FFS.  But the ACO is eligible for shared savings.  Within the shared savings program the CMS innovation center has setup advanced payment ACOs.  As an alternative to shared savings, in a Pioneer ACO, over time 50% of the FFS payments flow directly to the ACO as a bundled payment.  CMS has established quality measures for ACOs for Medicare.  The CMS program's purpose is to reward providers for reducing total cost of care for patients through prevention, disease management, and coordination. 
  
  • CMS initiated its Physician Group Practice Demonstration in 2005.  By 2008 the congressional budget office reported on Bonus-eligible organizations. 
    
  • CMS defines ACOs as organizations that "create incentives for health care providers to work together to treat an individual patient across care settings - including doctors' offices, hospitals and long-term care facilities."
  • CMS has developed APMs which include ACOs, and advanced APMs where the ACOs must be risk bearing. 
    
  • CMMI accepts providers' proposals to test various payment systems including shared savings and partial capitation.  
  • Private market ACOs have formed including: Providence Health & Services, Blue Shield California, Anthem Blue Cross, United Health Care, BCBS Minnesota, BCBS Illinois, Humana, CIGNA, Main Health Management Coalition, BCBS Massachusetts, Aetna.  
  ) need to be integrated.  In 2013 they are requiring interoperation of vendors of medical and radiation oncology with other technologies.  
• Premier suggests that ACOs can be constructed contractually without expanding transaction costs and undermining strategic coherence which would make them become uncompetitive - but this claim seems unlikely to be legitimate.  The transaction costs are likely to be higher and the independent businesses must either become phenotypically aligned, or remain strategically in conflict. 
  
• Startup Aledade demonstrates a way to integrate the PCP is a Primary Care Physician.  PCPs are viewed by legislators and regulators as central to the effective management of care.  When coordinated care had worked the PCP is a key participant.  In most successful cases they are central.  In certain Medicare ACO models (Pioneer) PCPs are committed to achieve meaningful use requirements.  Working against this is the: replacement of diagnostic skills by technological solutions, low FFS leverage of the PCP compared to specialists, demotivation of battling prior authorization for expensive treatments. 
  with the health care network and lower costs (Aug 2017)
  
• Role based security infrastructure is seen as a key enabler of ACOs.  Also seen as key are clinical data warehouses, corporate wide reporting and peer group benchmarking. 
  
• Public Health Information Exchanges (HIE a Health Information Exchange is responsible for the transmission of health care-related data among facilities, health information organizations and government agencies according to national standards.  They are designed to address legal, organizational and technical challenges that would otherwise impede the sustainability of health information interchange.  An HIE is a component of the HIT.  It must enable reliable and secure transfer of data among diverse systems and facilitate access and retrieval.  The two main types are private and public exchanges.  Private exchanges may be able to leverage homogeneous IT infrastructure to facilitate data sharing.  Public exchanges are likely to be heterogeneous.  RHIO provide the regional organizations to support such HIE.  They are there to ensure that infrastructure amplification initiates.  The government will ensure that low healthcare density areas are served by public HIE infrastructure.  Both centralized and federated technical solutions were initially considered for implementation by the RHIOs for deploying HIE as specified in the Markle Foundation's NHIN common framework.  Common framework clients such as appropriately architected HIE use SOAP messaging to interact with their local SNO's ISB and RLS.  The HIE SOAP query transactions follow the HL7 Query Model.  Alternatively some HIE's are now using direct messaging to support interoperation.  HIE deployment goals have been phased (1 - supporting care transitions, 2 - Quality and care management, 3 - Population health).  Some HIEs will support "EHR-lite" as part of their functionality.  HIE does not yet solve some difficult challenges:
  • Safeguarding the security of health information.  Currently HIEs conforming to the common framework only provide locations of clinical data held remotely.  
  • Providing effective life cycle management.  The HIE is dependent on the local set of entities to provide updates that match the current state of the entity data. 
    
  ) have been linked up in Nebraska, Kansas, Missouri and Illinois via secure direct messaging is a secure messaging technology used by HIEs (& Blue Button+) to directly interoperate.  It uses SMIME body in a SMTP protocol and X.509 certification. 
  .  But as of 2013 deployment in key states is still primitive.  Indiana has one of the most developed and studied HIE projects (IHIE is the state wide Indiana Health Information Exchange which leverages the IT and informatics team at the INPC.  It includes clinical and administrative claims data to support electronic delivery of test reports to physician offices.  It also maintains a report card and incentives on established quality measures to physicians, practice groups, payers and employers.  ). 
  
• Most healthcare providers are choosing patient portals provides web and or application based access to a patient's EHR based health care information and services.  Specific portal services are mandated by meaningful use.  They include at a minimum lab test results, problem list, medication list, and medication allergy list.   from their EMR vendor rather than best of breed, with Epic the leading vendor.  Meaningful use is the set of standards defined by CMS Incentive Programs that governs the use of electronic health records and allows eligible providers and hospitals to earn incentive payments by meeting specific criteria.  It aims to ensure that ARRA subsidies for HIS are used to generate health improvements.  It is staged:
  1. 2011-2012 Data capture and sharing - Criteria focus on electronically capturing health information in a standardized format.  Using that information to track key clinical conditions.  Communicating that information for care coordination processes.  Initiating the reporting of clinical quality measures and public health information.  Using information to engage patients and their families in their care.  Achieving meaningful use stage 1 requires meeting all core and selected menu objectives. 
     
  2. 2014 Advance clinical processes - More rigorous health information exchange requirements.  Increased requirements for e-prescribing and incorporating lab results.  Electronic transmission of patient care summaries across multiple settings.  More patient-controlled data.  A patient portal is required.  CMS hospital core measures, CMS hospital menu set measures, NPRMs of stage 2 meaningful use and certification criteria have been announced (2013).  
  • MU2 requires EHR systems to support direct messaging to send PHI to registered users. 
    
  3. 2016 Improved outcomes - Improving quality, safety, and efficiency, leading to improved health outcomes.  Decision support for national high-priority conditions.  Patient access to self-managed tools.  Access to comprehensive patient data through patient-centered HIE.  Improving population health.  
  requirements for access and messaging are driving the 'tactical' installations. 
  
• The majority (80% by end of 2013) of family physicians. This is at a faster rate than other medical specialties.  But there is a big disparity between states.   
• Hospitals driven by meaningful use incentives. 
  
• Full physician documentation with a small subset with complete EMR has reached 10% in 2013. 
  
• Closed loop medication administration is focused on improving how effectively patients take their medicines.  In the US in 2017 the problem is huge and costly (Apr 2017).  Chronic diseases such as Malaria illustrate the complexity of the task.  A coherent medical network with shared access to EHR should help.  So do blister packs with the days of the week marked.  M-health glow caps with a wireless transmitter that lights up if medication has not been taken as expected.  An improved prescription label is less open to confusion.  Codes on drugs can be scanned by smartphones to initiate download of an informational video.  Smart pillboxes control when pills are dispensed.  Measuring the contents of a medication bottle can alert for intervention if too much or too little is in the bottle.  Drug manufacturers see ways to get closer to the patient: Sanofi Toujeo deployment; Pharmacies are implementing VDS to support medication adherence: Connected Care;
  , clinical decision support protocols and CPOE is computerized provider order entry.  Certified EHR technologies are required to support CPOE ordering of medications, laboratory and radiology/imaging.  CPOE can provide physician support reducing medication errors significantly, as illustrated at Beth Israel.  ISVs such as Surescripts can then route the order to the pharmacy.   has reached 14% in 2013.
  
• Nursing and clinical documentation, CDSS is Clinical decision support system.  These support clinicians decision making by combining patient data with known medical knowledge to provide alerts, such as drug combination interactions or remiders of best care practices.  
  • Radiology CDSS order interactions are governed by PAMA and will use ACR select transactions. 
    
  and PACS is Picture Archiving and Communications System - a workflow for radiology imaging.  An alternative to RIS. 
  available outside radiology has reached 40% in 2013.  But this is pushing the focus of nurses from care to documentation (Dec 2015). 
  
• They are not standardized and interoperable (Dec 2015) which is limiting integration with 3rd party clinical decision support tools. 
  
• Drug databases could supply customized alerts but vendor activity impacted. 
  
• Order set are specifications of medications and procedures to be performed on a patient.  It is envisioned that EHR will ensure that these orders are validated against allergic reactions and drug interactions that may occur for the particular patient. 
  integration limited. 
  
• Care plans outline the patient's current and long-term needs and goals for care, identifies coordination needs, and addresses potential gaps.  This is consistant with the biopsychosocial model.  It also clarifies how the patient will reach the goals and who is responsible for implementing each part of the plan.  HL7's FHIR has defined a CarePlan resource.   integrated by Cerner, Fdb, Wolters Kluwer in partnership with main EMR vendors.  
  
• Molecular imaging allows the visualization of cellular function and molecular processes, allowing more precise and earlier diagnosis of disease.  It extends traditional imaging by:
  
  • Using biomarkers, including Nano sensors, which interact chemically with their surroundings, to image particular targets and pathways
    
  • Leveraging deep learning to reduce the required imaging, and target it more effectively
    
  • Providing quantitative data on the imaged process or function enabling Nano medicine.  
  • Extending mass spectrometry with MALDI to allow rapid (relative to sequencing or x-ray crystallography), low cost analysis of proteins, bacteria and viruses.  
  
  
• mass spectrometry with MALDI  is matrix-assisted laser desorption/ionization mass spectrometry.  It generates ions in the gas phase from large molecules.  The sample (a protein, DNA, sugar) is: 1. Mixed with an appropriate matrix material and is deployed to a metal plate.  2. Irradiated with a pulsed laser.  3. Ionized with an ablated gas; and then flowed to an appropriate mass spectrometer.  MALDI is low cost and rapid to perform but it is hard to make quantitatively repeatable. 
  
• Stanford Medical School professor, Lei Xing, details research in his Medical imaging, deep learning is an artificial intelligence approach where engineers deploy data into deep neural networks. 
  AI & nano medicine is the application of nanotechnology to medicine (May 2016, Feb 2019).  Commercial applications are focused on research and clinical tools for drug delivery, therapies, safer and more effective in vivo imaging, neuro-electronic interfaces, other Nano-sensors, and eventually cell repair machines!!  There are issues with determining toxicology etc. 
  lab to IEEE is the institute of electrical and electronic engineers. 
  nano-technology group at Varian Medical Systems (Feb 2019)
  
• Dementia is a classification of memory impairment, constrained feelings and enfeebled or extinct intellect.  The most common form for people under 60 is FTD.  Dementia has multiple causes including: vascular disease (inducing VCI) including strokes, head trauma, syphilis and mercury poisoning for treating syphilis, alcoholism, B12 deficiency (Sep 2016), privation, Androgen deprivation therapy (Oct 2016), stress, Parkinson's disease, Alzheimer's disease, and prion infections such as CJD and kuru.  The condition is typically chronic and treatment long term (Laguna Honda ward) and is predicted by Stanley Prusiner to become a major burden on the health system.  It may be possible to constrain the development some forms of dementia by: physical activity, hypertension management, and ongoing cognitive training.  Dementia appears to develop faster in women than men.  
  
• Alzheimer's is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and declarative memory and thinking problems (MCI).  Specific cells within the hippocampal circuitry and its gateway, the entorhinal cortex, are damaged.  The amygdala, cerebelum and other areas supporting implicit memory are not impacted during the early stages of the disease.  Grid cell destruction results in a sense of being lost.  The default mode network is disrupted.  Variants include: late-onset sporadic; with risk factors - ApoE4 for late onset Alzheimer's, presenilin, androgen deprivation therapy (Dec 2015), type 2 diabetes.  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation, Neurons of sporadic Alzheimer's sufferers show greater APP gene diversity due to somatic recombination; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form.  These are seen in fMRIs 10 to 15 years prior to detecting memory and thinking changes.  APP deployed in the cell membrane is cut into three parts.  The external part becomes amyloid-beta peptide which aggregates into Amyloid plaques, external to the neurons, if too much is generated or it is not removed fast enough. 
    
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016). 
    
  • Encouraging the garbage collection of amyloid and tau with gamma rhythms stimulation retards Alzheimer's in mice studies (Mar 2019)
    
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • Mutation driven misfolded Tau proteins can form tangles within the cytoplasm of neurons.  The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    
  • The brain becomes inflamed resulting in the killing of many more nerve cells.  The hippocampus disintegrates and the brain loses critical functions and memory loss becomes noticeable. 
    
  plaque inhibition trial by Eli Lilly with Solanezumab fails (Nov 2016) 
• NIA funded research by University of Michigan's Ken Langa finds dementia is a classification of memory impairment, constrained feelings and enfeebled or extinct intellect.  The most common form for people under 60 is FTD.  Dementia has multiple causes including: vascular disease (inducing VCI) including strokes, head trauma, syphilis and mercury poisoning for treating syphilis, alcoholism, B12 deficiency (Sep 2016), privation, Androgen deprivation therapy (Oct 2016), stress, Parkinson's disease, Alzheimer's disease, and prion infections such as CJD and kuru.  The condition is typically chronic and treatment long term (Laguna Honda ward) and is predicted by Stanley Prusiner to become a major burden on the health system.  It may be possible to constrain the development some forms of dementia by: physical activity, hypertension management, and ongoing cognitive training.  Dementia appears to develop faster in women than men.   rates dropping as US is the United States of America.   population ages (Nov 2016)
  
  
• Hypertension is high blood pressure.  It is directly associated with death rate due to pressure induced damage to the left ventricle and in general to cardiovascular diseases.  Treated with antihypertensives: Diuretics, Calcium channel blockers, Angiotensin receptor blockers or Beta blockers.   is a high risk, is an assessment of the likelihood of an independent problem occurring.  It can be assigned an accurate probability since it is independent of other variables in the system.  As such it is different from uncertainty. 
  factor for later dementia is a classification of memory impairment, constrained feelings and enfeebled or extinct intellect.  The most common form for people under 60 is FTD.  Dementia has multiple causes including: vascular disease (inducing VCI) including strokes, head trauma, syphilis and mercury poisoning for treating syphilis, alcoholism, B12 deficiency (Sep 2016), privation, Androgen deprivation therapy (Oct 2016), stress, Parkinson's disease, Alzheimer's disease, and prion infections such as CJD and kuru.  The condition is typically chronic and treatment long term (Laguna Honda ward) and is predicted by Stanley Prusiner to become a major burden on the health system.  It may be possible to constrain the development some forms of dementia by: physical activity, hypertension management, and ongoing cognitive training.  Dementia appears to develop faster in women than men.  , Kaiser researchers find (Oct 2017)
  
• Three hourly walks a week provides benefits for VCI is vascular cognitive impairment, the second most common dementia after Alzheimer's disease, it is due to damaged blood vessels in the brain.  It is often associated with hypertension and heart disease.  Surviving a heart attack results in a 35% increase in risk of VCI (Nov 2017).  In its early stages it makes the brain function less efficiently with more work required to perform a memory, decision-making or attention based task.   (May 2017)
• Heart attack is an AMI. It can induce cardiac arrest.  Blocking the formation of clots with platelet aggregation inhibitors, can help with treating and avoiding AMI.  Risk factors include: taking NSAID pain killers (May 2017).  There is uncertainty about why AMI occur.  Alternative hypotheses include:
  
  • Plaques started to gather in the coronary arteries and grew until no blood flow was possible.  If this is true it makes sense to preventatively treat the buildup with angioplasty. 
    
  • Plaques form anywhere in the body due to atherosclerosis and then break up and get lodged in the coronary artery and start to clot.  If this is true it makes sense to preventatively limit the buildup of plaques with drugs like statins or PCSK9 inhibitors. 
    
  survival associated with later VCI is vascular cognitive impairment, the second most common dementia after Alzheimer's disease, it is due to damaged blood vessels in the brain.  It is often associated with hypertension and heart disease.  Surviving a heart attack results in a 35% increase in risk of VCI (Nov 2017).  In its early stages it makes the brain function less efficiently with more work required to perform a memory, decision-making or attention based task.   (Nov 2017)
  
• Johns Hopkins study finds the number of chronic inflammatory events in middle age correlates with increased memory loss later in life (Feb 2019)
  
• Evolutionary biology
  
• Yale/Arizona study of Hadza is a Tanzanian hunter gatherer tribe that subsists by hunting and foraging.  They forage for berries, honey, baobab fruit and tubers. 
  shows high daily mobility (Nov 2016) 
• Precision is the integration of molecular research: genomics, proteomics, transcriptomics, metabolomics, cell signalling; and clinical data through a taxonomy based on CAS modeling overlaid on an information commons.  It aims to support treatment of disease and remove the organ and symptom based methodological flaws in the ICD.  Supporters of the D.S.M. note the aggressive shift to precision medicine at the NIMH under Dr. Insel, constrained useful clinical research (Nov 2015). 
  /personalized medicine is a medical strategy where decisions, practices, and products are tailored to the individual patient.  Research is looking at the impact of providing potentially deleterious genomic testing information to people: The REVEAL study found no increased anxiety induced by hearing that one's genome implied increased risk of developing late onset Alzheimer's disease.  The take-up of personalized medicine benefits from the focus on genomics, enabled by next generation sequencing of DNA, and detailed by the NIH director Francis Collins and includes:
  • NCCN intensive cell therapies
    
  • Direct to consumer genomic testing
    
  • Direct to consumer diagnostics
    
  • Pharmacogenomics tailored drug treatments reducing the risk and cost of adverse drug reactions.   
  
  
• UCSF's Computational Health Sciences leader Atul Butte reviews: DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used.   and limits to its impact, genome web sites: 23andMe etc., Precision medicine is the integration of molecular research: genomics, proteomics, transcriptomics, metabolomics, cell signalling; and clinical data through a taxonomy based on CAS modeling overlaid on an information commons.  It aims to support treatment of disease and remove the organ and symptom based methodological flaws in the ICD.  Supporters of the D.S.M. note the aggressive shift to precision medicine at the NIMH under Dr. Insel, constrained useful clinical research (Nov 2015). 
  (ICD is the International Classification of Diseases diagnosis codes which doctors must specify and associate with a correct CPT procedure code to have treatment accepted and reimbursed.  ICD is mainly focused on billing.  Methodological issues (Jun 2018) are driving a shift to precision medicine. 
  history and classification issues, Challenge of studying and understanding long term illness), Privacy, Whole genome vs. Specific strategies, Sequencing directions describes methods of DNA sequencing, that replace traditional Sanger sequencing, which have been implemented in commercial DNA sequencers after 2000.  The methods include:
  • Base-by-base is stepwise sequencing where there are 3' removable blockers on the DNA arrays. 
    
  • Pyrosequencing,  
  • Sequencing by synthesis,
    
  • Sequencing by ligation,
    
  • SMRT,
    
  • DNA colony sequencing,
  • DNA nanoball, 
  • Nanopore sequencing,
    
  • MPSS was the first of the next generation sequencing methods,
  • Polony sequencing.  
  : Helix; CRISPR is clustered replicating interspersed silent palindromic repeats; a technique for exact targeting, cutting and editing of DNA based on leveraging bacterial enzymatic defenses against viruses generalized to any DNA sequence in a prokaryotic or eukaryotic cell.  It was identified during studies of a bacterial adaptive immune system.  In that system bacterial proteins grab parts of a virus that has infected them and record it within the palindromic structures that mark an array of inserted viral DNA used as a log persisted over generations.  If a new infection occurs the viral DNA is compared with the sequences and if a match exists the CAS proteins break up the viral DNA initiating its destruction.  This bacterial system was then updated and repurposed by the researchers to support targeted genetic engineering.  As explained by Dr. Doudna, the CRISPR proteins and the 20 nucleotide RNA template migrate into the nucleus where they rapidly target DNA which complements the RNA template and the Cas9 enzyme performs the edits.  Being a bacterial system CRISPR Cas9 does not target eukaryotic heterochromatic DNA well.  It is not fully understood how they find the target sequence so quickly.  It has been shown that Cas9 will bind to sites with a 5-8 base match but then it releases rapidly without cutting.  To cut, Cas9 has to reconfigure, which does not occur in the mismatch situations.   and challenge of treatment delivery, Surprises: Interest in ancestry, Failure to comprehend risk, is an assessment of the likelihood of an independent problem occurring.  It can be assigned an accurate probability since it is independent of other variables in the system.  As such it is different from uncertainty. 
  ; Leverage of personal fitness probes, Problems of rapid change overloading doctors (Jun 2018)
  
• President Obama's precision medicine initiative
  
• NIH is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.   finances million-person cohort is a precision medicine activity funded through the NIH with $130 million in December 2015 by Congress (Jul 2016). 
  with participants: Community health centers, Harlem Hospital, Mayo clinic, New York Presbyterian, Northwestern University, University of Pittsburgh, Vanderbilt University, Weill Cornell; (Jul 2016)
• NIH is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.  's million person precision medicine is the integration of molecular research: genomics, proteomics, transcriptomics, metabolomics, cell signalling; and clinical data through a taxonomy based on CAS modeling overlaid on an information commons.  It aims to support treatment of disease and remove the organ and symptom based methodological flaws in the ICD.  Supporters of the D.S.M. note the aggressive shift to precision medicine at the NIMH under Dr. Insel, constrained useful clinical research (Nov 2015). 
  program All of US makes slow & costly progress - relative to smaller biobanks: UK, Iceland (deCode), VA - Department of Veterans Affairs.  Includes the Veterans Health Administration. 
  , Kaiser, Geisinger; causing some participants to back out: Kaiser, Geisinger (Regeneron); but Francis Collins asserts its scope is essential & Verily is still participating (Mar 2018)
  
• Mount Sinai Icahn SOM's Dr. Joel Dudley's precision medicine is the integration of molecular research: genomics, proteomics, transcriptomics, metabolomics, cell signalling; and clinical data through a taxonomy based on CAS modeling overlaid on an information commons.  It aims to support treatment of disease and remove the organ and symptom based methodological flaws in the ICD.  Supporters of the D.S.M. note the aggressive shift to precision medicine at the NIMH under Dr. Insel, constrained useful clinical research (Nov 2015). 
  (Big Data encompasses the IT systems and processes necessary to do population based data collection, management and analysis.  The very low cost, robust, data storage organized by infrastructure: HADOOP; allows digital data to be stored en mass.  Data scientists then apply assumptions about the world to the data, analogous to evolved mechanisms in vision, in the form of algorithms: Precision medicine, Protein folding modeling (Feb 2019) assumes coevolutionary methods can be applied to identify contact points in a protein's tertiary structure.  Rather than depending on averages, analysis at Verisk drills down to specifics and then highlights modeling problems by identifying the underlying CAS.  For the analysis to be useful it requires a hierarchy of supporting BI infrastructure:
  • Analytics utilization and integration delivered via SaaS and the Cloud to cope with the silos and data intensive nature. 
    
  • Analytics tools (BI) for PHM will be hard to develop.  
  • Complex data models must include clinical aspects of the patient specific data, including disease state population wide.  
  • A key aspect is providing clear signals about the nature of the data using data visualization. 
    
  • Data communication with the ability to exchange and transact.  HIEs and EMPI alliance approaches are all struggling to provide effective exchange. 
    
  • Data labeling and secure access and retreival.  While HIPAA was initially drafted as a secure MPI the index was removed from the legislation leaving the US without such a tool.  Silos imply that the security architecture will need to be robust. 
    
  • Raw data scrubbing, restructuring and standardization.  Even financial data is having to be restandarized shifting from ICD-9 to -10.  The intent is to transform the unstructured data via OCR and NLP to structured records to support the analytics process. 
    
  • Raw data warehousing is distributed across silos including PCP, Hospital system and network, cloud and SaaS for process, clinical and financial data. 
    
  • Data collection from the patient's proximate environment as well as provider CPOE, EHRs, workflow and process infrastructure.  The integration of the EHR into a big data collection tool is key. 
    
  ) study associates Roseoloviruses is a subset: HHV6 (HHV-6A, HHV-6B), HHV7; of Herpes viruses.  HHV6 typically infects human infants before age two, with symptoms of fever, diarrhea, and a rash known as roseola. 
  : HHV-6A is a double stranded DNA Roseolovirus.  It infects all tested humans and is neuroinflammatory, being seen in diseases such as MS. 
  , HHV7 is a double stranded DNA Roseolovirus. 
  ; with Alzheimer's disease is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and declarative memory and thinking problems (MCI).  Specific cells within the hippocampal circuitry and its gateway, the entorhinal cortex, are damaged.  The amygdala, cerebelum and other areas supporting implicit memory are not impacted during the early stages of the disease.  Grid cell destruction results in a sense of being lost.  The default mode network is disrupted.  Variants include: late-onset sporadic; with risk factors - ApoE4 for late onset Alzheimer's, presenilin, androgen deprivation therapy (Dec 2015), type 2 diabetes.  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation, Neurons of sporadic Alzheimer's sufferers show greater APP gene diversity due to somatic recombination; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form.  These are seen in fMRIs 10 to 15 years prior to detecting memory and thinking changes.  APP deployed in the cell membrane is cut into three parts.  The external part becomes amyloid-beta peptide which aggregates into Amyloid plaques, external to the neurons, if too much is generated or it is not removed fast enough. 
    
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016). 
    
  • Encouraging the garbage collection of amyloid and tau with gamma rhythms stimulation retards Alzheimer's in mice studies (Mar 2019)
    
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • Mutation driven misfolded Tau proteins can form tangles within the cytoplasm of neurons.  The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    
  • The brain becomes inflamed resulting in the killing of many more nerve cells.  The hippocampus disintegrates and the brain loses critical functions and memory loss becomes noticeable. 
    
  , judged by changes in the entorinal cortex is a main limbic association area between the hippocampus and the neocortex, in the medial temporal lobe.  It is a hub for memory and navigation: location awareness is supported by grid cells.  It is the first brain area impacted in Alzheimer's disease. 
  , hippocampus is a part of the medial temporal lobe of the brain involved in the temporary storage or coding of long-term episodic memory.  It includes the dentate gyrus.  Memory formation in the cells of the hippocampus uses the MAP kinase signalling network which is impacted by sleep deprivation.  The hippocampus dependent memory system is directly affected by cholinergic changes throughout the wake-sleep cycle.  Increased acetylcholine during REM sleep promotes information attained during wakefulness to be stored in the hippocampus by suppressing previous excitatory connections while facilitating encoding without interference from previously stored information.  During slow-wave sleep low levels of acetylcholine cause the release of the suppression and allow for spontaneous recovery of hippocampal neurons resulting in memory consolidation.  It was initially associated with memory formation by McGill University's Dr. Brenda Milner, via studies of 'HM' Henry Molaison, whose medial temporal lobes had been surgically destroyed leaving him unable to create new explicit memories.  The size of neurons' dendritic trees expands and contracts over a female rat's ovulatory cycle, with the peak in size and cognitive skills at the estrogen high point.  Adult neurogenesis occurs in the hippocampus (3% of neurons are replaced each month) where the new neurons integrate into preexisting circuits.  It is enhanced by learning, exercise, estrogen, antidepressants, environmental enrichment, and brain injury and inhibited by various stressors explains Sapolsky.  Prolonged stress makes the hippocampus atrophy.  He notes the new neurons are essential for integrating new information into preexisting schemas -- learning that two things you thought were the same are actually different.  Specific cells within the hippocampus and its gateway, the entorhinal cortex, are compromised by Alzheimer's disease.  It directly signals area 25. 
  , promoter enrichments for C2H2 zink finger is a large set of finger like binding domains in mammalian transcription factors with a Cys2-His2 (C2H2) fold group, which can bind in the major groove of DNA. 
  transcription factor are enzymes which associate with a transcription complex to bind to the DNA and control its transcription and hence translation into proteins.  The regulation of DNA transcription and protein synthesis are reviewed by Tsonis.  Transcription factors allow environmental state to become reflected in the control of DNA transcription.  Transcription factors can regulate multiple genes, allowing network effects & multiple transcription factors can regulate a gene allowing sophisticated control processes.  In AWF the transcription, translation and deployment infrastructure of the eukaryotic cell has been abstracted in a codelet based implementation. 
  binding motifs and signalling, is an emergent capability which is used by cooperating agents to support coordination & rival agents to support control and dominance.  In eukaryotic cells signalling is used extensively.  A signal interacts with the exposed region of a receptor molecule inducing it to change shape to an activated form.  Chains of enzymes interact with the activated receptor relaying, amplifying and responding to the signal to change the state of the cell.  Many of the signalling pathways pass through the nuclear membrane and interact with the DNA to change its state.  Enzymes sensitive to the changes induced in the DNA then start to operate generating actions including sending further signals.  Cell signalling is reviewed by Helmreich.  Signalling is a fundamental aspect of CAS theory and is discussed from the abstract CAS perspective in signals and sensors.  In AWF the eukaryotic signalling architecture has been abstracted in a codelet based implementation.  To be credible signals must be hard to fake.  To be effective they must be easily detected by the target recipient.  To be efficient they are low cost to produce and destroy. 
  links with ApoE4 is a gene variant which produces the E4 variant of APOE.  It is a risk-factor for late-onset sporadic Alzheimer's disease.  Being homozygote for E4 does not imply getting Alzheimer's but does increase the risk 20 fold.  ApoE2 may reduce the risk of Alzheimer's.  It appears that ApoE4 differentially affects women.  Apoe4 is known to be broken down into fragments which impare mitochondrial operation.  It also promotes amyloid plaque buildup.  Therapies are being developed based on small molecules which reshape ApoE4 to be more like ApoE3 reducing the breakdown.   
  . It seems likely that after remaining dormant for years the virus is a relatively small capsule containing genetic material which utilizes the cellular infrastructure of its target host to replicate its genetic material and operational proteins.  The relationship with the host is short term, relative to parasites, with the virus entering the host cell, leveraging the host infrastructure to replicate its self massively and then exiting the host cell by rupturing it. 
  activates (stressor is a multi-faceted condition reflecting high cortisol levels.  Dr. Robert Sapolsky's studies of baboons indicate that stress helps build readiness for fight or flight.  As these actions occur the levels of cortisol return to the baseline rate.  A stressor is anything that disrupts the regular homeostatic balance.  The stress response is the array of neural and endocrine changes that occur to respond effectively to the crisis and reestablish homeostasis. 
  
  • The short term response to the stressor
    
  • activates the amygdala which: Stimulates the brain stem resulting in inhibition of the parasympathetic nervous system and activation of the sympathetic nervous system with the hormones epinephrine and norepinephrine deployed around the body, Activates the PVN which generates a cascade resulting in glucocorticoid secretion to: get energy to the muscles with increased blood pressure for a powerful response.  The brain's acuity and cognition are stimulated.  The immune system is stimulated with beta-endorphin and repair activities curtail.  In order for the body to destroy bacteria in wounds, pro-inflammatory cytokines increase blood flow to the area.  The induced inflammation signals the brain to activate the insula and through it the ACC.  But when the stressor is
    
  • long term: loneliness, debt; and no action is necessary, or possible, long term damage ensues.  Damage from such stress may only occur in specific situations: Nuclear families coping with parents moving in.  Sustained stress provides an evolved amplifier of a position of dominance and status.  It is a strategy in female aggression used to limit reproductive competition.  Sustained stress:
    
  • Stops the frontal cortex from ensuring we do the harder thing, instead substituting amplification of the individual's propensity for risk-taking and impairing risk assessment! 
    
  • Activates the integration between the thalamus and amygdala. 
    
  • Acts differently on the amygdala in comparison to the frontal cortex and hippocampus: Stress strengthens the integration between the Amygdala and the hippocampus, making the hippocampus fearful. 
    
  • BLA & BNST respond with increased BDNF levels and expanded dendrites persistently increasing anxiety and fear conditioning. 
    
  • Makes it easier to learn a fear association and to consolidate it into long-term memory.  Sustained stress makes it harder to unlearn fear by making the prefrontal cortex inhibit the BLA from learning to break the fear association and weakening the prefrontal cortex's hold over the amygdala.  And glucocorticoids decrease activation of the medial prefrontal cortex during processing of emotional faces.  Accuracy of assessing emotions from faces suffers.  A terrified rat generating lots of glucocorticoids will cause dendrites in the hippocampus to atrophy but when it generates the same amount from excitement of running on a wheel the dendrites expand.  The activation of the amygdala seems to determine how the hippocampus responds. 
    
  • Depletes the nucleus accumbens of dopamine biasing rats toward social subordination and biasing humans toward depression. 
    
  • Disrupts working memory by amplifying norepinephrine signalling in the prefrontal cortex and amygdala to prefrontal cortex signalling until they become destructive.  It also desynchronizes activation in different frontal lobe regions impacting shifting of attention.  
  • Increases the risk of autoimmune disease (Jan 2017) 
  • During depression, stress inhibits dopamine signalling.  
  • Strategies for stress reduction include: Mindfulness. 
    
  ) & generates an immune has to support and protect an inventory of host cell types, detect and respond to invaders and maintain the symbiont equilibrium within the microbiome.  It detects microbes which have breached the secreted mucus barrier, driving them back and fortifying the barrier.  It culls species within the microbiome that are expanding beyond requirements.  It destroys invaders who make it into the internal transport networks.  As part of its initialization it has immune cells which suppress the main system to allow the microbiome to bootstrap.  The initial microbiome is tailored by the antibodies supplied from the mother's milk while breastfeeding.  The immune system consists of two main parts the older non-adaptive part and the newer adaptive part.  The adaptive part achieves this property by being schematically specified by DNA which is highly variable.  By rapid reproduction the system recombines the DNA variable regions in vast numbers of offspring cells which once they have been shown not to attack the host cell lines are used as templates for interacting with any foreign body (antigen).  When the immune cell's DNA hyper-variable regions are expressed as y-shaped antibody proteins they typically include some receptor like structures which match the surfaces of the typical antigen.  Once the antibody becomes bound to the antigen the immune system cells can destroy the invader. 
  response that stimulates plaques which kill neurons, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
  • Receptive element - dendrites
    
  • Transmitting element - axon and synaptic terminals.  The axon may be myelinated, focusing the signals through synaptic transmission, or unmyelinated - where crosstalk is leveraged. 
  • Highly variable DNA schema using transposons. 
    
  (Jun 2018)
• Identifying gene issues and mechanisms, from precision medicine is the integration of molecular research: genomics, proteomics, transcriptomics, metabolomics, cell signalling; and clinical data through a taxonomy based on CAS modeling overlaid on an information commons.  It aims to support treatment of disease and remove the organ and symptom based methodological flaws in the ICD.  Supporters of the D.S.M. note the aggressive shift to precision medicine at the NIMH under Dr. Insel, constrained useful clinical research (Nov 2015). 
  mutation data, allows rapid association of current medicines with rare diseases (Sep 2018)
• Verily, Stanford & Duke, work on project Baseline, to identify early markers of: cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016). 
  , cardiovascular disease refers to:
  
  • Conditions where narrowed and blocked blood vessels result in angina, hypertension, CHD and heart attacks and hemorrhagic/ischemic strokes.  Mutations of the gene PCSK9 have been implicated in cardiovascular disease.  Rare families with dominant inheritence of the mutations have an overactive protein, very high levels of blood cholesterol and cardiac disease. Other rare PCSK9 mutations result in an 88% reduced risk from heart disease.  Inflammation is associated with cardiovascular disease (Aug 2017). 
    
  ; from samples of: urine, blood, and stools; by following 10,000 healthy people's: microbiomes, the trillions of bacteria and viruses that live inside higher animals' guts, on their skin etc.  These bacteria and viruses seem to play a role in: immune responses, digesting food, making nutrients, controlling mental health and maintaining a healthy weight.  The signals from the gut microbiota are relayed by major nerve fibers: vagus; to the central nervous system.  The symbiotic relationship must be actively managed.  Human armpits include glands which provide food favoring certain symbionts who build a defensive shield above the skin.  In the human gut: Barriers are setup: Mucus secretions form a physical constraint and provide sites for bacteriophages to anchor and attack pathogenic bacteria; Symbiont tailored nourishment: Plant-heavy food creates opportunities for fibre specialists like Bacteroides thetaiotaomicron; is provided, Selective binding sites are provided, Poisons are deployed against the unwelcome, and Temperature, acidity and oxygenation are managed.    High throughput sequencing allows the characterization of bacterial populations inside guts.  Beginning at birth, as they pass down the birth canal infants are supplied with a microbiome from their mothers.  If they are borne via cesarean they never receive some of the key bacteria: Bifidobaterium infantis which is also dependent on oligosaccharides in breast milk; from their mothers.  A variety of diseases may be caused by changes in the microbiome:
  • Eczema can be related to changes in the skin microbiome. 
    
  • Obesity can be induced by changes to the gut microbiome.  
  • Chronic inflammation
    
  • Allergies
    
  • Type 1 diabetes
    
  , genomics combines recombinant DNA editing with tools: CRISPR; DNA next generation sequencing and bioinformatics  to sequence, assemble and analyse genomes.  , cognitive health, sleep facilitates salient memory formation and removal of non-salient memories.  The five different stages of the nightly sleep cycles support different aspects of memory formation.  The sleep stages follow Pre-sleep and include: Stage one characterized by light sleep and lasting 10 minutes, Stage two where theta waves and sleep spindles occur, Stage three and Stage four together represent deep slow-wave sleep (SWS) with delta waves, Stage five is REM sleep; sleep cycles last between 90-110 minutes each and as the night progresses SWS times reduce and REM times increase.   Sleep includes the operation of synapse synthesis and maintenance through DNA based activity including membrane trafficking, synaptic vesicle recycling, myelin structural protein formation and cholesterol and protein synthesis.  Sleep also controls inflammation (Jan 2019)  Sleep deprivation undermines the thalamus & nucleus accumbens management of pain. 
  patterns from Verily device; for four years.  Precision medicine is the integration of molecular research: genomics, proteomics, transcriptomics, metabolomics, cell signalling; and clinical data through a taxonomy based on CAS modeling overlaid on an information commons.  It aims to support treatment of disease and remove the organ and symptom based methodological flaws in the ICD.  Supporters of the D.S.M. note the aggressive shift to precision medicine at the NIMH under Dr. Insel, constrained useful clinical research (Nov 2015). 
  data will be shared with participants (Oct 2018)
  
• Genetic traits show how to effectively treat brain tumors (Jun 2015)
• Genomic testing uses genomic analysis to diagnose genetic disorders - for example Genomic Health's Oncotype DX & Agendia's MammaPrint.  The desire to see the genetic risk factors identified by such tests should depend on the risk * burden * Possibility of intervention.  Early tests look at only single gene mutations, but big data research tools are showing promise with large gene algorithms (Aug 2018).  Genomic testing can be performed direct-to-consumer.  Data is being collated on the genetic components of most diseases to enable more sophisticated diagnosis in the future such as the OPHG (EGAPP initiative), USPSTF recommendations and NCBI (Genetic test registry).  While there is only limited identification of the significant mutations and limited patient bases misdiagnosis is a problem (Aug 2016). 
  succeeds in indicating breast cancer is a variety of different cancerous conditions of the breast tissue.  World wide it is the leading type of cancer in women and is 100 times more common in women than men.  260,000 new cases of breast cancer will occur in the US in 2018 causing 41,000 deaths.  The varieties include: Hormone sensitive tumors that test negative for her2 (the most common type affecting three quarters of breast cancers in the US, BRCA1/2 positive, ductal carcinomas including DCIS, lobular carcinomas including LCIS.  Receptor presence on the cancer cells is used as a classification: Her2+/-, estrogen (ER)+/-, progesterone (PR)+/-.  Metastasis classes the cancer as stage 4.  Genetic risk factors include: BRCA, p53, PTEN, STK11, CHEK2, ATM, GATA3, BRIP1 and PALB2.  Treatments include: Tamoxifen, Raloxifene; where worrying racial disparities have been found (Dec 2013).  International studies indicate early stage breast cancer typed by a genomic test: Oncotype DX, MammaPrint; can be treated without chemotherapy (Aug 2016, Jun 2018) patients who can avoid chemotherapy is the treatment of cancers by highly cytotoxic chemicals: Paclitaxel, Platinum, 6-mercaptopurine; assuming that cancer cells are unusually active and will be differentially poisoned.  It has been successful in offering treatments when no other course was available, but non-specificity means that healthy cells also get poisoned resulting in side effects which increase with age: Permanent nerve damage, heart failure (4-5%) and leukemia (0.5-1%). 
  (Aug 2016). 
• International TAILORx study, written up by Montefiore Medical Center's Dr. Joseph Sparano and Vanderbilt University Medical Center's Dr. Ingrid Mayer, verifies that genomic testing uses genomic analysis to diagnose genetic disorders - for example Genomic Health's Oncotype DX & Agendia's MammaPrint.  The desire to see the genetic risk factors identified by such tests should depend on the risk * burden * Possibility of intervention.  Early tests look at only single gene mutations, but big data research tools are showing promise with large gene algorithms (Aug 2018).  Genomic testing can be performed direct-to-consumer.  Data is being collated on the genetic components of most diseases to enable more sophisticated diagnosis in the future such as the OPHG (EGAPP initiative), USPSTF recommendations and NCBI (Genetic test registry).  While there is only limited identification of the significant mutations and limited patient bases misdiagnosis is a problem (Aug 2016). 
  , this time with Oncotype DX is a trademark of Genomic Health.  It is a diagnostic test based on RNA biopsy assays and gene sequencing, of disease recurrence in sufferers of various types of cancer including:
  
  • Estrogen receptor positive breast cancer.  The tests may help predict the benefit of tamoxifen or aromatase inhibitor treatments in lymph node-negative patients. 
    
  • Colon cancer. 
    
  • Prostate cancer. 
    
  , can indicate when chemotherapy is the treatment of cancers by highly cytotoxic chemicals: Paclitaxel, Platinum, 6-mercaptopurine; assuming that cancer cells are unusually active and will be differentially poisoned.  It has been successful in offering treatments when no other course was available, but non-specificity means that healthy cells also get poisoned resulting in side effects which increase with age: Permanent nerve damage, heart failure (4-5%) and leukemia (0.5-1%). 
  can be avoided in treating early stage breast cancer is a variety of different cancerous conditions of the breast tissue.  World wide it is the leading type of cancer in women and is 100 times more common in women than men.  260,000 new cases of breast cancer will occur in the US in 2018 causing 41,000 deaths.  The varieties include: Hormone sensitive tumors that test negative for her2 (the most common type affecting three quarters of breast cancers in the US, BRCA1/2 positive, ductal carcinomas including DCIS, lobular carcinomas including LCIS.  Receptor presence on the cancer cells is used as a classification: Her2+/-, estrogen (ER)+/-, progesterone (PR)+/-.  Metastasis classes the cancer as stage 4.  Genetic risk factors include: BRCA, p53, PTEN, STK11, CHEK2, ATM, GATA3, BRIP1 and PALB2.  Treatments include: Tamoxifen, Raloxifene; where worrying racial disparities have been found (Dec 2013).  International studies indicate early stage breast cancer typed by a genomic test: Oncotype DX, MammaPrint; can be treated without chemotherapy (Aug 2016, Jun 2018) (Jun 2018)
  
• Gilead to acquire Kite Pharma for $11.9 billion (Aug 2017)
• Kite Pharma (Gilead)'s CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers (Aug 2016, Jul 2017, Oct 2017, Nov 2017).  But there are severe side effects.  -T gene therapy is the deployment of genes into patient's cells to treat or prevent diseases.  It can be performed outside the body (ex vivo) or in place (in vivo).  It requires a vector such as a: Virus, Ligandal style nanoparticle, electric field (Jul 2018); to perform the deployment.  But viruses are: Difficult to sanitize (bringing in oncogenes etc.) and hard to target as needed,  Unable to target where the DNA is deployed into the target cell chromosomes, Key targets of the immune system.  The process is disease specific:
  • Blood cancers: NHL; can be treated with ex vivo CAR-T (Jul 2017, Oct 2017)
  • Cystic fibrosis requires a virus that infects the airways and then deploys a non-cystic fibrosis allele into the nucleus of the patient's cells.  The obstacles to this process have been challenging: 
    
  • The virus must not have any problematic effects.  In the case of cystic fibrosis one virus activated a cancer gene leaving several trial subjects with leukemia. 
    
  • Efficiency of delivery has to be very high and this has not proved possible as of 2015. 
    
  • The newly delivered DNA must remain intact and be replicated and transcribed.  This has not proved to be the case. 
    
  • The process has not been able to avoid an immune response.  Gene therapy has consequently been of limited value for cystic fibrosis.  
  • Hemophilia A and B; virus delivered in vivo therapies enter final stage trials (Aug 2018)
    
  • ADA based SCID was the first human treatment with gene therapy.  A normal ADA gene was inserted ex vivo into immune system cells.  Initially the updated cells did not live as long as needed. 
    
  • Sickle-cell anemia requires a non-sickle-cell trait allele of the hemoglobin gene to be vectored into the bone marrow of the affected person.  
  • T-lymphocyte DNA updates for: mutation induced autoimmune diseases, melanoma treatment; using gene editing delivered with an electric field. 
    
  Yescarta, is approved is a $6.3 billion bill to increase funding for research into cancer, Alzheimer's disease and other disease, support mental health networks and adjust regulations for drugs and medical devices.  The act does not constrain drug prices.  It is funded with money taken from a preventative health care fund.  It aims to:
  • Expand the funding of the NIH.  
  • Allocates an additional $4.8 billion over 10 years.  Much of the expanded funding is focused on Alzheimer's and cancer.  This funding will still have to be appropriated by Congress. 
    
  • Empowers the NIH:
    
  • Provides them with authority to finance high-risk, high-reward research using special procurement procedures instead of grants and contracts, 
  • Requires the director to establish "Eureka prizes" for biomedical research and treatment improvements. 
    
  • Advances the Precision Medicine Initiative,
    
  • Support the moonshot to cure cancer. 
    
  • Align the federal drug regulatory structure with the processes of the biotechnology industry.  Critics argue it lowers drug and device approval standards, and raises the influence of surrogate endpoints. 
    
  • The F.D.A. is allocated half a billion dollars to help staff the expedited processes. 
    
  • It provides an expedited pathway for breakthrough medical technologies (offering options for life-threatening conditions with few treatment options). 
    
  • F.D.A. must consider the least burdensome means to show device safety. 
    
  • Streamline the mental health network.  It strengthens the enforcement of the mental health parity law.  
  • Creates the Presidentially appointed position of assistant secretary for mental health and substance use.  
  • Directs federal agencies to step up enforcement of laws that require equal insurance coverage for mental and physical illnesses. 
    
  • Stem the problem of opioid drug abuse with a $1 billion investment that will allow expanded access of treatment programs.  
  by F.D.A. Food and Drug Administration.  , for adults with CD19 expressing aggressive forms of NHL is non-Hodgkin lymphoma, It is:
  • A group of blood cancers that include all (> 60) types of lymphoma except HL.  
  • Risk factors include: poor immune function, autoimmune disease, Helicobacter pylori infection, hepatitis C, obesity, Epstein-Barr virus infection, HIV infection, radiation therapy, chemotherapy, PCBs, dioxin, phenoxy herbicides. 
    
  (Oct 2017)
  
• Bluebird Bio gene therapy is the deployment of genes into patient's cells to treat or prevent diseases.  It can be performed outside the body (ex vivo) or in place (in vivo).  It requires a vector such as a: Virus, Ligandal style nanoparticle, electric field (Jul 2018); to perform the deployment.  But viruses are: Difficult to sanitize (bringing in oncogenes etc.) and hard to target as needed,  Unable to target where the DNA is deployed into the target cell chromosomes, Key targets of the immune system.  The process is disease specific:
  • Blood cancers: NHL; can be treated with ex vivo CAR-T (Jul 2017, Oct 2017)
  • Cystic fibrosis requires a virus that infects the airways and then deploys a non-cystic fibrosis allele into the nucleus of the patient's cells.  The obstacles to this process have been challenging: 
    
  • The virus must not have any problematic effects.  In the case of cystic fibrosis one virus activated a cancer gene leaving several trial subjects with leukemia. 
    
  • Efficiency of delivery has to be very high and this has not proved possible as of 2015. 
    
  • The newly delivered DNA must remain intact and be replicated and transcribed.  This has not proved to be the case. 
    
  • The process has not been able to avoid an immune response.  Gene therapy has consequently been of limited value for cystic fibrosis.  
  • Hemophilia A and B; virus delivered in vivo therapies enter final stage trials (Aug 2018)
    
  • ADA based SCID was the first human treatment with gene therapy.  A normal ADA gene was inserted ex vivo into immune system cells.  Initially the updated cells did not live as long as needed. 
    
  • Sickle-cell anemia requires a non-sickle-cell trait allele of the hemoglobin gene to be vectored into the bone marrow of the affected person.  
  • T-lymphocyte DNA updates for: mutation induced autoimmune diseases, melanoma treatment; using gene editing delivered with an electric field. 
    
  for sickle-cell anemia is a recessive single gene disease where the sufferer's hemoglobin causes the red blood cells to distort.  It is a side effect of the evolved protection from malaria provided by sickle cell trait.  Potential treatments include gene therapy and drugs that block the sickling of red blood cells.  Carrier screening was undermined by there being no effective prenatal test limiting the benefit of the information and because the white doctors were not trusted by their black patients.  In the future iPS cells could have the problem mutations replaced with ex vivo gene therapy. 
  in trials: Boston Children's, Northwestern; resulting in patients with no symptoms, mid trail.  Red blood stem cells is a biological cell which is partly or wholly undifferentiated.  A totipotent cell can generate a complete embryo and placenta.  Embryos include pluripotent cells which can generate any tissue in the body.  Adult humans' cells have turned off this ability but still include multipotent stem cells that differentiate into multiple cell types.   Typically a cell's local environment will have the signals required for it to obtain context and differentiate appropriately.  This will include both the external environment and the internal state of the cell which has replicated from a parent and obtained its epi-genetic state.   So introduction of undifferentiated stem cells into an injured area is not likely to have either aspect of the environment suitable.  Consequently development is aiming to encourage differentiation to progenitor cells for the damaged region.  This requires delivering the cells to the appropriate part of the body.  To avoid rejection by the immune system techniques aim to use cell lines developed from the patient's cells.  The techniques to generate these cell lines include: SCNT, iPS.  Possible mechanisms of stem cell therapy are: Generation of new differentiated cells, Stimulation of growth of new blood vessels to repopulate damaged regions, Secretion of growth factors, Treatment of diabetes (1 and 2) with addition of pancreatic cells, Assistance of other mechanisms; are removed from the bone marrow, the sickle-cell gene mutation is removed from the DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used.   and the stem-cells are flowed back into the body, where they must reenter the bone marrow for the therapy to work.  Genetic update can use newly discovered large viral vector.   An alternative to gene therapy uses a gene edit using CRISPR is clustered replicating interspersed silent palindromic repeats; a technique for exact targeting, cutting and editing of DNA based on leveraging bacterial enzymatic defenses against viruses generalized to any DNA sequence in a prokaryotic or eukaryotic cell.  It was identified during studies of a bacterial adaptive immune system.  In that system bacterial proteins grab parts of a virus that has infected them and record it within the palindromic structures that mark an array of inserted viral DNA used as a log persisted over generations.  If a new infection occurs the viral DNA is compared with the sequences and if a match exists the CAS proteins break up the viral DNA initiating its destruction.  This bacterial system was then updated and repurposed by the researchers to support targeted genetic engineering.  As explained by Dr. Doudna, the CRISPR proteins and the 20 nucleotide RNA template migrate into the nucleus where they rapidly target DNA which complements the RNA template and the Cas9 enzyme performs the edits.  Being a bacterial system CRISPR Cas9 does not target eukaryotic heterochromatic DNA well.  It is not fully understood how they find the target sequence so quickly.  It has been shown that Cas9 will bind to sites with a 5-8 base match but then it releases rapidly without cutting.  To cut, Cas9 has to reconfigure, which does not occur in the mismatch situations.  .  Another treatment strategy blocks the genetic transition from fetal to adult hemoglobin: fetal does not sickle.  NIH is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.   is launching a funding program 'Cure Sickle-Cell' (Jan 2019)
  
• Kite Pharma is a close partner of the NCI is the national cancer institute. 
  leveraging public research investments in CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers (Aug 2016, Jul 2017, Oct 2017, Nov 2017).  But there are severe side effects.  s.  N.I.H. is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.   should ask for more says Rachel Sachs, like Sloan-Kettering and Hutchinson get from Juno (Dec 2016)
• J&J's Sylvant MAB as a terminator in medication names indicates the drug is a monoclonal antibody biologic.  , Pfizer's Rapamune used in treatment of Mayo Clinic diagnosed Castleman disease is a rare condition with symptoms of: Enlarged lymph nodes, hyperactivation of the immune system, excessive releases of cytokines, proliferation of lymphocytes and organ disfuction.  It can affect subcomponents of the body or be multicentric when it is severe and deadly.  Its cause is not defined: some argue it is viral, others an inherited genetic disorder or a cancer.  It has been treated with: steroids, chemotherapy, J&J's targeted neoplastic disease therapy Sylvant (siltuximab) & Pfizer's Rapamune (sirolimus).  .  CDCN at University of Pennsylvania formed by Dr. Fajgenbaum to improve research coordination; Everylife advocates to F.D.A. Food and Drug Administration.   (Feb 2017)
• Tax payers continue to fund the opioid epidemic, supported by President Trump, his commission, the NIH is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.  , and Purdue; with help from misleading marketing of abuse-deterrent pharmaceuticals are formulated to make crushing or altering the pills harder.  However, abuse-deterrent opioids when swallowed can still induce addiction.  Some experts consider conflating abuse-deterrent with less additive as misleading (Nov 2017). 
  
  opioids, Georgetown's PharmedOut argues (Nov 2017)
  
• NCI is the national cancer institute. 
  research by Stanford SOM's Dr. Mackall, reported in Nature Medicine, targets tumor: Leukemia is a group of cancers of blood forming tissues: bone marrow, lymphatic network; where abnormal white blood cells are generated.  One type of leukemia is induced when TAD boundaries near the TAL1 gene fail allowing promotors from across the TAD border to distort the operation of the TAL transcription factor.  Mutation clusters common in leukemia have been identified in CHIP. 
  , Lymphoma is when lymphocytes continue reproducing, and do not die - a blood cancer. 
  ; cell surface protein CD22 with CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers (Aug 2016, Jul 2017, Oct 2017, Nov 2017).  But there are severe side effects.  -T, while Stanford & Seattle Children's are testing a CAR-T targeting both CD19 & CD22 (Nov 2017)
• Cuban immunotherapy is indirect treatment of disease by altering the immune system.  Targeted diseases include: cancers -- immuno-oncology, organ transplants. 
  vaccine are a core strategy of public health and have significantly extended global wellbeing over 200 years.  Smallpox & polio were virtually eradicated.  Recent successes include: HPV vaccine: Gardasil.  They induce active acquired immunity to a particular disease.  But the development and deployment of vaccines is complex:
  • The business model for vaccine development has been failing (Aug 2015): 
    
  • No Zika vaccine was available as the epidemic grew (Mar 2016).  No vaccine for: CMV;
    
  • Major foundations: Michael J. Fox, Gates, Wellcome; are working to improve the situation including sponsorship of the GAVI alliance.  A geographic cluster is forming in Seattle including PATH (Apr 2016). 
    
  • Commercial developers include: Affiris, Cell Genesis, Chiron, CSL, Sanofi, Valeant;
    
  • Vaccine deployment traditionally benefited from centrally managed vertical health programs.  But political issues are now constraining success with less than 95-99% coverage required for herd immunity (Aug 2015, Sep 2015, Nov 2015, Nov 2016, Jul 2018).  
  • Where clinics have been driven into local neighborhoods health improves (Apr 2016).  
  • Retail clinics (Mar 2016): CVS Minute Clinics focus on vaccination. 
    
  • NNT is a useful metric for vaccine benefit.  Influenza vaccine has an NNT of between 37 and 77, is cheap and causes little harm, so it is very beneficial. 
    
  • Key vaccines include: BCG, C. difficile (May 2015), Cholera (El Tor), Cervical Cancer (Gardasil HPV Jun 2018, Oct 2018), Dengvaxia (Mexico Dec 2015), Gvax, Influenza, Malaria vaccine, Provenge, Typbar-TCV (XDR typhoid Pakistan Apr 2018);
  • Regulation involves: FDA (CBER), with CMS monitoring (star ratings, PACE (Aug 2016), Report cards (Sep 2015)) & CDC promoting vaccines: as a sepsis measure, To control C. difficile (May 2015);  
  • Coding : CVX, MVX;
    
  • Research on vaccines includes: 
  • NIH: AIDS vaccines (AVRC), Focus on using genetic analysis to improve vaccine response.  
  • NCI:
  • Roswell Park clinical trial of immuno-oncology vaccine cimavax. 
    
  • Geisinger: effective process leverage in treatment. 
    
  • Stanford Edge immuno-oncology for cancer vaccines.  
  • P53-driven-cancer focused, gene therapy (Jun 2015). 
    
  Cimavax is a non-small cell lung cancer immuno-oncology vaccine.  It is an active vaccine, containing the ligand EGF and P64k and Montanide ISA 51 which together stimulate the immune system to generate antibodies targeted at EGF.  This results in the EGF concentration in the blood dropping.  Many cancers: Lung, Colon, Kidney, Head, Neck; leverage EGFR to stimulate cell growth. 
  is smuggled to US by non-small cell lung cancer affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
  • Non-small-cell carcinomas are of three sub-types:
  • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
    
  • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
    
  • Large-cell carcinomas (5 to 10% of lung cancers).
    
  • Small-cell carcinomas.
    
  sufferers (Nov 2016). 
  
• Obesity is an addictive disorder where the brain is induced to require more eating, often because of limits to the number of fat cells available to report satiation (Jul 2016).  Brain images of drug-addicted people and obese people have found similar changes in the brain.  Obese people's reward network tends to be less responsive to dopamine and have a lower density of dopamine receptors.  Obesity spreads like a virus through a social network with a 171% likelihood that a friend of someone who becomes obese will also become so.  Obesity is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes, asthma and heart disease.  It is suspected that this is contributing to the increase in maternal deaths in the US (Sep 2016).  Obesity is a complex condition best viewed as representing many different diseases, which is affected by the: Amount of brown adipose tissue (Oct 2016), Asprosin signalling by white adipose tissue (Nov 2016), Genetic alleles including 25 which guarantee an obese outcome, side effects of some pharmaceuticals for: Psychiatric disorders, Diabetes, Seizure, Hypertension, Auto-immunity; Acute diseases: Hypothyroidism, Cushing's syndrome, Hypothalamus disorders; State of the gut microbiome.  Infections, but not antibiotics, appear associated with childhood obesity (Nov 2016). 
  mechanism outlined by research on lipodystrophy is a rare genetic disorder, characterized by an abnormal lack of fatty tissue but the symptoms of obesity.  It results in reduced production of leptin. 
  (Jul 2016). 
  
• Irisin is a hormone which stimulates white adipose (fat) tissue to turn brown.  Irisin is created in working muscles in mice.  After entering the bloodstream it migrates to other tissues, in particular adipose cells where it signals a pathway that promotes UCP1 generation and causes some of the white adipose cells to turn brown.  Brown adipose: Burns calories, Controls insulin and blood sugar; and reduces the risk of type-2-diabetes.   Irisin signals white adipose stem cells to become bone cells.  Irisin has no apparent effect on brown adipose cells.  When irisin was injected into mice being fed a high fat, high calorie diet it inhibited them becoming obese. 
  may explain why exercise limits obesity (Oct 2016).  
• 'Thin gene' FBN1 is a gene which encodes fibrillin and in white adipose tissue the hormone asprosin. 
  asprosin is a protein based hormone produced in white adipose tissue that signals the brain and liver to release glucose into the blood stream.  It is encoded by the FBN1 gene.  cAMP is the second messenger in the signalling network. 
  signalling, is an emergent capability which is used by cooperating agents to support coordination & rival agents to support control and dominance.  In eukaryotic cells signalling is used extensively.  A signal interacts with the exposed region of a receptor molecule inducing it to change shape to an activated form.  Chains of enzymes interact with the activated receptor relaying, amplifying and responding to the signal to change the state of the cell.  Many of the signalling pathways pass through the nuclear membrane and interact with the DNA to change its state.  Enzymes sensitive to the changes induced in the DNA then start to operate generating actions including sending further signals.  Cell signalling is reviewed by Helmreich.  Signalling is a fundamental aspect of CAS theory and is discussed from the abstract CAS perspective in signals and sensors.  In AWF the eukaryotic signalling architecture has been abstracted in a codelet based implementation.  To be credible signals must be hard to fake.  To be effective they must be easily detected by the target recipient.  To be efficient they are low cost to produce and destroy. 
  viewed as an experimental probe for obesity is an addictive disorder where the brain is induced to require more eating, often because of limits to the number of fat cells available to report satiation (Jul 2016).  Brain images of drug-addicted people and obese people have found similar changes in the brain.  Obese people's reward network tends to be less responsive to dopamine and have a lower density of dopamine receptors.  Obesity spreads like a virus through a social network with a 171% likelihood that a friend of someone who becomes obese will also become so.  Obesity is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes, asthma and heart disease.  It is suspected that this is contributing to the increase in maternal deaths in the US (Sep 2016).  Obesity is a complex condition best viewed as representing many different diseases, which is affected by the: Amount of brown adipose tissue (Oct 2016), Asprosin signalling by white adipose tissue (Nov 2016), Genetic alleles including 25 which guarantee an obese outcome, side effects of some pharmaceuticals for: Psychiatric disorders, Diabetes, Seizure, Hypertension, Auto-immunity; Acute diseases: Hypothyroidism, Cushing's syndrome, Hypothalamus disorders; State of the gut microbiome.  Infections, but not antibiotics, appear associated with childhood obesity (Nov 2016). 
  by Atul Chopra (Nov 2016)
• Poor application of statistics in prior trials results in misdiagnosis of Blacks / minorities (Aug 2016). 
• Personalized medicine is a medical strategy where decisions, practices, and products are tailored to the individual patient.  Research is looking at the impact of providing potentially deleterious genomic testing information to people: The REVEAL study found no increased anxiety induced by hearing that one's genome implied increased risk of developing late onset Alzheimer's disease.  The take-up of personalized medicine benefits from the focus on genomics, enabled by next generation sequencing of DNA, and detailed by the NIH director Francis Collins and includes:
  • NCCN intensive cell therapies
    
  • Direct to consumer genomic testing
    
  • Direct to consumer diagnostics
    
  • Pharmacogenomics tailored drug treatments reducing the risk and cost of adverse drug reactions.   
  & immunotherapy is indirect treatment of disease by altering the immune system.  Targeted diseases include: cancers -- immuno-oncology, organ transplants. 
  clinical trials are constrained by: Limited patient base argue: Yale CC, MS-KCC, Genentech; Companies with me-too products requesting trials -- a situation companies with F.D.A. Food and Drug Administration.   approval: Merck; are happy to see.  Targeted therapies: GSK, Pfizer, Loxo Oncology; have even less potential patients which is a concern at Fred Hutchinson (Aug 2017)
  
• NIH is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.   allows stem cell is a biological cell which is partly or wholly undifferentiated.  A totipotent cell can generate a complete embryo and placenta.  Embryos include pluripotent cells which can generate any tissue in the body.  Adult humans' cells have turned off this ability but still include multipotent stem cells that differentiate into multiple cell types.   Typically a cell's local environment will have the signals required for it to obtain context and differentiate appropriately.  This will include both the external environment and the internal state of the cell which has replicated from a parent and obtained its epi-genetic state.   So introduction of undifferentiated stem cells into an injured area is not likely to have either aspect of the environment suitable.  Consequently development is aiming to encourage differentiation to progenitor cells for the damaged region.  This requires delivering the cells to the appropriate part of the body.  To avoid rejection by the immune system techniques aim to use cell lines developed from the patient's cells.  The techniques to generate these cell lines include: SCNT, iPS.  Possible mechanisms of stem cell therapy are: Generation of new differentiated cells, Stimulation of growth of new blood vessels to repopulate damaged regions, Secretion of growth factors, Treatment of diabetes (1 and 2) with addition of pancreatic cells, Assistance of other mechanisms; research to grow human parts in animals (Aug 2016).
  
• Watson supported genomics combines recombinant DNA editing with tools: CRISPR; DNA next generation sequencing and bioinformatics  to sequence, assemble and analyse genomes.   for oncologists with: Quest (Oct 2016), MS-KCC, Broad Institute;
• Fred Hutchinson's Dr. Radich announces paper card can support central diagnosis of CML is chronic myelogenous leukemia.  It is a leukemia characterized by the unregulated growth of myeloid cells in the bone marrow.  The growth is encouraged by the cellular signalling system (gene change that generates a faulty tyrosine kinase) being locked on.  Visual methods allowed Dr. Janet Rowley's team to recognize that most CML includes the Philadelphia chromosome.  It encodes the chimeric always on tyrosine kinase protein seen only in CML.  Targeted treatments such as Gleevec block the pathway for the tyrosine kinase. 
  from dried blood, for Max Foundation advanced drug treatment matching (Nov 2016)
  
• Genomics combines recombinant DNA editing with tools: CRISPR; DNA next generation sequencing and bioinformatics  to sequence, assemble and analyse genomes.  
  
• Gene editing with CRISPR is clustered replicating interspersed silent palindromic repeats; a technique for exact targeting, cutting and editing of DNA based on leveraging bacterial enzymatic defenses against viruses generalized to any DNA sequence in a prokaryotic or eukaryotic cell.  It was identified during studies of a bacterial adaptive immune system.  In that system bacterial proteins grab parts of a virus that has infected them and record it within the palindromic structures that mark an array of inserted viral DNA used as a log persisted over generations.  If a new infection occurs the viral DNA is compared with the sequences and if a match exists the CAS proteins break up the viral DNA initiating its destruction.  This bacterial system was then updated and repurposed by the researchers to support targeted genetic engineering.  As explained by Dr. Doudna, the CRISPR proteins and the 20 nucleotide RNA template migrate into the nucleus where they rapidly target DNA which complements the RNA template and the Cas9 enzyme performs the edits.  Being a bacterial system CRISPR Cas9 does not target eukaryotic heterochromatic DNA well.  It is not fully understood how they find the target sequence so quickly.  It has been shown that Cas9 will bind to sites with a 5-8 base match but then it releases rapidly without cutting.  To cut, Cas9 has to reconfigure, which does not occur in the mismatch situations.   may allow leverage of pig organs in human transplants (Oct 2015) once the delivery mechanism is completed.  Ligandal has an interesting approach described by founder Andre Watson (May 2016). 
  
• Novartis & University of Cambridge researchers find P53 is a tumor suppressor which improves the specificity of transcription's DNA binding and promotes the transcriptional activity of E2F.  P53's activity is controlled by phosphorylation by cyclin Cdk complexes allowing indirect control of the cell cycle.  Among the many genes controlled by p53 are cyclin genes, genes for an inhibitor of cyclin-dependent kinases (Cdk), and the bax gene, which promotes apoptosis.  p53 can thus promote cell proliferation.  It can drive cells into apoptosis.  But it can also stop cell proliferation by arresting the cell cycle.  Normally there is a dynamic balance between proliferation of cells and their death.  In cancer proliferation may become unregulated due to oncogenic mutations or over expression of key regulatory signalling G proteins such as Ras.  Mutations of the p53 suppressor gene are the most frequent suppressor gene mutations in human cancers.  Elephants like humans, have a relatively low buildup of cancer with age.  Elephant's cells have twenty copies of p53 gene pairs which ensure cells with damaged DNA go into apoptosis blocking cancer onset.  P53 has been shown to be involved in irregular brain cell activity in epilepsy and ASD. 
  blocks Crispr is clustered replicating interspersed silent palindromic repeats; a technique for exact targeting, cutting and editing of DNA based on leveraging bacterial enzymatic defenses against viruses generalized to any DNA sequence in a prokaryotic or eukaryotic cell.  It was identified during studies of a bacterial adaptive immune system.  In that system bacterial proteins grab parts of a virus that has infected them and record it within the palindromic structures that mark an array of inserted viral DNA used as a log persisted over generations.  If a new infection occurs the viral DNA is compared with the sequences and if a match exists the CAS proteins break up the viral DNA initiating its destruction.  This bacterial system was then updated and repurposed by the researchers to support targeted genetic engineering.  As explained by Dr. Doudna, the CRISPR proteins and the 20 nucleotide RNA template migrate into the nucleus where they rapidly target DNA which complements the RNA template and the Cas9 enzyme performs the edits.  Being a bacterial system CRISPR Cas9 does not target eukaryotic heterochromatic DNA well.  It is not fully understood how they find the target sequence so quickly.  It has been shown that Cas9 will bind to sites with a 5-8 base match but then it releases rapidly without cutting.  To cut, Cas9 has to reconfigure, which does not occur in the mismatch situations.   action, detecting DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used.   changes and blocking DNA synthesis and invoking apoptosis, programmed cell death is a signal initiated DNA controlled process which results in eukaryotic cells self-destructing.  .  Gene editing companies: Crispr therapeutics, Intellia Therapeutics, Editas Medicine; take a beating (Jun 2018)
  
• HGP is the human genome project an international research project to determine the sequence of DNA base pairs of humans and identify and map physically and functionally all the genes in the human genome.  The HapMap project proved very helpful for discovering the SNPs. 
  2: The human genome synthesis project (May 2016)
  
• Juno Immuno-oncology uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
  • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
    
  • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
    
  • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
    
  • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
    
  CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers (Aug 2016, Jul 2017, Oct 2017, Nov 2017).  But there are severe side effects.  -T trial for adult ALL is acute lymphocytic/lymphoblastic leukemia.  The cancer starts in the lymphocytes of the bone marrow.  Too many lymphocytes are produced instead of mature white blood cells.  In 2010 combination chemotherapy, including 6-mercaptopurine, cures 85 to 90% of children suffering from ALL.   suspended after deaths (Jul 2016)
• BMS checkpoint inhibitors release the immune system's checkpoints: PD-1, CTLA-4; on attacking host cells: by 1) stopping T-cell division and 2) reducing their life spans.  They are used in immuno-oncology where, in 2016: They are approved for treatment of: Advanced melanoma, HL, lung, kidney, liver cancer; They have a general success rate of 20 - 40% and higher for melanoma.   Checkpoint inhibitors work best for tumors that have many mutations: melanomas, lung and bladder cancers.  They are enhanced by adjunct treatments that kill tumor cells generating debris to stimulate the immune system.  The drugs include: ipilimumab (CTLA-4 inhbition), nivolumab, pembrolizumab, atezolizumab (PD-1 inhibitors);  They are costly and often have high copayments.  They cause auto-immune side effects including inflammation, rheumatoid arthritis and damage to glands: Adrenal, Thyroid, Pituitary.  Powerful steroids such as prednisone can help reduce the inflammation.  Damaged glands require sustained hormone treatment.  Checkpoint inhibitor research is funded by the CRI.  cause heart damage in rare cases Vanderbilt cardio-oncology/Brigham & Women's find (Nov 2016)
  
• Active surveillance is an approach to early-stage prostate cancer which replaces treatment, such as surgery or radiation, with monitoring to ensure the cancers aren't growing rapidly.  It started to be used in about 2000 and so will take time to build a predictive history of the success of the regimen (10 year longitudinal study results Sep 2016).  Active surveillance treatements include: Oncotype DX, PSA, STHLM3; of prostate cancer is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  Research in mice may explain a link between obesity and prostate cancer (Jan 2018).  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
  • Sarcomas
  • Small cell carcinomas
  • Neuroendocrine tumors
  • Transitional cell carcinomas
  with Oncotype DX (Dec 2015)
  
• longitudinal study shows relative merits of different early prostate cancer treatments (Sep 2016)
  
• Aging analyzed by Salk Institute's Belmonte & Ocampo modelling tissue regeneration via epigenetic represent state surfaces within cells and eggs which can be operationally modified so as to provide a heritable structure.  DNA, histones and other stable structures provide surfaces where these states may be setup.  Egg carriers are in a particularly powerful position to induce epi-genetic changes.  Sapolsky notes [childhood] events which persistently alter brain structure and behavior via epi-genetic mechanisms including: pair-bonding in prairie voles, as they first mate, is supported by changes in oxytocin & vasopressin receptor gene regulation in the nucleus accumbens. 
  state resetting (Dec 2016)
• Octopuses and aging (Dec 2016)
• Calico aging process researchers, Kenyon & Bohnert, identify sperm signalled, is an emergent capability which is used by cooperating agents to support coordination & rival agents to support control and dominance.  In eukaryotic cells signalling is used extensively.  A signal interacts with the exposed region of a receptor molecule inducing it to change shape to an activated form.  Chains of enzymes interact with the activated receptor relaying, amplifying and responding to the signal to change the state of the cell.  Many of the signalling pathways pass through the nuclear membrane and interact with the DNA to change its state.  Enzymes sensitive to the changes induced in the DNA then start to operate generating actions including sending further signals.  Cell signalling is reviewed by Helmreich.  Signalling is a fundamental aspect of CAS theory and is discussed from the abstract CAS perspective in signals and sensors.  In AWF the eukaryotic signalling architecture has been abstracted in a codelet based implementation.  To be credible signals must be hard to fake.  To be effective they must be easily detected by the target recipient.  To be efficient they are low cost to produce and destroy. 
  oocyte protein repair processes (Nov 2017)
  
• Adult survivors of deadly childhood disease mutations found in genomic database search (Apr 2016).  
• Rare gene mutation of ANGPTL3 is angiopoietin-like 3, a protein encoded by the ANGPTL3 gene, that participates in angiogenesis in the liver.  The preprotein is proteolytically processed into active proteins which inhibit triglyceride metabolism.  Gene knockouts result in reduced plasma lipid concentrations. 
  that stops inhibition of triglyceride metabolism in angiogenesis is the formation of new blood vessels from existing vessels.  It is important in growth, development and wound healing.  To become malignant many tumors stimulate angiogenesis. 
  found associated with reduced CVD is cardiovascular disease which refers to:
  • Conditions where narrowed and blocked blood vessels result in angina, hypertension, CHD and heart attacks and hemorrhagic/ischemic strokes.  Mutations of the gene PCSK9 have been implicated in cardiovascular disease.  Rare families with dominant inheritence of the mutations have an overactive protein, very high levels of blood cholesterol and cardiac disease. Other rare PCSK9 mutations result in an 88% reduced risk from heart disease.  Inflammation is associated with cardiovascular disease (Aug 2017). 
    
  .  Prompts medical studies: Massachusetts General Hospital, University of Pennsylvania, Washington University; & commercial research & development: Regeneron ANGPTL3 drug, Ionis; for blockbuster drug (May 2017)
• Atopic dermatitis, is also called eczema is a long lasting inflammation of the skin.  It can be successfully treated with dupilumab.   (Eczema) biologic are drugs made in living cells.  Typically they are proteins developed using genetic engineering to develop the cellular host, and to customize animal source, DNA to produce human target proteins.  Such biologics partially solve the problem of previous protein sources, extracted from animals or human sources, of contamination and immune responses.  The strategy is very effective for blood transported proteins such as antibodies (MABs), hormones and blood factors.  But intra-cellular proteins still demand delivery and accurate cell targeting.  This creates analogous problems to those of gene therapy. 
  MAB as a terminator in medication names indicates the drug is a monoclonal antibody biologic.   drug treatment dupilumab is a monoclonal antibody which blocks two immune system pathways: interleukin 4 and interleukin 13; that are over produced in atopic dermatitis, by binding to the alpha subunit of the interleukin-4 receptor.  It was developed by Regeneron and marketed as Dupixent.   (Dupixent) has successful trials (Oct 2016). 
  
• Genetic traits show how to effectively treat Brain tumors (Jun 2015)
• Gates Foundation funds Dr. Stephen Long to Genetically engineer photosynthesis to improve plant yields with Syngenta access (Nov 2016). 
• CHIP is:
  
  • The Children's Health Insurance Program started in 1997 as part of the BBA as SCHIP.  It provides health insurance coverage for children in families with income below 200 percent of the poverty line.  The coverage is focused on care specialized for children including: developmental delays, chronic conditions including asthma and obesity.  CHIP's funding must be iteratively re-authorized by Congress.  CHIP is financed federally, but states must enroll eligible children.  In many states one agency administers CHIP and Medicaid.  CHIP is leveraged by families that have employer based insurance with costly premiums, so the families only cover the adults.  
  • Clonal Hematopoiesis of Indeterminate Potential, where stem cells develop a somatic mutation cluster pair often found in leukemia, which is expressed in white blood cells they produce.  The mutation clusters give these stem cells a competitive advantage and they accumulate over time.  The white blood cells form inflammatory plaques.  CHIP increases with age, increasing the risk of dying, of clot fragment induced heart attacks and stroke, over the subsequent 10 years by 54%
  mechanism identified: somatic, Schematic structures which are used to support the operation of the agent.  They are modified as the agent's state changes unlike the germ-line schemata.   mutated stem cells is a biological cell which is partly or wholly undifferentiated.  A totipotent cell can generate a complete embryo and placenta.  Embryos include pluripotent cells which can generate any tissue in the body.  Adult humans' cells have turned off this ability but still include multipotent stem cells that differentiate into multiple cell types.   Typically a cell's local environment will have the signals required for it to obtain context and differentiate appropriately.  This will include both the external environment and the internal state of the cell which has replicated from a parent and obtained its epi-genetic state.   So introduction of undifferentiated stem cells into an injured area is not likely to have either aspect of the environment suitable.  Consequently development is aiming to encourage differentiation to progenitor cells for the damaged region.  This requires delivering the cells to the appropriate part of the body.  To avoid rejection by the immune system techniques aim to use cell lines developed from the patient's cells.  The techniques to generate these cell lines include: SCNT, iPS.  Possible mechanisms of stem cell therapy are: Generation of new differentiated cells, Stimulation of growth of new blood vessels to repopulate damaged regions, Secretion of growth factors, Treatment of diabetes (1 and 2) with addition of pancreatic cells, Assistance of other mechanisms;, with certain leukemia is a group of cancers of blood forming tissues: bone marrow, lymphatic network; where abnormal white blood cells are generated.  One type of leukemia is induced when TAD boundaries near the TAL1 gene fail allowing promotors from across the TAD border to distort the operation of the TAL transcription factor.  Mutation clusters common in leukemia have been identified in CHIP. 
  mutations, accumulate in bone marrow and generate white blood cells that are highly inflammatory; encouraging: arthritis, clot formation or coagulation is formation of a clot:
  • Platlets become activated, adhere and aggregate supported by
  • Fibrin polymerization, deposition and maturation.  
  and collapse resulting in high incidence of heart attack is an AMI. It can induce cardiac arrest.  Blocking the formation of clots with platelet aggregation inhibitors, can help with treating and avoiding AMI.  Risk factors include: taking NSAID pain killers (May 2017).  There is uncertainty about why AMI occur.  Alternative hypotheses include:
  
  • Plaques started to gather in the coronary arteries and grew until no blood flow was possible.  If this is true it makes sense to preventatively treat the buildup with angioplasty. 
    
  • Plaques form anywhere in the body due to atherosclerosis and then break up and get lodged in the coronary artery and start to clot.  If this is true it makes sense to preventatively limit the buildup of plaques with drugs like statins or PCSK9 inhibitors. 
    
  and stroke is when brain cells are deprived of oxygen and begin to die.  750,000 patients a year suffer strokes in the US.  85% of those strokes are caused by clots.  There are two structural types: Ischemic and hemorrhagic.  Thrombectomy has been found to be a highly effective treatment for some stroke situations (Jan 2018). 
  ; Dana-Farber's Ebert, Broad Institute/Massachusetts General's Kathiresan conclude from Big Data encompasses the IT systems and processes necessary to do population based data collection, management and analysis.  The very low cost, robust, data storage organized by infrastructure: HADOOP; allows digital data to be stored en mass.  Data scientists then apply assumptions about the world to the data, analogous to evolved mechanisms in vision, in the form of algorithms: Precision medicine, Protein folding modeling (Feb 2019) assumes coevolutionary methods can be applied to identify contact points in a protein's tertiary structure.  Rather than depending on averages, analysis at Verisk drills down to specifics and then highlights modeling problems by identifying the underlying CAS.  For the analysis to be useful it requires a hierarchy of supporting BI infrastructure:
  • Analytics utilization and integration delivered via SaaS and the Cloud to cope with the silos and data intensive nature. 
    
  • Analytics tools (BI) for PHM will be hard to develop.  
  • Complex data models must include clinical aspects of the patient specific data, including disease state population wide.  
  • A key aspect is providing clear signals about the nature of the data using data visualization. 
    
  • Data communication with the ability to exchange and transact.  HIEs and EMPI alliance approaches are all struggling to provide effective exchange. 
    
  • Data labeling and secure access and retreival.  While HIPAA was initially drafted as a secure MPI the index was removed from the legislation leaving the US without such a tool.  Silos imply that the security architecture will need to be robust. 
    
  • Raw data scrubbing, restructuring and standardization.  Even financial data is having to be restandarized shifting from ICD-9 to -10.  The intent is to transform the unstructured data via OCR and NLP to structured records to support the analytics process. 
    
  • Raw data warehousing is distributed across silos including PCP, Hospital system and network, cloud and SaaS for process, clinical and financial data. 
    
  • Data collection from the patient's proximate environment as well as provider CPOE, EHRs, workflow and process infrastructure.  The integration of the EHR into a big data collection tool is key. 
    
  genomics combines recombinant DNA editing with tools: CRISPR; DNA next generation sequencing and bioinformatics  to sequence, assemble and analyse genomes.   (Jan 2018) 
• Epigenetics represent state surfaces within cells and eggs which can be operationally modified so as to provide a heritable structure.  DNA, histones and other stable structures provide surfaces where these states may be setup.  Egg carriers are in a particularly powerful position to induce epi-genetic changes.  Sapolsky notes [childhood] events which persistently alter brain structure and behavior via epi-genetic mechanisms including: pair-bonding in prairie voles, as they first mate, is supported by changes in oxytocin & vasopressin receptor gene regulation in the nucleus accumbens. 
  
  
• Multi-generational environmental effects may be epigenetic represent state surfaces within cells and eggs which can be operationally modified so as to provide a heritable structure.  DNA, histones and other stable structures provide surfaces where these states may be setup.  Egg carriers are in a particularly powerful position to induce epi-genetic changes.  Sapolsky notes [childhood] events which persistently alter brain structure and behavior via epi-genetic mechanisms including: pair-bonding in prairie voles, as they first mate, is supported by changes in oxytocin & vasopressin receptor gene regulation in the nucleus accumbens. 
  (Dec 2015)
• Aging analyzed by Salk Institute's Belmonte & Ocampo modelling tissue regeneration via epigenetic represent state surfaces within cells and eggs which can be operationally modified so as to provide a heritable structure.  DNA, histones and other stable structures provide surfaces where these states may be setup.  Egg carriers are in a particularly powerful position to induce epi-genetic changes.  Sapolsky notes [childhood] events which persistently alter brain structure and behavior via epi-genetic mechanisms including: pair-bonding in prairie voles, as they first mate, is supported by changes in oxytocin & vasopressin receptor gene regulation in the nucleus accumbens. 
  state resetting (Dec 2016)
• Human genome is divided into TAD is topalogically associating domain, an aspect of the way chromosomes fold up into compact chromatin. In humans there are approximately 2,000 TADs of varying sizes.  TAD borders act as folding instructions and specify rules for genetic operations.  Genetic operations do not normally cross TAD boundaries.  Cohesin and CTCF are found clustered at the TAD borders.  Failure of the TAD borders is associated with cancers of the: colon, esophagus, brain and blood. 
  s.  Failure of the boundaries associated with malformations and cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016). 
  : Leukemia is a group of cancers of blood forming tissues: bone marrow, lymphatic network; where abnormal white blood cells are generated.  One type of leukemia is induced when TAD boundaries near the TAL1 gene fail allowing promotors from across the TAD border to distort the operation of the TAL transcription factor.  Mutation clusters common in leukemia have been identified in CHIP. 
  (Jan 2017)
• Neuroscience deals with the structure, development, chemistry, pharmacology, function and pathology of networks of biological neurons. 
  
  
• Alzheimer's is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and declarative memory and thinking problems (MCI).  Specific cells within the hippocampal circuitry and its gateway, the entorhinal cortex, are damaged.  The amygdala, cerebelum and other areas supporting implicit memory are not impacted during the early stages of the disease.  Grid cell destruction results in a sense of being lost.  The default mode network is disrupted.  Variants include: late-onset sporadic; with risk factors - ApoE4 for late onset Alzheimer's, presenilin, androgen deprivation therapy (Dec 2015), type 2 diabetes.  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation, Neurons of sporadic Alzheimer's sufferers show greater APP gene diversity due to somatic recombination; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form.  These are seen in fMRIs 10 to 15 years prior to detecting memory and thinking changes.  APP deployed in the cell membrane is cut into three parts.  The external part becomes amyloid-beta peptide which aggregates into Amyloid plaques, external to the neurons, if too much is generated or it is not removed fast enough. 
    
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016). 
    
  • Encouraging the garbage collection of amyloid and tau with gamma rhythms stimulation retards Alzheimer's in mice studies (Mar 2019)
    
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • Mutation driven misfolded Tau proteins can form tangles within the cytoplasm of neurons.  The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    
  • The brain becomes inflamed resulting in the killing of many more nerve cells.  The hippocampus disintegrates and the brain loses critical functions and memory loss becomes noticeable. 
    
  as a behavioral disorder (Jul 2016)
• Boston University SOM's Matthew Pase finds sugary drinks tied to rapid brain aging and Alzheimer's is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and declarative memory and thinking problems (MCI).  Specific cells within the hippocampal circuitry and its gateway, the entorhinal cortex, are damaged.  The amygdala, cerebelum and other areas supporting implicit memory are not impacted during the early stages of the disease.  Grid cell destruction results in a sense of being lost.  The default mode network is disrupted.  Variants include: late-onset sporadic; with risk factors - ApoE4 for late onset Alzheimer's, presenilin, androgen deprivation therapy (Dec 2015), type 2 diabetes.  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation, Neurons of sporadic Alzheimer's sufferers show greater APP gene diversity due to somatic recombination; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form.  These are seen in fMRIs 10 to 15 years prior to detecting memory and thinking changes.  APP deployed in the cell membrane is cut into three parts.  The external part becomes amyloid-beta peptide which aggregates into Amyloid plaques, external to the neurons, if too much is generated or it is not removed fast enough. 
    
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016). 
    
  • Encouraging the garbage collection of amyloid and tau with gamma rhythms stimulation retards Alzheimer's in mice studies (Mar 2019)
    
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • Mutation driven misfolded Tau proteins can form tangles within the cytoplasm of neurons.  The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    
  • The brain becomes inflamed resulting in the killing of many more nerve cells.  The hippocampus disintegrates and the brain loses critical functions and memory loss becomes noticeable. 
    
  markers (Apr 2017)
• Mount Sinai Icahn SOM's Dr. Joel Dudley's precision medicine is the integration of molecular research: genomics, proteomics, transcriptomics, metabolomics, cell signalling; and clinical data through a taxonomy based on CAS modeling overlaid on an information commons.  It aims to support treatment of disease and remove the organ and symptom based methodological flaws in the ICD.  Supporters of the D.S.M. note the aggressive shift to precision medicine at the NIMH under Dr. Insel, constrained useful clinical research (Nov 2015). 
  (Big Data encompasses the IT systems and processes necessary to do population based data collection, management and analysis.  The very low cost, robust, data storage organized by infrastructure: HADOOP; allows digital data to be stored en mass.  Data scientists then apply assumptions about the world to the data, analogous to evolved mechanisms in vision, in the form of algorithms: Precision medicine, Protein folding modeling (Feb 2019) assumes coevolutionary methods can be applied to identify contact points in a protein's tertiary structure.  Rather than depending on averages, analysis at Verisk drills down to specifics and then highlights modeling problems by identifying the underlying CAS.  For the analysis to be useful it requires a hierarchy of supporting BI infrastructure:
  • Analytics utilization and integration delivered via SaaS and the Cloud to cope with the silos and data intensive nature. 
    
  • Analytics tools (BI) for PHM will be hard to develop.  
  • Complex data models must include clinical aspects of the patient specific data, including disease state population wide.  
  • A key aspect is providing clear signals about the nature of the data using data visualization. 
    
  • Data communication with the ability to exchange and transact.  HIEs and EMPI alliance approaches are all struggling to provide effective exchange. 
    
  • Data labeling and secure access and retreival.  While HIPAA was initially drafted as a secure MPI the index was removed from the legislation leaving the US without such a tool.  Silos imply that the security architecture will need to be robust. 
    
  • Raw data scrubbing, restructuring and standardization.  Even financial data is having to be restandarized shifting from ICD-9 to -10.  The intent is to transform the unstructured data via OCR and NLP to structured records to support the analytics process. 
    
  • Raw data warehousing is distributed across silos including PCP, Hospital system and network, cloud and SaaS for process, clinical and financial data. 
    
  • Data collection from the patient's proximate environment as well as provider CPOE, EHRs, workflow and process infrastructure.  The integration of the EHR into a big data collection tool is key. 
    
  ) study associates Roseoloviruses is a subset: HHV6 (HHV-6A, HHV-6B), HHV7; of Herpes viruses.  HHV6 typically infects human infants before age two, with symptoms of fever, diarrhea, and a rash known as roseola. 
  : HHV-6A is a double stranded DNA Roseolovirus.  It infects all tested humans and is neuroinflammatory, being seen in diseases such as MS. 
  , HHV7 is a double stranded DNA Roseolovirus. 
  ; with Alzheimer's disease is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and declarative memory and thinking problems (MCI).  Specific cells within the hippocampal circuitry and its gateway, the entorhinal cortex, are damaged.  The amygdala, cerebelum and other areas supporting implicit memory are not impacted during the early stages of the disease.  Grid cell destruction results in a sense of being lost.  The default mode network is disrupted.  Variants include: late-onset sporadic; with risk factors - ApoE4 for late onset Alzheimer's, presenilin, androgen deprivation therapy (Dec 2015), type 2 diabetes.  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation, Neurons of sporadic Alzheimer's sufferers show greater APP gene diversity due to somatic recombination; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form.  These are seen in fMRIs 10 to 15 years prior to detecting memory and thinking changes.  APP deployed in the cell membrane is cut into three parts.  The external part becomes amyloid-beta peptide which aggregates into Amyloid plaques, external to the neurons, if too much is generated or it is not removed fast enough. 
    
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016). 
    
  • Encouraging the garbage collection of amyloid and tau with gamma rhythms stimulation retards Alzheimer's in mice studies (Mar 2019)
    
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • Mutation driven misfolded Tau proteins can form tangles within the cytoplasm of neurons.  The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    
  • The brain becomes inflamed resulting in the killing of many more nerve cells.  The hippocampus disintegrates and the brain loses critical functions and memory loss becomes noticeable. 
    
  , judged by changes in the entorinal cortex is a main limbic association area between the hippocampus and the neocortex, in the medial temporal lobe.  It is a hub for memory and navigation: location awareness is supported by grid cells.  It is the first brain area impacted in Alzheimer's disease. 
  , hippocampus is a part of the medial temporal lobe of the brain involved in the temporary storage or coding of long-term episodic memory.  It includes the dentate gyrus.  Memory formation in the cells of the hippocampus uses the MAP kinase signalling network which is impacted by sleep deprivation.  The hippocampus dependent memory system is directly affected by cholinergic changes throughout the wake-sleep cycle.  Increased acetylcholine during REM sleep promotes information attained during wakefulness to be stored in the hippocampus by suppressing previous excitatory connections while facilitating encoding without interference from previously stored information.  During slow-wave sleep low levels of acetylcholine cause the release of the suppression and allow for spontaneous recovery of hippocampal neurons resulting in memory consolidation.  It was initially associated with memory formation by McGill University's Dr. Brenda Milner, via studies of 'HM' Henry Molaison, whose medial temporal lobes had been surgically destroyed leaving him unable to create new explicit memories.  The size of neurons' dendritic trees expands and contracts over a female rat's ovulatory cycle, with the peak in size and cognitive skills at the estrogen high point.  Adult neurogenesis occurs in the hippocampus (3% of neurons are replaced each month) where the new neurons integrate into preexisting circuits.  It is enhanced by learning, exercise, estrogen, antidepressants, environmental enrichment, and brain injury and inhibited by various stressors explains Sapolsky.  Prolonged stress makes the hippocampus atrophy.  He notes the new neurons are essential for integrating new information into preexisting schemas -- learning that two things you thought were the same are actually different.  Specific cells within the hippocampus and its gateway, the entorhinal cortex, are compromised by Alzheimer's disease.  It directly signals area 25. 
  , promoter enrichments for C2H2 zink finger is a large set of finger like binding domains in mammalian transcription factors with a Cys2-His2 (C2H2) fold group, which can bind in the major groove of DNA. 
  transcription factor are enzymes which associate with a transcription complex to bind to the DNA and control its transcription and hence translation into proteins.  The regulation of DNA transcription and protein synthesis are reviewed by Tsonis.  Transcription factors allow environmental state to become reflected in the control of DNA transcription.  Transcription factors can regulate multiple genes, allowing network effects & multiple transcription factors can regulate a gene allowing sophisticated control processes.  In AWF the transcription, translation and deployment infrastructure of the eukaryotic cell has been abstracted in a codelet based implementation. 
  binding motifs and signalling, is an emergent capability which is used by cooperating agents to support coordination & rival agents to support control and dominance.  In eukaryotic cells signalling is used extensively.  A signal interacts with the exposed region of a receptor molecule inducing it to change shape to an activated form.  Chains of enzymes interact with the activated receptor relaying, amplifying and responding to the signal to change the state of the cell.  Many of the signalling pathways pass through the nuclear membrane and interact with the DNA to change its state.  Enzymes sensitive to the changes induced in the DNA then start to operate generating actions including sending further signals.  Cell signalling is reviewed by Helmreich.  Signalling is a fundamental aspect of CAS theory and is discussed from the abstract CAS perspective in signals and sensors.  In AWF the eukaryotic signalling architecture has been abstracted in a codelet based implementation.  To be credible signals must be hard to fake.  To be effective they must be easily detected by the target recipient.  To be efficient they are low cost to produce and destroy. 
  links with ApoE4 is a gene variant which produces the E4 variant of APOE.  It is a risk-factor for late-onset sporadic Alzheimer's disease.  Being homozygote for E4 does not imply getting Alzheimer's but does increase the risk 20 fold.  ApoE2 may reduce the risk of Alzheimer's.  It appears that ApoE4 differentially affects women.  Apoe4 is known to be broken down into fragments which impare mitochondrial operation.  It also promotes amyloid plaque buildup.  Therapies are being developed based on small molecules which reshape ApoE4 to be more like ApoE3 reducing the breakdown.   
  . It seems likely that after remaining dormant for years the virus is a relatively small capsule containing genetic material which utilizes the cellular infrastructure of its target host to replicate its genetic material and operational proteins.  The relationship with the host is short term, relative to parasites, with the virus entering the host cell, leveraging the host infrastructure to replicate its self massively and then exiting the host cell by rupturing it. 
  activates (stressor is a multi-faceted condition reflecting high cortisol levels.  Dr. Robert Sapolsky's studies of baboons indicate that stress helps build readiness for fight or flight.  As these actions occur the levels of cortisol return to the baseline rate.  A stressor is anything that disrupts the regular homeostatic balance.  The stress response is the array of neural and endocrine changes that occur to respond effectively to the crisis and reestablish homeostasis. 
  
  • The short term response to the stressor
    
  • activates the amygdala which: Stimulates the brain stem resulting in inhibition of the parasympathetic nervous system and activation of the sympathetic nervous system with the hormones epinephrine and norepinephrine deployed around the body, Activates the PVN which generates a cascade resulting in glucocorticoid secretion to: get energy to the muscles with increased blood pressure for a powerful response.  The brain's acuity and cognition are stimulated.  The immune system is stimulated with beta-endorphin and repair activities curtail.  In order for the body to destroy bacteria in wounds, pro-inflammatory cytokines increase blood flow to the area.  The induced inflammation signals the brain to activate the insula and through it the ACC.  But when the stressor is
    
  • long term: loneliness, debt; and no action is necessary, or possible, long term damage ensues.  Damage from such stress may only occur in specific situations: Nuclear families coping with parents moving in.  Sustained stress provides an evolved amplifier of a position of dominance and status.  It is a strategy in female aggression used to limit reproductive competition.  Sustained stress:
    
  • Stops the frontal cortex from ensuring we do the harder thing, instead substituting amplification of the individual's propensity for risk-taking and impairing risk assessment! 
    
  • Activates the integration between the thalamus and amygdala. 
    
  • Acts differently on the amygdala in comparison to the frontal cortex and hippocampus: Stress strengthens the integration between the Amygdala and the hippocampus, making the hippocampus fearful. 
    
  • BLA & BNST respond with increased BDNF levels and expanded dendrites persistently increasing anxiety and fear conditioning. 
    
  • Makes it easier to learn a fear association and to consolidate it into long-term memory.  Sustained stress makes it harder to unlearn fear by making the prefrontal cortex inhibit the BLA from learning to break the fear association and weakening the prefrontal cortex's hold over the amygdala.  And glucocorticoids decrease activation of the medial prefrontal cortex during processing of emotional faces.  Accuracy of assessing emotions from faces suffers.  A terrified rat generating lots of glucocorticoids will cause dendrites in the hippocampus to atrophy but when it generates the same amount from excitement of running on a wheel the dendrites expand.  The activation of the amygdala seems to determine how the hippocampus responds. 
    
  • Depletes the nucleus accumbens of dopamine biasing rats toward social subordination and biasing humans toward depression. 
    
  • Disrupts working memory by amplifying norepinephrine signalling in the prefrontal cortex and amygdala to prefrontal cortex signalling until they become destructive.  It also desynchronizes activation in different frontal lobe regions impacting shifting of attention.  
  • Increases the risk of autoimmune disease (Jan 2017) 
  • During depression, stress inhibits dopamine signalling.  
  • Strategies for stress reduction include: Mindfulness. 
    
  ) & generates an immune has to support and protect an inventory of host cell types, detect and respond to invaders and maintain the symbiont equilibrium within the microbiome.  It detects microbes which have breached the secreted mucus barrier, driving them back and fortifying the barrier.  It culls species within the microbiome that are expanding beyond requirements.  It destroys invaders who make it into the internal transport networks.  As part of its initialization it has immune cells which suppress the main system to allow the microbiome to bootstrap.  The initial microbiome is tailored by the antibodies supplied from the mother's milk while breastfeeding.  The immune system consists of two main parts the older non-adaptive part and the newer adaptive part.  The adaptive part achieves this property by being schematically specified by DNA which is highly variable.  By rapid reproduction the system recombines the DNA variable regions in vast numbers of offspring cells which once they have been shown not to attack the host cell lines are used as templates for interacting with any foreign body (antigen).  When the immune cell's DNA hyper-variable regions are expressed as y-shaped antibody proteins they typically include some receptor like structures which match the surfaces of the typical antigen.  Once the antibody becomes bound to the antigen the immune system cells can destroy the invader. 
  response that stimulates plaques which kill neurons, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
  • Receptive element - dendrites
    
  • Transmitting element - axon and synaptic terminals.  The axon may be myelinated, focusing the signals through synaptic transmission, or unmyelinated - where crosstalk is leveraged. 
  • Highly variable DNA schema using transposons. 
    
  (Jun 2018)
• Alzheimer's is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and declarative memory and thinking problems (MCI).  Specific cells within the hippocampal circuitry and its gateway, the entorhinal cortex, are damaged.  The amygdala, cerebelum and other areas supporting implicit memory are not impacted during the early stages of the disease.  Grid cell destruction results in a sense of being lost.  The default mode network is disrupted.  Variants include: late-onset sporadic; with risk factors - ApoE4 for late onset Alzheimer's, presenilin, androgen deprivation therapy (Dec 2015), type 2 diabetes.  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation, Neurons of sporadic Alzheimer's sufferers show greater APP gene diversity due to somatic recombination; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form.  These are seen in fMRIs 10 to 15 years prior to detecting memory and thinking changes.  APP deployed in the cell membrane is cut into three parts.  The external part becomes amyloid-beta peptide which aggregates into Amyloid plaques, external to the neurons, if too much is generated or it is not removed fast enough. 
    
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016). 
    
  • Encouraging the garbage collection of amyloid and tau with gamma rhythms stimulation retards Alzheimer's in mice studies (Mar 2019)
    
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • Mutation driven misfolded Tau proteins can form tangles within the cytoplasm of neurons.  The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    
  • The brain becomes inflamed resulting in the killing of many more nerve cells.  The hippocampus disintegrates and the brain loses critical functions and memory loss becomes noticeable. 
    
  (May 2014, May 2016)
  
• Obama brain initiative (Sep 2015)
  
• Brain maps (Connectome based Jul 2016)
  
• Syngenta's Paraquat is NN-dimethyl-44-bipyridinium dichloride, a systemic weed killer, used on oranges, coffee and suger cane, manufactured and sold by the Swiss pesticide company Syngenta.  It is banned in the EU, but still allowed to be sold and used in the US.  Drinking even a sip can be lethal.  Recent research by the NIH links paraquat to Parkinson's disease.  The 2011 research found Iowa and North Carolina farmers and family members that handled paraquat or rotenone were 2.5 times more likely to develop Parkinson's disease.  A 2012 study found paraquat increased the likelihood 11 fold for people with certain genetic variations.  The link is disputed by Syngenta. 
  linked by N.I.H. is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.   to Parkinson's disease corresponds to the breakdown of certain interneurons in the brain.  It is not fully understood why this occurs.  Dopamine system neuron breakdown generates the classical symptoms of tremors and rigidity.  In some instances an uncommon LRRK2 gene mutation confers a high risk of Parkinson's disease.  In rare cases Italian and Greek families are impacted in their early forties and fifties resulting from a single letter mutation in alpha-synuclein which alters the alpha-synuclein protein causing degeneration in the substantia nigra, after a build up of Lewy bodies in the neurons.  But poisoning from MPTP has also been shown to destroy dopamine system neurons.  DeLong showed that MPTP poisoning results in overactivity in the subthalamic nucleus.  People who have an appendectomy in their 20s are at lower risk of developing Parkinson's disease.  The Alpha-synuclein protein is known to build up in the appendix in association with changes in the gut microbiome.  This buildup may support the 'flow' of alpha-synuclein from the gut along neurons that route to the brain.  Paraquat has also been linked to Parkinson's disease.  Parkinson's disease does not directly kill many sufferers.  But it impacts swallowing which encourages development of pneumonia through inhaling or aspirating food.  And it undermines balance which can increase the possibility of falls.  Dememtia can also develop.  Treatment with deep-brain stimulation, after surgical implantation of electrodes in the subthalamic nucleus removes the symptoms of Parkinson's disease in some patients. 
  .  E.P.A. is the Environmental Protection Agency of the Federal government. 
  considers restrictions in US is the United States of America.   (Dec 2016)
• Syngenta's Eric Fyrwald responds to the NYT December & January articles (Jan 2017)
• Temporal Interference is a technique for targeting electrical stimulation at neurons within a brain by superposing two very high frequency electronic fields which only interfere constructively at the target neuron and at a low enough frequency to have an effect on the neuron. 
  technique developed by MIT is Massachusetts Institute of Technology.   Picower Institute of Learning's Tsai shows promise in mice (Jun 2017)
  
• Brigham & Women's finds mothers' sounds needed for babies' brains to grow (Feb 2015)
• McGurk effect is an illusion, described by Harry McGurk and John MacDonald, where a video shows a person speaking, and saying 'da da da da'.  But on closing your eyes you hear what is being said as 'ba ba ba'.   The illusion is generated by setting up conflicting signals: The mouth is moving to say 'ga'; while the sound is 'ba'.  the brain resolves the conflict into a single intermediate percept 'da'.  The illusion demonstrates how late in the processing chain and reconstructed our conscious experience is.  Imaging indicates the illusion is constructud in the frontal lobes and or superior temporal sulcus and is then sent back to the early sensory regions. 
  (Feb 2017)
• Memories in the brain includes functionally different types: Declarative, or explicit, (episodic and semantic), Implicit, Procedural, Spatial, Temporal, Verbal; Hebb suggested that glutamate receptive neurons learn by (NMDA channel based) synaptic strengthening: short term memory.  This was shown to happen for explicit memory formation in the hippocampus.  This strengthening is sustained by subsequent LTP.  The non-real-time learning and planning processes operate through consciousness using the working memory structures, and then via sleep, the salient ones are consolidated while the rest are destroyed and garbage collected.   actively destroyed in fruit flies using Rac is a class of small monomeric GTP-binding proteins including Rac1 and Rac2.  Rac GTPases are implicated in memory removal (Feb 2010) and control of cytoskeleton assembly. 
  (Feb 2010) 
• Purpose of sleep facilitates salient memory formation and removal of non-salient memories.  The five different stages of the nightly sleep cycles support different aspects of memory formation.  The sleep stages follow Pre-sleep and include: Stage one characterized by light sleep and lasting 10 minutes, Stage two where theta waves and sleep spindles occur, Stage three and Stage four together represent deep slow-wave sleep (SWS) with delta waves, Stage five is REM sleep; sleep cycles last between 90-110 minutes each and as the night progresses SWS times reduce and REM times increase.   Sleep includes the operation of synapse synthesis and maintenance through DNA based activity including membrane trafficking, synaptic vesicle recycling, myelin structural protein formation and cholesterol and protein synthesis.  Sleep also controls inflammation (Jan 2019)  Sleep deprivation undermines the thalamus & nucleus accumbens management of pain. 
  is to forget.  The mechanism includes removing synapses, a neuron structure which provides a junction with other neurons.  It generates signal molecules, either excitatory or inhibitory, which are kept in vesicles until the synapse is stimulated when the signal molecules are released across the synaptic cleft from the neuron.  The provisioning of synapses is under genetic control and is part of long term memory formation as identified by Eric Kandel.  Modulation signals (from slow receptors) initiate the synaptic strengthening which occurs in memory. 
  .  Wisconsin-Madison's de Vivo supports synaptic homeostasis is Tonini & Cirelli's hypothesis that proposes sleep-wake cycles cause generalized synaptic weakening which leads to down-selection of weak synapses.  Pruning does not strike every synapse.  They argue that well established memories are left intact. 
  .  Johns Hopkins's Diering shows Homer1A is the product of the Homer1 gene short form splice.  The HomeriA has an EVH1 domain which competes with the long splice forms such as Homer1B and Homer1C, uncoupling mGluR signalling and shrinking dendritic spline structures.  Homer1a is expressed by neuronal activity.   is shipped to synapses where in sleep it pairs back synapses (Feb 2017). 
• Northeastern & Mass. General hospital psychologist Feldman Barrett's fMRI is functional magnetic resonance imaging.  Seiji Ogawa leveraged the coupling of neuronal circuit activity and blood flow through the associated glial cells to build a 3 dimensional picture of brain cell activity.  As haemoglobin gives up its oxygen to support the neural activity it becomes magnetic and acts as a signal detected by the fMRI.  fMRI easily visualizes the state of activity in the living human brain at millimeter resolution, up to several times a second but it cannot track the time course of neural firing so it is augmented with EEG.   studies found superagers' is a older person who remains as mentally agile: in terms of memory and attention; as a twenty year old according to neurologist Marsel Mesulam.  In fMRI analyses superagers are found to retain well developed 'emotional' brain regions: midcingulate cortex, anterior insula; which are major hubs for general communication throughout the brain.  In comparison in other older people these regions have thined and their mental responses are relatively poor.  The superagers maintain the communication networks by regularly performing hard tiring and taxing mental or physical work (Jan 2016). 
  hard mental work sustains their major neural communication networks (Jan 2017)
• Cohen & Andersen's review common reference frames is a coordinate system (set of axis) centered on a particular aspect of the situation that describes the location of an object.  The brain supports many frames of reference including for vision (2009), hearing & movement planning (Jul 2002).  Auditory stimuli are initially coded in a head-centered reference frame.  The motor system codes actions in reference frames that depend on motor effectors.  Eye movements are codes in a reference frame that depends on the difference between current and desired arm position.  It is often necessary to transform the location representation of the sensory stimulus into a representation appropriate for the motor act.  An eye-centered reference frame depends on the location of the eye in the head.  A retinotopic reference frame depends on the retinal location that is activated by a visual stimulus.  Double-saccade tasks show how the location of the second visual target is coded relative to current and desired eye position (eye-centered).  
  for movement plans in the posterior parietal cortex of the cerebral cortex is at the back of the brain divided into two.  It associates sensory signals of various modalities with:
  
  • Details about the location of the body: supramarginal gyrus; and
    
  • Models interpreting touch, visual signals, language and mathematics. 
    
  (Jul 2002)
• Columbia psychiatrist hopes Dr. Joshua Gordon will reduce Thomas Insel's shift of funding at the NIMH is the National Institute of Mental Health. 
  to neuroscience deals with the structure, development, chemistry, pharmacology, function and pathology of networks of biological neurons. 
  (Oct 2016)
• Working memory is a dominant function of the dorsolateral prefrontal cortex and the areas it connects with.  Prefrontal neurons implement an active memory continuing to fire after the signal is gone for potentially dozens of seconds from the inferior temporal cortex (multi-sensory integration area) and lower level sensory neurons characterized by Hubel & Weisel, while the short-term memory task continues.  If the prefrontal cortex gets distracted the memory is lost from consciousness.  Earl Miller argues the prefrontal cortex implements the rules that decide which working memory neurons will fire (Spring 2017).  Working memory develops from childhood through the late teens, and depends on pyramidal neurons within the PFC. 
  is a prefrontal cortex (PFC) is
  
  • The front part of the frontal lobe of the cerebral cortex.  It evolved most recently.  During adolescence when the PFC is still deploying, older brain agents provide equivalent strategies: ventral striatum.  The PFC has been implicated in planning, working memory: dorsolateral; decision making: Orbitofrontal cortex; and social behavior.  It regulates feelings.  Different PFC circuits track internal reward driven strategies and externally signalled advice.  The PFC chooses between conflicting options, letting go or restraint, especially between cognition and emotions.  It imposes an overarching strategy for managing working memory.  It is essential for thinking about multiple items with different labels.  It includes neurons that are interested in particular sub-categories: Dog, Cat.  Once it has made a decision it signals the rest of the frontal lobe just behind it.  Glucocorticoids decrease excitability of the PFC.  
  brain wave are repetitive firing of sets of neurons.  They are seen throughout the central nervous system. 
  based phenomena argues MIT is Massachusetts Institute of Technology.   neuroscientist Earl Miller (Spring 2017).  
• Epidemiology studies patterns, causes and effects of health and disease in populations.  It identifies risk factors for disease and focuses on preventative health care.  Being observational it suffers from a core limitation.  It can only show association, not causation.  It can suggest hypothesis but it can not disprove them.  
  
• Understanding of effects of diet
  
• Boston University & Tufts study shows fast-food is defined by Nhanes as any item obtained from a fast-food/pizza establishment.  Gordon discusses the development of fast-food restaurants in the US.  Michael Pollan compares the industrial processed food supply chain with organic and hunter gatherer equivalents. 
  at: Arby's, Burger King, Carl's Jr., Dairy Queen, Hardees, Jack in the Box, KFC, Long John Silver's, McDonald's, Wendy's; has got bigger and saltier over the last 20 years (Mar 2019)
• Vanderbilt University Medical Center's Titze reports on salt's effects on the body (May 2017)
• Salt's impact on wellbeing indicates the state of an organism is within homeostatic balance.  It is described by Angus Deaton as all the things that are good for a person:
  • Material wellbeing includes income and wealth and its measures: GDP, personal income and consumption.  It can be traded for goods and services which recapture time.  Material wellbeing depends on investments in:
  • Infrastructure
    
  • Physical
    
  • Property rights, contracts and dispute resolution
    
  • People and their education
    
  • Capturing of basic knowledge via science.  
  • Engineering to turn science into goods and services and then continuously improve them. 
    
  • Physical and psychological wellbeing are represented by health and happiness; and education and the ability to participate in civil society through democracy and the rule of law.  University of Wisconsin's Ryff focuses on Aristotle's flourishing.  Life expectancy as a measure of population health, highly weights reductions in child mortality. 
    
  , hypertension is high blood pressure.  It is directly associated with death rate due to pressure induced damage to the left ventricle and in general to cardiovascular diseases.  Treated with antihypertensives: Diuretics, Calcium channel blockers, Angiotensin receptor blockers or Beta blockers.   leading to: kidney failure is end-stage renal disease.  This is the last stage of CKD.  It is associated with adolescents who have hypertension.  There are more than 200,000 cases a year in the U.S.  Richard Nixon encouraged and signed Social Security amendments that provided Medicare for anyone suffering from ESRD.  There are two main treatment strategies:
  1. Kidney transplants allow recovery from the disease but are limited by the availability of matching donated kidneys, enabled by UNOS, and the patient's awareness of the option to have a transplant.  
  2. Kidney dialysis performed at a dialysis center. 
     
  , heart attack is an AMI. It can induce cardiac arrest.  Blocking the formation of clots with platelet aggregation inhibitors, can help with treating and avoiding AMI.  Risk factors include: taking NSAID pain killers (May 2017).  There is uncertainty about why AMI occur.  Alternative hypotheses include:
  
  • Plaques started to gather in the coronary arteries and grew until no blood flow was possible.  If this is true it makes sense to preventatively treat the buildup with angioplasty. 
    
  • Plaques form anywhere in the body due to atherosclerosis and then break up and get lodged in the coronary artery and start to clot.  If this is true it makes sense to preventatively limit the buildup of plaques with drugs like statins or PCSK9 inhibitors. 
    
  , strokes is when brain cells are deprived of oxygen and begin to die.  750,000 patients a year suffer strokes in the US.  85% of those strokes are caused by clots.  There are two structural types: Ischemic and hemorrhagic.  Thrombectomy has been found to be a highly effective treatment for some stroke situations (Jan 2018). 
  ; Food processors: General Mills, Pepperidge Farm, Sara Lee, Oroweat; respond effectively (Nov 2017)
• Study associates hypertension is high blood pressure.  It is directly associated with death rate due to pressure induced damage to the left ventricle and in general to cardiovascular diseases.  Treated with antihypertensives: Diuretics, Calcium channel blockers, Angiotensin receptor blockers or Beta blockers.   with diet not age: Yanomamo is a tribe of contemporary Venezuelan hunter gatherers.  They are still isolated from modern societies (Nov 2018).  They have been a popular model of historic hunter gatherers: discussed in Behave, and in The Origin of Wealth. 
  (are still isolated) and Yekwana (get western food) compared as they age.  Yanomamo average blood pressure 95/63 remains same as they age to 60.  Yekwana 104/66 increases with age to 114/73.  Johns Hopkins's epidemiologist studies patterns, causes and effects of health and disease in populations.  It identifies risk factors for disease and focuses on preventative health care.  Being observational it suffers from a core limitation.  It can only show association, not causation.  It can suggest hypothesis but it can not disprove them.   Noel Mueller concludes cutting salt intake in half will prevent 15 million cases of US is the United States of America.   hypertension (Nov 2018)
• Harvard study concludes cocoa associated epidemiologically studies patterns, causes and effects of health and disease in populations.  It identifies risk factors for disease and focuses on preventative health care.  Being observational it suffers from a core limitation.  It can only show association, not causation.  It can suggest hypothesis but it can not disprove them.   with reduced risk, is an assessment of the likelihood of an independent problem occurring.  It can be assigned an accurate probability since it is independent of other variables in the system.  As such it is different from uncertainty. 
  of AF is atrial fibrillation, an abnormal heart rhythm: rapid, irregular.  It:
  • Can lead to blood clots, stroke, CHF, dementia and other complications.  
  • Fibrillations allow blood to pool in the heart chambers and form small clots which can then lodge in small arteries and block blood flow. 
    
  • Has become much more common being induced by endemic diseases: hypertension, obesity and type-2-diabetes. 
    
  • Cocoa reduces risk of AF (May 2017)
  • Treatments include: digoxin;
    
  (May 2017)
• NIH is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.   funded Harvard School of Public Health study concludes eating nuts is associated with a lowered risk of heart disease is cardiovascular disease which refers to:
  • Conditions where narrowed and blocked blood vessels result in angina, hypertension, CHD and heart attacks and hemorrhagic/ischemic strokes.  Mutations of the gene PCSK9 have been implicated in cardiovascular disease.  Rare families with dominant inheritence of the mutations have an overactive protein, very high levels of blood cholesterol and cardiac disease. Other rare PCSK9 mutations result in an 88% reduced risk from heart disease.  Inflammation is associated with cardiovascular disease (Aug 2017). 
    
  (Nov 2017)
  
• Swedish researchers found lowered risk, is an assessment of the likelihood of an independent problem occurring.  It can be assigned an accurate probability since it is independent of other variables in the system.  As such it is different from uncertainty. 
  of: heart attack is an AMI. It can induce cardiac arrest.  Blocking the formation of clots with platelet aggregation inhibitors, can help with treating and avoiding AMI.  Risk factors include: taking NSAID pain killers (May 2017).  There is uncertainty about why AMI occur.  Alternative hypotheses include:
  
  • Plaques started to gather in the coronary arteries and grew until no blood flow was possible.  If this is true it makes sense to preventatively treat the buildup with angioplasty. 
    
  • Plaques form anywhere in the body due to atherosclerosis and then break up and get lodged in the coronary artery and start to clot.  If this is true it makes sense to preventatively limit the buildup of plaques with drugs like statins or PCSK9 inhibitors. 
    
  , heart failure is congestive heart failure which occurs when the heart is unable to generate enough blood flow to meet the body's demands.  There are two main types: failure due to left ventricular dysfunction and abnormal diastolic function increasing the stiffness of the left ventricle and decreasing its relaxation.  Heart expansion in CHF distorts the mitral valve which exacerbates the problems.  MitraClip surgery trials found effective in correcting the mitral valve damage (Sep 2018).  Treatments include: digoxin; , stroke is when brain cells are deprived of oxygen and begin to die.  750,000 patients a year suffer strokes in the US.  85% of those strokes are caused by clots.  There are two structural types: Ischemic and hemorrhagic.  Thrombectomy has been found to be a highly effective treatment for some stroke situations (Jan 2018). 
  , AF is atrial fibrillation, an abnormal heart rhythm: rapid, irregular.  It:
  • Can lead to blood clots, stroke, CHF, dementia and other complications.  
  • Fibrillations allow blood to pool in the heart chambers and form small clots which can then lodge in small arteries and block blood flow. 
    
  • Has become much more common being induced by endemic diseases: hypertension, obesity and type-2-diabetes. 
    
  • Cocoa reduces risk of AF (May 2017)
  • Treatments include: digoxin;
    
  ; was due to: youth, exercise, higher education level, lower BMI is body mass index.  , less likely to smoke, ate fruits and vegitables; not due to nuts (Apr 2018)
  
• High fat diet appears to enable operation of PTEN is a gene encoding the protein phosphatidylinositol-3,4,5-triphospate 3- phosphatase, which controls apoptosis through the PI3K/Akt pathway.  Mutations which inhibit the action of the protein allow cells to remain alive when they have been signalled to die.  A potentially cancerous situation. 
  loss induced prostate cancer is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  Research in mice may explain a link between obesity and prostate cancer (Jan 2018).  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
  • Sarcomas
  • Small cell carcinomas
  • Neuroendocrine tumors
  • Transitional cell carcinomas
  cells and support metastasis, replacing PML is:
  
  • Progressive mulitifocal leukoencephalopathy, a rare but fatal viral infection that attacks the brain's myelin.  
  • Promyelocytic leukemia tumor suppressor gene, DNA which encodes a protein that modulates cell growth and division, and induces apoptosis. 
    
  suppressor are proteins: P53; which normally slow down cell growth but in cancer have lost this constraining capability. 
  inhibition, Beth Israel Deaconess researchers report (Jan 2018)
• Weight hysteresis supported by sensory osteocytes in the bones of animals (Jan 2018)
• Trials
  
• Hospital based clinical trials
  
• Alzheimer's is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and declarative memory and thinking problems (MCI).  Specific cells within the hippocampal circuitry and its gateway, the entorhinal cortex, are damaged.  The amygdala, cerebelum and other areas supporting implicit memory are not impacted during the early stages of the disease.  Grid cell destruction results in a sense of being lost.  The default mode network is disrupted.  Variants include: late-onset sporadic; with risk factors - ApoE4 for late onset Alzheimer's, presenilin, androgen deprivation therapy (Dec 2015), type 2 diabetes.  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation, Neurons of sporadic Alzheimer's sufferers show greater APP gene diversity due to somatic recombination; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form.  These are seen in fMRIs 10 to 15 years prior to detecting memory and thinking changes.  APP deployed in the cell membrane is cut into three parts.  The external part becomes amyloid-beta peptide which aggregates into Amyloid plaques, external to the neurons, if too much is generated or it is not removed fast enough. 
    
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016). 
    
  • Encouraging the garbage collection of amyloid and tau with gamma rhythms stimulation retards Alzheimer's in mice studies (Mar 2019)
    
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • Mutation driven misfolded Tau proteins can form tangles within the cytoplasm of neurons.  The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    
  • The brain becomes inflamed resulting in the killing of many more nerve cells.  The hippocampus disintegrates and the brain loses critical functions and memory loss becomes noticeable. 
    
  plaque inhibition trial by Eli Lilly with Solanezumab fails (Nov 2016) 
• Boston University SOM's Matthew Pase finds sugary drinks tied to rapid brain aging and Alzheimer's is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and declarative memory and thinking problems (MCI).  Specific cells within the hippocampal circuitry and its gateway, the entorhinal cortex, are damaged.  The amygdala, cerebelum and other areas supporting implicit memory are not impacted during the early stages of the disease.  Grid cell destruction results in a sense of being lost.  The default mode network is disrupted.  Variants include: late-onset sporadic; with risk factors - ApoE4 for late onset Alzheimer's, presenilin, androgen deprivation therapy (Dec 2015), type 2 diabetes.  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation, Neurons of sporadic Alzheimer's sufferers show greater APP gene diversity due to somatic recombination; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form.  These are seen in fMRIs 10 to 15 years prior to detecting memory and thinking changes.  APP deployed in the cell membrane is cut into three parts.  The external part becomes amyloid-beta peptide which aggregates into Amyloid plaques, external to the neurons, if too much is generated or it is not removed fast enough. 
    
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016). 
    
  • Encouraging the garbage collection of amyloid and tau with gamma rhythms stimulation retards Alzheimer's in mice studies (Mar 2019)
    
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • Mutation driven misfolded Tau proteins can form tangles within the cytoplasm of neurons.  The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    
  • The brain becomes inflamed resulting in the killing of many more nerve cells.  The hippocampus disintegrates and the brain loses critical functions and memory loss becomes noticeable. 
    
  markers (Apr 2017)
• Stage 2 clinical trial of Eisai/Biogen's BAN2401 is reporting positive results, removing plaques and reducing cognitive decline a bit in early Alzheimer is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and declarative memory and thinking problems (MCI).  Specific cells within the hippocampal circuitry and its gateway, the entorhinal cortex, are damaged.  The amygdala, cerebelum and other areas supporting implicit memory are not impacted during the early stages of the disease.  Grid cell destruction results in a sense of being lost.  The default mode network is disrupted.  Variants include: late-onset sporadic; with risk factors - ApoE4 for late onset Alzheimer's, presenilin, androgen deprivation therapy (Dec 2015), type 2 diabetes.  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation, Neurons of sporadic Alzheimer's sufferers show greater APP gene diversity due to somatic recombination; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form.  These are seen in fMRIs 10 to 15 years prior to detecting memory and thinking changes.  APP deployed in the cell membrane is cut into three parts.  The external part becomes amyloid-beta peptide which aggregates into Amyloid plaques, external to the neurons, if too much is generated or it is not removed fast enough. 
    
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016). 
    
  • Encouraging the garbage collection of amyloid and tau with gamma rhythms stimulation retards Alzheimer's in mice studies (Mar 2019)
    
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • Mutation driven misfolded Tau proteins can form tangles within the cytoplasm of neurons.  The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    
  • The brain becomes inflamed resulting in the killing of many more nerve cells.  The hippocampus disintegrates and the brain loses critical functions and memory loss becomes noticeable. 
    
  's patients (Jul 2018)
• Poor application of statistics in prior trials results in misdiagnosis of Blacks / minorities (Aug 2016). 
• Heart disease is cardiovascular disease which refers to:
  • Conditions where narrowed and blocked blood vessels result in angina, hypertension, CHD and heart attacks and hemorrhagic/ischemic strokes.  Mutations of the gene PCSK9 have been implicated in cardiovascular disease.  Rare families with dominant inheritence of the mutations have an overactive protein, very high levels of blood cholesterol and cardiac disease. Other rare PCSK9 mutations result in an 88% reduced risk from heart disease.  Inflammation is associated with cardiovascular disease (Aug 2017). 
    
  treatment stents is a small wire cage that can be inserted into an artery to prop it open.  They were introduced as an alternative to bypass surgery in the 1990s.  Stents are expensive.  Medicare payments vary depending on what kind of stent is used and how many, but are generally in the range $10,000 to $17,000 in 2015.   Double blind trials show that stents have no effect on chest pain relief (Nov 2017)
  found to provide no relief for chest pain emerged as a mental experience, Damasio asserts, constructed by the mind using mapping structures and events provided by nervous systems.  But feeling pain is supported by older biological functions that support homeostasis.  These capabilities reflect the organism's underlying emotive processes that respond to wounds: antibacterial and analgesic chemical deployment, flinching and evading actions; that occur in organisms without nervous systems.  Later in evolution, after organisms with nervous systems were able to map non-neural events, the components of this complex response were 'imageable'.  Today, a wound induced by an internal disease is reported by old, unmyelinated C nerve fibers.  A wound created by an external cut is signalled by evolutionarily recent myelinated fibers that result in a sharp well-localized report, that initially flows to the dorsal root ganglia, then to the spinal cord, where the signals are mixed within the dorsal and ventral horns, and then are transmitted to the brain stem nuclei, thalamus and cerebral cortex.  The pain of a cut is located, but it is also felt through an emotive response that stops us in our tracks.  Pain amplifies the aggression response of people by interoceptive signalling of brain regions providing social emotions including the PAG projecting to the amygdala; making aggressive people more so and less aggressive people less so.  Fear of pain is a significant contributor to female anxiety.  Pain is the main reason people visit the ED in the US.  Pain is mediated by the thalamus and nucleus accumbens, unless undermined by sleep deprivation. 
  (Nov 2017)
  
• Columbia/New York-Presbyterian principal investigator Dr. Gregg Stone reported heart failure is congestive heart failure which occurs when the heart is unable to generate enough blood flow to meet the body's demands.  There are two main types: failure due to left ventricular dysfunction and abnormal diastolic function increasing the stiffness of the left ventricle and decreasing its relaxation.  Heart expansion in CHF distorts the mitral valve which exacerbates the problems.  MitraClip surgery trials found effective in correcting the mitral valve damage (Sep 2018).  Treatments include: digoxin; now has a powerful treatment, Abbott labs's MitraClip, a small device that improves the efficiency of the mitral valve allows blood to flow from the heart's left atrium to the left ventricle.  If it fails the heart will have trouble pumping blood around the body resulting in CHF.   that has been damaged by a heart attack is an AMI. It can induce cardiac arrest.  Blocking the formation of clots with platelet aggregation inhibitors, can help with treating and avoiding AMI.  Risk factors include: taking NSAID pain killers (May 2017).  There is uncertainty about why AMI occur.  Alternative hypotheses include:
  
  • Plaques started to gather in the coronary arteries and grew until no blood flow was possible.  If this is true it makes sense to preventatively treat the buildup with angioplasty. 
    
  • Plaques form anywhere in the body due to atherosclerosis and then break up and get lodged in the coronary artery and start to clot.  If this is true it makes sense to preventatively limit the buildup of plaques with drugs like statins or PCSK9 inhibitors. 
    
  , a 614 patient trial including patients at: University of Pennsylvania, Mount Sinai, NYU Langone; showed.  The device still needs F.D.A. Food and Drug Administration.   approval for the trialed surgery (Sep 2018)
  
• Robert Califf nominated by President Obama for FDA Food and Drug Administration.   commissioner's research praised: Cleveland Clinic (Sep 2015)
  
• Aaron Carroll promotes Pragmatic trials are designed to show real-world effectiveness of the trialed intervention in a broad patient group.  They aim to overcome the problems with ideal trials, which include: Patients won't participate when they feel one trial arm will harm them, They will be trapped by the trial agreement, and will be tagged a failure if they abandon the trail.  , with a design defined 50 years ago, aim to reflect real world conditions.  Precis-2 tool helps design trials across a continuum: pragmatic to ideal; with attributes: eligibility, recruitment, setting, organization, delivery, adherence, follow-up, primary-outcome, primary-analysis; SPACE trial is the strategies for prescribing analgesics comparative effectiveness trial with one arm treated with increasing levels of typical opioid treatments while the other arm used increasing levels of non-opioids.  240 Patients with chronic back, hip or knee pain were followed for 12 months.  SPACE used a pragmatic trial design to overcome ideal trial design limitations.  Aaron Carroll explains the treatment strategies reflected how actual care occurs: medications were adjusted based on patient preferences, and responses.  Providers could switch patients to different drugs at the same level; change the dose or frequency of doses; add other drugs to manage side effects; and move patients up or down levels of intensity.  They were also allowed to use any non-pharmacological pain therapies they liked.  The study found no difference between the two arms for how much pain affected their activity, and pain intensity was better for the non-opioid arm and adverse symptoms were lower too. 
  chronic pain emerged as a mental experience, Damasio asserts, constructed by the mind using mapping structures and events provided by nervous systems.  But feeling pain is supported by older biological functions that support homeostasis.  These capabilities reflect the organism's underlying emotive processes that respond to wounds: antibacterial and analgesic chemical deployment, flinching and evading actions; that occur in organisms without nervous systems.  Later in evolution, after organisms with nervous systems were able to map non-neural events, the components of this complex response were 'imageable'.  Today, a wound induced by an internal disease is reported by old, unmyelinated C nerve fibers.  A wound created by an external cut is signalled by evolutionarily recent myelinated fibers that result in a sharp well-localized report, that initially flows to the dorsal root ganglia, then to the spinal cord, where the signals are mixed within the dorsal and ventral horns, and then are transmitted to the brain stem nuclei, thalamus and cerebral cortex.  The pain of a cut is located, but it is also felt through an emotive response that stops us in our tracks.  Pain amplifies the aggression response of people by interoceptive signalling of brain regions providing social emotions including the PAG projecting to the amygdala; making aggressive people more so and less aggressive people less so.  Fear of pain is a significant contributor to female anxiety.  Pain is the main reason people visit the ED in the US.  Pain is mediated by the thalamus and nucleus accumbens, unless undermined by sleep deprivation. 
  pragmatic trial, where one arm was treated with increasing levels of typical opioid treatments and other arm used increasing levels of non-opioids, concluded the non-opioids were more effective and less problematic.  Antimicrobial catheter is a thin tube that can be inserted into the body.   vs non-antimicrobial pragmatic trial showed urinary tract infection levels in routine practice were unchanged.  Various studies of asthma is inflammation of the airways resulting in their narrowing, swelling and generating additional mucus which inhibits breathing.  Its prevalence doubled in the US between 1980 and 2000.  Asthma is the most common chronic disease in childhood, the most common reason for being away from school and the most common reason for hospitalization.  10 to 13% of children's asthma cases are due to obesity.  Among obese children 23 to 27% of asthma cases are due to obesity.  Diagnosis: Propeller Health; Treatments include: Xolair;
  treatment were found to be equivalent.  But pragmatic trials are hard to get funding for, are expensive, complex and hard to setup (Jul 2018)
  
• NIH is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.   funded New York Presbyterian study and MD Anderson/Medtronic trial both find cervical cancer is mostly caused by HPV infection.  Cervical cancer surgery performs a radical hysterectomy, where the uterus, part of the vagina and other surrounding tissues are removed.  In 2017 it was concluded that the rates of cervical cancer had been previously under estimated and far more black women were impacted (Jan 2017).  Prophylactic vaccination of young girls is dramatically reducing occurence of this cancer.   deaths & re-occurrence increased with MIS is minimally invasive surgery, which aims to replace open surgery with techniques that reduce pain and recovery time by use robots or laparoscopes. 
  instead of open surgery (Oct 2018)
• TAVR is transcatheter aortic valve replacement, where MIS is used to deploy a valve replacement device through an incision in the groin (Mar 2019). 
  found in large clinical trials by: Columbia's Leon + Baylor Scott and White's Mack, Beth Israel Deaconess's Popma; funded by Edwards Lifesciences & Medtronic; to be safe and effective replacement for open heart surgery, for a broad range of patients.  It is not yet known how long such devices operate before failing (Mar 2019)
  
• F.D.A. Food and Drug Administration.   approves UCB's romosozumab is a humanized MAB that targets the bone cell growth inhibitor signal sclerostin, as a treatment for osteoporosis. 
  for postmenopausal women at high risk of fracture, marketed by Amgen as Evenity, for osteoporosis is a set of diseases where the bones are being broken down faster than they are being renewed.  The effect is for bones to lose strength and become brittle.  The more bone mass developed the less likely osteoporosis becomes.  The risk increases with age and more often impacts women.  Certain hormone levels have an impact: Increased glucocorticoids and reduced sex hormone levels increase bone loss, over active: Thyroid, Parathyroid and Adrenal glands.  Some medical treatments can accelerate bone loss (prostate cancer treatments).  Osteoporosis treatments include:
  • Amgen's Evenity (romosozumab) a sclerostin inhibitor (Apr 2019)
    
  • Eli-Lilly's Forteo (teriparatide) a parathyroid hormone analog which encourages bone growth but is very expensive.  And it is only allowed to be taken for two years since it was associated with bone cancer in rats. 
    
  • Biphosphonates reduce the rate of bone loss but have frightening side effects in a small number of patients (Jun 2016). 
    
  .  The MAB as a terminator in medication names indicates the drug is a monoclonal antibody biologic.   is given as a monthly injection.  Drug makers will now focus on making a version that is taken aurally.  There are risks, is an assessment of the likelihood of an independent problem occurring.  It can be assigned an accurate probability since it is independent of other variables in the system.  As such it is different from uncertainty. 
  with the treatment: heart attacks is an AMI. It can induce cardiac arrest.  Blocking the formation of clots with platelet aggregation inhibitors, can help with treating and avoiding AMI.  Risk factors include: taking NSAID pain killers (May 2017).  There is uncertainty about why AMI occur.  Alternative hypotheses include:
  
  • Plaques started to gather in the coronary arteries and grew until no blood flow was possible.  If this is true it makes sense to preventatively treat the buildup with angioplasty. 
    
  • Plaques form anywhere in the body due to atherosclerosis and then break up and get lodged in the coronary artery and start to clot.  If this is true it makes sense to preventatively limit the buildup of plaques with drugs like statins or PCSK9 inhibitors. 
    
  and stroke is when brain cells are deprived of oxygen and begin to die.  750,000 patients a year suffer strokes in the US.  85% of those strokes are caused by clots.  There are two structural types: Ischemic and hemorrhagic.  Thrombectomy has been found to be a highly effective treatment for some stroke situations (Jan 2018). 
  , and side effects: headaches and joint pain.  The F.D.A. requested Amgen research the cardiovascular refers to:
  
  • Conditions where narrowed and blocked blood vessels result in angina, hypertension, CHD and heart attacks and hemorrhagic/ischemic strokes.  Mutations of the gene PCSK9 have been implicated in cardiovascular disease.  Rare families with dominant inheritence of the mutations have an overactive protein, very high levels of blood cholesterol and cardiac disease. Other rare PCSK9 mutations result in an 88% reduced risk from heart disease.  Inflammation is associated with cardiovascular disease (Aug 2017). 
    
  risk.  Two large clinical trials found the MAB increased bone density 15% without breaking bone down.  The MAB blocks production of sclerostin is a glycoprotein signal generated primarily by osteocytes, which inhibits bone growth.  Sclerostin binds to LRP5/6 receptors inhibiting the Wnt signalling pathway. 
  by bone cells, which otherwise normally halts the production of bone and increases breakdown (Apr 2019)
  
• F.D.A. Food and Drug Administration.   post-trial infrastructure
  
• Bladder cancer affects 77,000 new people each year in the US.  And there are 16,000 deaths.  It is typically fast growing, and is often associated with mutated Ras, which may indicate it can be treated by reducing the methylation of the DNA (Dec 2015).   A rare form is plasmacytoid.  Bladder cancer is traditionally treated with surgery, chemotherapy and radiation but these have not been effective with the advanced disease.  New treatments are being deployed:
  • Immuno-oncology immune checkpoint inhibitor Tecentriq (May 2016) is approved for locally advanced or metastatic urothelial carcenoma which accounts for 90% of bladder cancers, where the disease is not controlled by platinum chemotherapy.  Bladder cancer tends to result in many mutations which typically present to the immune system making it a good candidate for immuno-oncology. 
    
  treatment based on Roche immuno-oncology uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
  • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
    
  • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
    
  • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
    
  • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
    
  approved by F.D.A. Food and Drug Administration.   & Merck Keytruda effective against Melanoma is a cancer of the melanocytes.  It is a less common form of skin cancer but is the most deadly once it has invaded deeply into layers of skin.  It is primarily caused by UV light.  It is tied to mutations in the signalling pathway (BRAF) and regulatory genes (P53) with a key dependency on crestin reactivation (Jan 2016).   (May 2016)
• Problematic cancers is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016). 
  : Pancreatic is most often an exocrine tumor.  Islet cell tumors are less common.  These are rare cancers: less than 200,000 US cases per year, but the five year survival rates are extremely low 3%.  They all have KRAS mutations.  They are associated with obesity.  Diagnostics are starting to leverage genomics and big databases (23 and me).  Treatments include:
  • Avastin
    
  • Tarceva 
  , Prostate is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  Research in mice may explain a link between obesity and prostate cancer (Jan 2018).  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
  • Sarcomas
  • Small cell carcinomas
  • Neuroendocrine tumors
  • Transitional cell carcinomas
  , Uterus, Bone; with DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used.   repair: Caretaker proteins, detect and repair mutations of the DNA.  Genes coding for mismatch proteins include: MLH1, MSH2, MLH3.  Mutations in these genes are associated with high risk of colon and uterine cancer.  The gene BRCA1 is also involved in DNA repair.  
  ; inhibition, respond in trial by Johns Hopkins/MS-KCC's Diaz, to PD-1 is programmed cell death protein 1 (CD279) is encoded by the PDCD1 gene.  It is a cell surface receptor that belongs to the immunoglobulin superfamily. It is expressed on T-cells and pro-B cells.  It acts as an immune checkpoint preventing the activation of T-cells to help self-tolerance and reduce autoimmunity.  When it fails people can suffer from: Lupus, Crohn's disease, Rheumatoid arthritis.  PD-1 inhibitor drugs activate the immune system to attack tumors.   PD-1 inhibitors are being approved for Melanoma and squamous-cell form of lung cancer.   blocker - Keytruda, encouraging F.D.A. Food and Drug Administration.   to issue approval for treating this mutational mechanism, for which there is a specific test (Jun 2017)
• Personalized medicine is a medical strategy where decisions, practices, and products are tailored to the individual patient.  Research is looking at the impact of providing potentially deleterious genomic testing information to people: The REVEAL study found no increased anxiety induced by hearing that one's genome implied increased risk of developing late onset Alzheimer's disease.  The take-up of personalized medicine benefits from the focus on genomics, enabled by next generation sequencing of DNA, and detailed by the NIH director Francis Collins and includes:
  • NCCN intensive cell therapies
    
  • Direct to consumer genomic testing
    
  • Direct to consumer diagnostics
    
  • Pharmacogenomics tailored drug treatments reducing the risk and cost of adverse drug reactions.   
  & immunotherapy is indirect treatment of disease by altering the immune system.  Targeted diseases include: cancers -- immuno-oncology, organ transplants. 
  clinical trials are constrained by: Limited patient base argue: Yale CC, MS-KCC, Genentech; Companies with me-too products requesting trials -- a situation companies with F.D.A. Food and Drug Administration.   approval: Merck; are happy to see.  Targeted therapies: GSK, Pfizer, Loxo Oncology; have even less potential patients which is a concern at Fred Hutchinson (Aug 2017)
  
• Major immuno-oncology uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
  • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
    
  • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
    
  • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
    
  • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
    
  trial of Keytruda, by NYU Langone Perlmutter Cancer Center's Dr. Leena Gandhi, funded by Merck, suggests non-squamous non-small-cell lung cancer affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
  • Non-small-cell carcinomas are of three sub-types:
  • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
    
  • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
    
  • Large-cell carcinomas (5 to 10% of lung cancers).
    
  • Small-cell carcinomas.
    
  patients with a biomarker have improved outcomes with early application of Keytruda and chemotherapy.  Result may change clinical practice (Apr 2018)
• Major DCIS is ductal carcinoma in situ where abnormal cells have been found piled up confined to the lining of the milk ducts of the breast.  They are detectable in a mammogram and can look like cancer cells to a pathologist.  The cells could be spread along the whole of the milk duct suggesting a need for mastectomy rather than lumpectomy analogous to cervical cancer treatments after a Pap test.  It is now known that the DCIS may disappear over time, or stop growing and remain stable.  Most women diagnosed with early stage DCIS have surgical or chemotherapy treatment, which does not alter their life expectancy (Aug 2015).  No data is available detailing a correlation with breast cancer.  But it is now understood that metastatic cancers are different from localized cancers. 
  study questions use of aggressive treatment (Aug 2015, Cardiologist comment Aug 2015)
  
• AstraZeneca's Crestor revenues already impacted by generics, when its Mystic lung cancer affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
  • Non-small-cell carcinomas are of three sub-types:
  • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
    
  • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
    
  • Large-cell carcinomas (5 to 10% of lung cancers).
    
  • Small-cell carcinomas.
    
  drug fails trial primary endpoint, putting the company under more pressure.  Collaborates with Merck (Jul 2017)
  
• Medical centers driving checkpoint inhibitor release the immune system's checkpoints: PD-1, CTLA-4; on attacking host cells: by 1) stopping T-cell division and 2) reducing their life spans.  They are used in immuno-oncology where, in 2016: They are approved for treatment of: Advanced melanoma, HL, lung, kidney, liver cancer; They have a general success rate of 20 - 40% and higher for melanoma.   Checkpoint inhibitors work best for tumors that have many mutations: melanomas, lung and bladder cancers.  They are enhanced by adjunct treatments that kill tumor cells generating debris to stimulate the immune system.  The drugs include: ipilimumab (CTLA-4 inhbition), nivolumab, pembrolizumab, atezolizumab (PD-1 inhibitors);  They are costly and often have high copayments.  They cause auto-immune side effects including inflammation, rheumatoid arthritis and damage to glands: Adrenal, Thyroid, Pituitary.  Powerful steroids such as prednisone can help reduce the inflammation.  Damaged glands require sustained hormone treatment.  Checkpoint inhibitor research is funded by the CRI.  trials (Aug 2016)
• BMS checkpoint inhibitor release the immune system's checkpoints: PD-1, CTLA-4; on attacking host cells: by 1) stopping T-cell division and 2) reducing their life spans.  They are used in immuno-oncology where, in 2016: They are approved for treatment of: Advanced melanoma, HL, lung, kidney, liver cancer; They have a general success rate of 20 - 40% and higher for melanoma.   Checkpoint inhibitors work best for tumors that have many mutations: melanomas, lung and bladder cancers.  They are enhanced by adjunct treatments that kill tumor cells generating debris to stimulate the immune system.  The drugs include: ipilimumab (CTLA-4 inhbition), nivolumab, pembrolizumab, atezolizumab (PD-1 inhibitors);  They are costly and often have high copayments.  They cause auto-immune side effects including inflammation, rheumatoid arthritis and damage to glands: Adrenal, Thyroid, Pituitary.  Powerful steroids such as prednisone can help reduce the inflammation.  Damaged glands require sustained hormone treatment.  Checkpoint inhibitor research is funded by the CRI.  trials (Jul 2016, Jan 2017)
• BMS/NCI is the national cancer institute. 
  funded PD-1 is programmed cell death protein 1 (CD279) is encoded by the PDCD1 gene.  It is a cell surface receptor that belongs to the immunoglobulin superfamily. It is expressed on T-cells and pro-B cells.  It acts as an immune checkpoint preventing the activation of T-cells to help self-tolerance and reduce autoimmunity.  When it fails people can suffer from: Lupus, Crohn's disease, Rheumatoid arthritis.  PD-1 inhibitor drugs activate the immune system to attack tumors.   PD-1 inhibitors are being approved for Melanoma and squamous-cell form of lung cancer.   checkpoint inhibitor release the immune system's checkpoints: PD-1, CTLA-4; on attacking host cells: by 1) stopping T-cell division and 2) reducing their life spans.  They are used in immuno-oncology where, in 2016: They are approved for treatment of: Advanced melanoma, HL, lung, kidney, liver cancer; They have a general success rate of 20 - 40% and higher for melanoma.   Checkpoint inhibitors work best for tumors that have many mutations: melanomas, lung and bladder cancers.  They are enhanced by adjunct treatments that kill tumor cells generating debris to stimulate the immune system.  The drugs include: ipilimumab (CTLA-4 inhbition), nivolumab, pembrolizumab, atezolizumab (PD-1 inhibitors);  They are costly and often have high copayments.  They cause auto-immune side effects including inflammation, rheumatoid arthritis and damage to glands: Adrenal, Thyroid, Pituitary.  Powerful steroids such as prednisone can help reduce the inflammation.  Damaged glands require sustained hormone treatment.  Checkpoint inhibitor research is funded by the CRI.  immuno-oncology uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
  • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
    
  • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
    
  • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
    
  • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
    
  study by MD Anderson's Dr. Hussain Tawbi reports Opdivo & Yervoy combination used to treat melanoma is a cancer of the melanocytes.  It is a less common form of skin cancer but is the most deadly once it has invaded deeply into layers of skin.  It is primarily caused by UV light.  It is tied to mutations in the signalling pathway (BRAF) and regulatory genes (P53) with a key dependency on crestin reactivation (Jan 2016).   (and likely other cancers of 200,000 people a year) patients with consequent metastatic brain cancers, at 28 AMC is Academic medical center.  They perform education, research and patient care.  They include one or more health professions schools, such as a medical school and a hospital.  The major AMCs are represented by the United HealthSystem Consortium.   The costly strategies of the AMCs and increased difficulty of finding enough targeted patients for research studies (Aug 2017) is forcing integration with larger hospital systems.  AMCs offer researchers clinical research support: Virus vectors (Nov 2017);
  s: MS-KCC; find survival rate expands beyond a year, like Jimmy Carter after he was treated with Keytruda.  But 50% of patients had significant side effects of which 20% quit the treatment (Aug 2018)
  
• Opdivo fails broadly targeted advanced lung cancer affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
  • Non-small-cell carcinomas are of three sub-types:
  • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
    
  • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
    
  • Large-cell carcinomas (5 to 10% of lung cancers).
    
  • Small-cell carcinomas.
    
  trial (Aug 2016)
• NCI is the national cancer institute. 
  sponsored Washington University School of Medicine designed clinical trial - BMS Opdivo treatment of HTLV-1 is human T-cell leukemia virus type 1, a human retrovirus, which causes adult T-cell leukemia/lymphoma and a demyelinating disease.  It infects millions of people in: Japan, Africa, South America, Caribbean, Australia; but only 5% of those infected develop the cancer.  It is transmitted between humans by: sex, breast-feeding, needle-sharing, transfusions, and transplants. 
  virus induced adult T-cell leukemia is a group of cancers of blood forming tissues: bone marrow, lymphatic network; where abnormal white blood cells are generated.  One type of leukemia is induced when TAD boundaries near the TAL1 gene fail allowing promotors from across the TAD border to distort the operation of the TAL transcription factor.  Mutation clusters common in leukemia have been identified in CHIP. 
  -lymphoma is when lymphocytes continue reproducing, and do not die - a blood cancer. 
  , an immuno-oncology uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
  • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
    
  • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
    
  • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
    
  • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
    
  checkpoint inhibitor release the immune system's checkpoints: PD-1, CTLA-4; on attacking host cells: by 1) stopping T-cell division and 2) reducing their life spans.  They are used in immuno-oncology where, in 2016: They are approved for treatment of: Advanced melanoma, HL, lung, kidney, liver cancer; They have a general success rate of 20 - 40% and higher for melanoma.   Checkpoint inhibitors work best for tumors that have many mutations: melanomas, lung and bladder cancers.  They are enhanced by adjunct treatments that kill tumor cells generating debris to stimulate the immune system.  The drugs include: ipilimumab (CTLA-4 inhbition), nivolumab, pembrolizumab, atezolizumab (PD-1 inhibitors);  They are costly and often have high copayments.  They cause auto-immune side effects including inflammation, rheumatoid arthritis and damage to glands: Adrenal, Thyroid, Pituitary.  Powerful steroids such as prednisone can help reduce the inflammation.  Damaged glands require sustained hormone treatment.  Checkpoint inhibitor research is funded by the CRI.  treatment, failed (Jun 2018)
• Atopic dermatitis, is also called eczema is a long lasting inflammation of the skin.  It can be successfully treated with dupilumab.   (Eczema) biologic are drugs made in living cells.  Typically they are proteins developed using genetic engineering to develop the cellular host, and to customize animal source, DNA to produce human target proteins.  Such biologics partially solve the problem of previous protein sources, extracted from animals or human sources, of contamination and immune responses.  The strategy is very effective for blood transported proteins such as antibodies (MABs), hormones and blood factors.  But intra-cellular proteins still demand delivery and accurate cell targeting.  This creates analogous problems to those of gene therapy. 
  MAB as a terminator in medication names indicates the drug is a monoclonal antibody biologic.   drug treatment dupilumab is a monoclonal antibody which blocks two immune system pathways: interleukin 4 and interleukin 13; that are over produced in atopic dermatitis, by binding to the alpha subunit of the interleukin-4 receptor.  It was developed by Regeneron and marketed as Dupixent.   (Dupixent) has successful trials (Oct 2016). 
  
• Cuban immunotherapy is indirect treatment of disease by altering the immune system.  Targeted diseases include: cancers -- immuno-oncology, organ transplants. 
  vaccine are a core strategy of public health and have significantly extended global wellbeing over 200 years.  Smallpox & polio were virtually eradicated.  Recent successes include: HPV vaccine: Gardasil.  They induce active acquired immunity to a particular disease.  But the development and deployment of vaccines is complex:
  • The business model for vaccine development has been failing (Aug 2015): 
    
  • No Zika vaccine was available as the epidemic grew (Mar 2016).  No vaccine for: CMV;
    
  • Major foundations: Michael J. Fox, Gates, Wellcome; are working to improve the situation including sponsorship of the GAVI alliance.  A geographic cluster is forming in Seattle including PATH (Apr 2016). 
    
  • Commercial developers include: Affiris, Cell Genesis, Chiron, CSL, Sanofi, Valeant;
    
  • Vaccine deployment traditionally benefited from centrally managed vertical health programs.  But political issues are now constraining success with less than 95-99% coverage required for herd immunity (Aug 2015, Sep 2015, Nov 2015, Nov 2016, Jul 2018).  
  • Where clinics have been driven into local neighborhoods health improves (Apr 2016).  
  • Retail clinics (Mar 2016): CVS Minute Clinics focus on vaccination. 
    
  • NNT is a useful metric for vaccine benefit.  Influenza vaccine has an NNT of between 37 and 77, is cheap and causes little harm, so it is very beneficial. 
    
  • Key vaccines include: BCG, C. difficile (May 2015), Cholera (El Tor), Cervical Cancer (Gardasil HPV Jun 2018, Oct 2018), Dengvaxia (Mexico Dec 2015), Gvax, Influenza, Malaria vaccine, Provenge, Typbar-TCV (XDR typhoid Pakistan Apr 2018);
  • Regulation involves: FDA (CBER), with CMS monitoring (star ratings, PACE (Aug 2016), Report cards (Sep 2015)) & CDC promoting vaccines: as a sepsis measure, To control C. difficile (May 2015);  
  • Coding : CVX, MVX;
    
  • Research on vaccines includes: 
  • NIH: AIDS vaccines (AVRC), Focus on using genetic analysis to improve vaccine response.  
  • NCI:
  • Roswell Park clinical trial of immuno-oncology vaccine cimavax. 
    
  • Geisinger: effective process leverage in treatment. 
    
  • Stanford Edge immuno-oncology for cancer vaccines.  
  • P53-driven-cancer focused, gene therapy (Jun 2015). 
    
  Cimavax is a non-small cell lung cancer immuno-oncology vaccine.  It is an active vaccine, containing the ligand EGF and P64k and Montanide ISA 51 which together stimulate the immune system to generate antibodies targeted at EGF.  This results in the EGF concentration in the blood dropping.  Many cancers: Lung, Colon, Kidney, Head, Neck; leverage EGFR to stimulate cell growth. 
  is smuggled to US by non-small cell lung cancer affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
  • Non-small-cell carcinomas are of three sub-types:
  • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
    
  • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
    
  • Large-cell carcinomas (5 to 10% of lung cancers).
    
  • Small-cell carcinomas.
    
  sufferers (Nov 2016). 
  
• CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers (Aug 2016, Jul 2017, Oct 2017, Nov 2017).  But there are severe side effects.  -T trials history detailed, including: Saint Judes's Dr. Campana - Juno, University of Pennsylvania's Dr. June - Novartis; Trials progressing (Aug 2016)
  
but

• Juno Immuno-oncology uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
  • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
    
  • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
    
  • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
    
  • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
    
  CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers (Aug 2016, Jul 2017, Oct 2017, Nov 2017).  But there are severe side effects.  -T trial for adult ALL is acute lymphocytic/lymphoblastic leukemia.  The cancer starts in the lymphocytes of the bone marrow.  Too many lymphocytes are produced instead of mature white blood cells.  In 2010 combination chemotherapy, including 6-mercaptopurine, cures 85 to 90% of children suffering from ALL.   suspended after deaths (Jul 2016)
• Additional years of treatment with aromatase inhibitors limit the synthesis of estrogen by aromatase.  Breast and ovarian cancers grow more stimulated by estrogen. 
  reduced [re-]occurrence of breast cancer is a variety of different cancerous conditions of the breast tissue.  World wide it is the leading type of cancer in women and is 100 times more common in women than men.  260,000 new cases of breast cancer will occur in the US in 2018 causing 41,000 deaths.  The varieties include: Hormone sensitive tumors that test negative for her2 (the most common type affecting three quarters of breast cancers in the US, BRCA1/2 positive, ductal carcinomas including DCIS, lobular carcinomas including LCIS.  Receptor presence on the cancer cells is used as a classification: Her2+/-, estrogen (ER)+/-, progesterone (PR)+/-.  Metastasis classes the cancer as stage 4.  Genetic risk factors include: BRCA, p53, PTEN, STK11, CHEK2, ATM, GATA3, BRIP1 and PALB2.  Treatments include: Tamoxifen, Raloxifene; where worrying racial disparities have been found (Dec 2013).  International studies indicate early stage breast cancer typed by a genomic test: Oncotype DX, MammaPrint; can be treated without chemotherapy (Aug 2016, Jun 2018) but did not reduce mortality in postmenopausal women (Jun 2016). 
• NCI is the national cancer institute. 
  's Rosenberg's TIL is tumor infiltrating lymphocyte, a class of lymphocyte that is considered to invade tumors and attack them.  TILs are isolated from the patient's tumors and cloned in large numbers.  Once the patient's native lymphocytes have been depleted with chemotherapy the TILs are infused in combination with interleukin-2 to attack the tumor. 
  therapy kills six KRAS is a gene that encodes the GTPase KRas, which is part of many signal transduction pathways that propagate growth factors.  Mutations in KRAS are essential for the development of many cancers. 
  tumors (Dec 2016)
• Androgen deprivation therapy lowers the levels of male sex hormones.  These hormones stimulate the growth of prostrate cancer cells.  But the treatment: Bicalutamide, Lupron; is associated with increased rates of: Depression (Apr 2016), Dementia (Oct 2016) including Alzheimer's disease (Dec 2015).   after prostate cancer is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  Research in mice may explain a link between obesity and prostate cancer (Jan 2018).  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
  • Sarcomas
  • Small cell carcinomas
  • Neuroendocrine tumors
  • Transitional cell carcinomas
  surgery found in NCI is the national cancer institute. 
  study to save lives after reccurence (Feb 2017)
• NCI is the national cancer institute. 
  sponsored Washington University School of Medicine designed clinical trial - BMS Opdivo treatment of HTLV-1 is human T-cell leukemia virus type 1, a human retrovirus, which causes adult T-cell leukemia/lymphoma and a demyelinating disease.  It infects millions of people in: Japan, Africa, South America, Caribbean, Australia; but only 5% of those infected develop the cancer.  It is transmitted between humans by: sex, breast-feeding, needle-sharing, transfusions, and transplants. 
  virus induced adult T-cell leukemia is a group of cancers of blood forming tissues: bone marrow, lymphatic network; where abnormal white blood cells are generated.  One type of leukemia is induced when TAD boundaries near the TAL1 gene fail allowing promotors from across the TAD border to distort the operation of the TAL transcription factor.  Mutation clusters common in leukemia have been identified in CHIP. 
  -lymphoma is when lymphocytes continue reproducing, and do not die - a blood cancer. 
  , an immuno-oncology uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
  • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
    
  • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
    
  • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
    
  • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
    
  checkpoint inhibitor release the immune system's checkpoints: PD-1, CTLA-4; on attacking host cells: by 1) stopping T-cell division and 2) reducing their life spans.  They are used in immuno-oncology where, in 2016: They are approved for treatment of: Advanced melanoma, HL, lung, kidney, liver cancer; They have a general success rate of 20 - 40% and higher for melanoma.   Checkpoint inhibitors work best for tumors that have many mutations: melanomas, lung and bladder cancers.  They are enhanced by adjunct treatments that kill tumor cells generating debris to stimulate the immune system.  The drugs include: ipilimumab (CTLA-4 inhbition), nivolumab, pembrolizumab, atezolizumab (PD-1 inhibitors);  They are costly and often have high copayments.  They cause auto-immune side effects including inflammation, rheumatoid arthritis and damage to glands: Adrenal, Thyroid, Pituitary.  Powerful steroids such as prednisone can help reduce the inflammation.  Damaged glands require sustained hormone treatment.  Checkpoint inhibitor research is funded by the CRI.  treatment, failed (Jun 2018)
• BMS/NCI is the national cancer institute. 
  funded PD-1 is programmed cell death protein 1 (CD279) is encoded by the PDCD1 gene.  It is a cell surface receptor that belongs to the immunoglobulin superfamily. It is expressed on T-cells and pro-B cells.  It acts as an immune checkpoint preventing the activation of T-cells to help self-tolerance and reduce autoimmunity.  When it fails people can suffer from: Lupus, Crohn's disease, Rheumatoid arthritis.  PD-1 inhibitor drugs activate the immune system to attack tumors.   PD-1 inhibitors are being approved for Melanoma and squamous-cell form of lung cancer.   checkpoint inhibitor release the immune system's checkpoints: PD-1, CTLA-4; on attacking host cells: by 1) stopping T-cell division and 2) reducing their life spans.  They are used in immuno-oncology where, in 2016: They are approved for treatment of: Advanced melanoma, HL, lung, kidney, liver cancer; They have a general success rate of 20 - 40% and higher for melanoma.   Checkpoint inhibitors work best for tumors that have many mutations: melanomas, lung and bladder cancers.  They are enhanced by adjunct treatments that kill tumor cells generating debris to stimulate the immune system.  The drugs include: ipilimumab (CTLA-4 inhbition), nivolumab, pembrolizumab, atezolizumab (PD-1 inhibitors);  They are costly and often have high copayments.  They cause auto-immune side effects including inflammation, rheumatoid arthritis and damage to glands: Adrenal, Thyroid, Pituitary.  Powerful steroids such as prednisone can help reduce the inflammation.  Damaged glands require sustained hormone treatment.  Checkpoint inhibitor research is funded by the CRI.  immuno-oncology uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
  • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
    
  • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
    
  • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
    
  • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
    
  study by MD Anderson's Dr. Hussain Tawbi reports Opdivo & Yervoy combination used to treat melanoma is a cancer of the melanocytes.  It is a less common form of skin cancer but is the most deadly once it has invaded deeply into layers of skin.  It is primarily caused by UV light.  It is tied to mutations in the signalling pathway (BRAF) and regulatory genes (P53) with a key dependency on crestin reactivation (Jan 2016).   (and likely other cancers of 200,000 people a year) patients with consequent metastatic brain cancers, at 28 AMC is Academic medical center.  They perform education, research and patient care.  They include one or more health professions schools, such as a medical school and a hospital.  The major AMCs are represented by the United HealthSystem Consortium.   The costly strategies of the AMCs and increased difficulty of finding enough targeted patients for research studies (Aug 2017) is forcing integration with larger hospital systems.  AMCs offer researchers clinical research support: Virus vectors (Nov 2017);
  s: MS-KCC; find survival rate expands beyond a year, like Jimmy Carter after he was treated with Keytruda.  But 50% of patients had significant side effects of which 20% quit the treatment (Aug 2018)
  
• HL7 is health level 7 (name implying focused on application level protocols in health care).  It includes a variety of standards: Arden Syntax, RIM, CDA, CCOW, claims attachments, FHIR, SPL and messaging and has developed a EHR system functional model providing a standardized description of the functions provided.  The formation of HL7 messaging communications streams has a relatively high overhead.  HL7 version 2 is generally deployed.  The version 2 messaging standardizes health care data interchange with messages originally based on character delimited '|' segments (containing character delimited '^' composite fields (containing character delimited '&' subcomponents) in a non XML structure interchanged widely over a secure network stack.  The first field in a message segment is the 3 character segment name.  HL7 is generally transmitted over MLLP.  HL7 v2 has been extended with an XML encoding.  HL7 v2 messages have to be augmented to transmit over TCP/IP.  The US Government mandate that licenced recipients of HL7 messages understand all aspects of the information transferred.  That is point-to-point specific since each sender has their own interpretation of what information goes in what HL7 fields.  The usual solution to this situation and rule is (1) an interface engine placed between the two points which maps the sender's information from the fields it uses for transmission to the recipients interpretation of HL7 field usage and (2) a lot of testing to show the mappings are correct and reliable.  Because of the impact of changing the interpretation of use of HL7 (on all the interface engines of point connected partners) operational adjustments to HL7 are difficult.  Version 3 of HL7 adopts a different strategy.  It introduces a Meta model (RIM) of the data and so when adopted changes the strategies available for interconnection.  It is XML based.  But the operational difficulty of switching to version 3 has left most systems tied to version 2.   interoperability constraints. 
  
• Telehealth is the use of remote health care.  It includes telepharmacy and clinical telehealth for stroke and psychiatry.  It also includes sessions between primary care providers and patients and assisted caregiving such as medication reminders and DME usage monitors. 
  differentiation and network effects.  
• Patients play with the settings on the home devices invalidating the inputs.  
• Flaws seen in online treatment (May 2016)
  
• Revenue cycle is either:
  
  • Restrictive cardiomyopathy, a rare disease where scar tissue makes the heart muscle rigid and reduces the efficiency.  Or
    
  • Revenue Cycle Management aligns treatment with reimbursement.  Customer service will be involved.  IT will architect the core billing, decision support and ad-hoc services, constructed by RCM vendors, into systems to support RCM.  The Hospital's central business office will aim to maximize cash recoveries.  As per Deming, mistakes in the RCM pipeline result in rework and lost cash flow and revenue of between 4 - 12%.  The staff must be trained and fully engaged in the design and operation of the pipeline.  The front end processes are best placed to capture all the information needed to make the cycle successful.  The activities include:
  • Scheduling and Appointments - where visits and procedures are booked and demographic and insurance information is collected.  If this information is incorrect it is likely the claims will not forward to third party payers.  When resources and their states are accurately known an optimal set of plans can be constructed to efficiently and effectively flow patients through the system.  But that is difficult to guarantee because of a number of interrelated problems:
  • Scale - as the number of resources increases the ability of a central scheduling system to represent all of them accurately and reliably becomes impossible. 
    
  • Ubiquity - a CAS strategy for ensuring availability is to have an over-abundance of equivalent resource that can be used for schedule allocation.  But often these resource levels are set by local decision makers who all respond at about the same time to imposed funding changes.  The effect is to suddenly and unpredictably undermine the guarantee of over-abundance.  Sometimes the assumption of equivalence also fails as in the desire of a patient to see only a specific surgeon. 
    
  • Changes can ripple through the plans requiring coordination meetings and notifications or guaranteed receipt of status updates. 
    
  • Verification checks for:
    
  • Referral - Is there PCP authorization?  Is the PCP referred service covered by the patient's plan,
    
  • Authorization - obtain Insurance authorization if required, and
    
  • Pre-certification - is there 'need' for inpatient care or other care before admission by the MCO.  Otherwise could introduce problems including not obtaining/verifying the insurance name, number and eligibility, not securing pre-certification and pre-authorization with time limits, not copying the insurance card, not checking for secondary coverage, not detecting expired referral or authorization,
    
  • Pre-registration - provide advice about their financial obligations and what documents to bring to the procedure.  If there is a copay or an outstanding payment to be paid these should be processed,
    
  • Registration - some patients are scheduled outside of the main admitting process (by OP clinic or E.D.) and this must be detected and the scheduling verification and pre-registration process be performed,
    
  • Time of service payments - co pays and self pays,
    
  • Coding - identify diagnosis (ICD 9 -> ICD-10 codes) and treatment (CPT) activities and charges for the episode.  More than 80% of hospital cases are coded in error. 
    
  • Demographics and billing data entry - enter charges and adjust capitated charges,
    
  • Patient statements - submit primary and secondary claims (following HIPAA formats) with or without involvement of a clearinghouse, produce patient statements including time of service, outstanding balance, charged amount with codes, insurance details, forms used (UB 92/04 and HCFA 1500).  A paper based claims filing has a rejection rate of 30%.  Duplicate claim payment rates of 1 - 2% of medical expenses are common.  Duplicate claims detection is often not part of the process.  Payer's goals are in conflict with Provider goals.  
    
  • Collections and payment posting - Post all payments and adjustments and deposit money into the bank,
    
  • Denials and appeals - resubmission and appeal of claims, denial analysis and bad debts and write offs.  To reduce denial rates and appeals the reimbursement contracts payer processes and actual denials must be analyzed and understood. 
    
  • Account follow up - Patient inquiries, resubmission of claims and issue refunds. 
    
  • Financial counseling;
  optimization - is viewed as a solution to the challenges of acute care hospitals by allowing effective integration with higher profit post-acute care.  
• Science funding policy shift.  Lack of reported results viewed as wasting many millions.  
• NIH is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.   switches NHLBI funding focus to a few deep studies with real-world impact (Oct 2015).  
• NIH funding peaked in 2008; since then has dropped by 30%.  But 2016's spending bill adds a large increase in its funds (Dec 2015). 
  
• 21st Century Cures Act is a $6.3 billion bill to increase funding for research into cancer, Alzheimer's disease and other disease, support mental health networks and adjust regulations for drugs and medical devices.  The act does not constrain drug prices.  It is funded with money taken from a preventative health care fund.  It aims to:
  • Expand the funding of the NIH.  
  • Allocates an additional $4.8 billion over 10 years.  Much of the expanded funding is focused on Alzheimer's and cancer.  This funding will still have to be appropriated by Congress. 
    
  • Empowers the NIH:
    
  • Provides them with authority to finance high-risk, high-reward research using special procurement procedures instead of grants and contracts, 
  • Requires the director to establish "Eureka prizes" for biomedical research and treatment improvements. 
    
  • Advances the Precision Medicine Initiative,
    
  • Support the moonshot to cure cancer. 
    
  • Align the federal drug regulatory structure with the processes of the biotechnology industry.  Critics argue it lowers drug and device approval standards, and raises the influence of surrogate endpoints. 
    
  • The F.D.A. is allocated half a billion dollars to help staff the expedited processes. 
    
  • It provides an expedited pathway for breakthrough medical technologies (offering options for life-threatening conditions with few treatment options). 
    
  • F.D.A. must consider the least burdensome means to show device safety. 
    
  • Streamline the mental health network.  It strengthens the enforcement of the mental health parity law.  
  • Creates the Presidentially appointed position of assistant secretary for mental health and substance use.  
  • Directs federal agencies to step up enforcement of laws that require equal insurance coverage for mental and physical illnesses. 
    
  • Stem the problem of opioid drug abuse with a $1 billion investment that will allow expanded access of treatment programs.  
  targets $6.3 billion for cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016). 
  & Alzheimer's is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and declarative memory and thinking problems (MCI).  Specific cells within the hippocampal circuitry and its gateway, the entorhinal cortex, are damaged.  The amygdala, cerebelum and other areas supporting implicit memory are not impacted during the early stages of the disease.  Grid cell destruction results in a sense of being lost.  The default mode network is disrupted.  Variants include: late-onset sporadic; with risk factors - ApoE4 for late onset Alzheimer's, presenilin, androgen deprivation therapy (Dec 2015), type 2 diabetes.  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation, Neurons of sporadic Alzheimer's sufferers show greater APP gene diversity due to somatic recombination; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form.  These are seen in fMRIs 10 to 15 years prior to detecting memory and thinking changes.  APP deployed in the cell membrane is cut into three parts.  The external part becomes amyloid-beta peptide which aggregates into Amyloid plaques, external to the neurons, if too much is generated or it is not removed fast enough. 
    
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016). 
    
  • Encouraging the garbage collection of amyloid and tau with gamma rhythms stimulation retards Alzheimer's in mice studies (Mar 2019)
    
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • Mutation driven misfolded Tau proteins can form tangles within the cytoplasm of neurons.  The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    
  • The brain becomes inflamed resulting in the killing of many more nerve cells.  The hippocampus disintegrates and the brain loses critical functions and memory loss becomes noticeable. 
    
  research, expanding the NIH is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.   budget, mental health deployment and F.D.A. Food and Drug Administration.   regulation of medical devices & drugs (Nov 2016) 
• President Obama and Congress finance million-person cohort is a precision medicine activity funded through the NIH with $130 million in December 2015 by Congress (Jul 2016). 
  (Jul 2016)
• Columbia psychiatrist hopes Dr. Joshua Gordon will reduce Thomas Insel's shift of funding at the NIMH is the National Institute of Mental Health. 
  to neuroscience deals with the structure, development, chemistry, pharmacology, function and pathology of networks of biological neurons. 
  (Oct 2016)
• Social media 
• Economics is the study of trade between humans.  Traditional Economics is based on an equilibrium model of the economic system.  Traditional Economics includes: microeconomics, and macroeconomics.  Marx developed an alternative static approach.  Limitations of the equilibrium model have resulted in the development of: Keynes's dynamic General Theory of Employment Interest & Money, and Complexity Economics.  Since trading depends on human behavior, economics has developed behavioral models including: behavioral economics. 
  
• Nobel for economics is the study of trade between humans.  Traditional Economics is based on an equilibrium model of the economic system.  Traditional Economics includes: microeconomics, and macroeconomics.  Marx developed an alternative static approach.  Limitations of the equilibrium model have resulted in the development of: Keynes's dynamic General Theory of Employment Interest & Money, and Complexity Economics.  Since trading depends on human behavior, economics has developed behavioral models including: behavioral economics. 
  of contract theory for MIT's Holmstrom (Oct 2016). 
• Sparse code processing agents - IBM's Watson in healthcare (Jan 2014), Apple's Siri in speech recognition etc.  The race to gain the most leveraged platform is hotting up (Mar 2016). 
  
• Development technologies
• open source - openstack
• Topical development languages: Python, C sharp, 
• Volume and complexity of applicable information (T7) to apply in medicine 
• Robotics: Robots are being enhanced to support 
  
• UMN's He Mind-controlled robotic arm (Spring 2017)
• Robotic systems perform remote surgery with virtual reality is the full immersion of a human user into a virtually generated world.  Hence the user is not able to interact or think about the real world at the same time.  The use of sensors detecting the user's skin, eyes, ears, and other state and signal generators for touch, hearing, visuals etc. supports the transportation of the brain into an alternate situation where the user can interact.  As long as the sensors are broadly detecting the state of the user's body and the signals are generated at greater than 60 per second it is a truly real experience.  Unfortunately it is hard to fool gravity so these systems can induce motion sickness.  Virtual reality is likely to be significant in medicine in:
  • Training with new tools including surgical instruments. 
    
  • Remote treatment including surgery where the feedback allows the surgeon to operate robotic instruments experiencing the remote OR. 
    
  (Aug 2014)
• Smart technology
  
• MIT & DOD - U.S. Department of Defense. 
  work with Warwick Mills on AFFA is Advanced Functional Fabrics of America. 
  fabrics (Mar 2016)
• Sensor transformation (O4):  
• Stanford Medical School professor, Lei Xing, details research in his Medical imaging, deep learning is an artificial intelligence approach where engineers deploy data into deep neural networks. 
  AI & nano medicine is the application of nanotechnology to medicine (May 2016, Feb 2019).  Commercial applications are focused on research and clinical tools for drug delivery, therapies, safer and more effective in vivo imaging, neuro-electronic interfaces, other Nano-sensors, and eventually cell repair machines!!  There are issues with determining toxicology etc. 
  lab to IEEE is the institute of electrical and electronic engineers. 
  nano-technology group at Varian Medical Systems (Feb 2019)
  
• Researchers (state in May 2016) and startups: Bikanta; are leveraging nano-scale sensors.  
  
• Research and engineering on cell based bots to be deployed as sensors, and drug delivery mechanisms led by MIT's Roger Kamm (Sep 2016). 
• Screening transformation
  
• Carrier screening can provide powerful information for recessively inherited conditions.  It has been used for: Tay-Sachs disease, sickle-cell trait, cystic fibrosis, spinal muscular atrophy; with differing effects.  As more people have complete DNA sequencing carrier screening prior to pregnancy will make increasing sense.  Carrier screening:
  • Is being considered for: 
  • SMA but this requires a complicated and costly genetic test, 
  • Fragile X syndrome may be offered to all females,
    
  • Requires informed consent since it can result in difficult choices. 
    
  • Test reliability depends on the number of potential mutations are involved and how many of these are tested for in the screen.  As of 2010 even cystic fibrosis CFTR gene screening only looks at the 23 most common of the 1000 potential mutations. 
    
  for single gene recessive conditions enabled by international Human Genome data as discussed by NIH is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.  's Francis Collins. 
  
• Maternal screening includes a variety of tests during pregnancy to assess the status of the fetus.  There is a degree of uncertainty with the tests facilitating counciling and implying a prospective mother should be given the choice not to have the tests.  Tests include:
  • Ultrasound to check for anatomical abnormalities including congenital heart defects. 
    
  • Maternal blood tests for chromosomal disorders such as Down syndrome and neural tube defects.  The development of liquid biopsys will allow assessment of fetal DNA and RNA in maternal blood.  
  for birth defects via maternal blood test: liquid biopsy uses a tiny blood sample used for diagnostic testing.  Often the testing is based on using DNA sequencing to detect DNA in the blood from cancer cells.  By identifying the mutations in a patient's tumor accurate treatments can be selected, and recurrence can be detected.  But aging generates many similar mutations which could lead to false positives in a broad screening test.  Research and development is ongoing (Jun 2016). 
  . 
  
• Dec 2013 Hypertension Guidelines Can Be Eased, Panel Says
  
• Dec 2015 USPSTF is United States preventative services task force.  It is an independent expert panel focused on prevention and evidence-based medicine appointed by HHS.   recommends switch to 24-hour ambulatory blood pressure monitoring uses a device, worn for 24 hours, that automatically measures blood pressure every 15 to 30 minutes during the day and every 30 to 60 minutes at night.  . 
• Oct 2015 ACS recommends fewer mammograms and USPSTF is United States preventative services task force.  It is an independent expert panel focused on prevention and evidence-based medicine appointed by HHS.  , ACOG is the American Congress of Obstetricians and Gynecologists. 
  say they will respond. 
• ACS shifts to starting colon cancer is a major hereditary cancer also called colorectal cancer.  It:
  
  • Follows a slow, many yearlong, progression from a benign polyp to a localized cancer to an invasive one.  Two bacteria: Bacteroides fragilis, Escherichia coli variant; from the gut microbiome have been implicated in the early stages of tumor induction (Feb 2018).  It
    
  • Is often associated with Ras mutations and the high risk allele TCF7L2.  30 to 50% of colon cancers have KRAS mutations.  Intensive medical surveillance and removal of polyps can be lifesaving for those at high risk.  Types of colon cancer include the single gene mutation hereditary: FAP, HNPCC; 
  • Is linked to obesity. 
    
  screening at 45, as people are increasingly getting: colorectal cancer is also called colon cancer.  It:
  • Follows a slow, many yearlong, progression from a benign polyp to a localized cancer to an invasive one.  Two bacteria: Bacteroides fragilis, Escherichia coli variant; from the gut microbiome have been implicated in the early stages of tumor induction (Feb 2018).  It
    
  • Is often associated with Ras mutations and the high risk allele TCF7L2.  30 to 50% of colon cancers have KRAS mutations.  Intensive medical surveillance and removal of polyps can be lifesaving for those at high risk.  Types of colon cancer include the single gene mutation hereditary: FAP, HNPCC; 
  • Is linked to obesity. 
    
  - person born in 1990 is four times as likely as a person born in 1950, colon cancer - 2 times as likely; at a comparable age.  This new recommendation currently conflicts with the 2016 USPSTF is United States preventative services task force.  It is an independent expert panel focused on prevention and evidence-based medicine appointed by HHS.   guidelines (May 2018)
  
• Oct 2015 AAP recommends screening for childhood hunger. 
• Propel's smartphone app FreshEBT assists with SNAP is the supplemental nutrition action program, food stamps program.  It helps about 40 million low-income Americans in 2018.  One in four children is on SNAP.  The program is federally funded but administered by the states.  Most states outsource the operation to private contractors: Conduent, FIS;  , but is blocked by Government contractor Conduent (Apr 2018)
  
• Nov 2015 USPSTF is United States preventative services task force.  It is an independent expert panel focused on prevention and evidence-based medicine appointed by HHS.   prostate cancer is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  Research in mice may explain a link between obesity and prostate cancer (Jan 2018).  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
  • Sarcomas
  • Small cell carcinomas
  • Neuroendocrine tumors
  • Transitional cell carcinomas
  screening (May 2016, 2) recommendations working but questioned by studies setup by ACS. 
• Over screening 
• Overdiagnosis is identification of disease when no symptoms or impacts will occur.  It typically results from false positives during screening (Aug 2016).  It can result in unnecessary and problematic treatment. 
  results in unnecessary thyroid is an endocrine gland in the neck, which secretes hormones: Thyroxine; controlling body wide metabolic and protein synthesis rates and calcium homeostatis.  The thyroid is under the direct control of the anterior pituitary (TSH signals) and indirectly the hypothalamus (TRH).   removal (Aug 2016).  
• Overtreatment is the application of unnecessary health care.  It is a complex problem:
  • Overtreatment needs to be adaptive.  As people age their medicine levels typically need to be changed.  Often, as in the case of blood pressure, and blood sugar reduction, they should be reduced to avoid inducing falls (Nov 2015).  
  • Patients with chronic diseases, such as type 2 diabetes, often require different treatment settings.  And again these vary with age. 
    
  • Patients who have learned a regime, and been told it was successful, may resist instructions to change it.  Some worry that they will impact their health care provider's treatment performance measures. 
    
  
  
• Nov 2015, (2) Overtreated elders with poor results
• Overdiagnosis is identification of disease when no symptoms or impacts will occur.  It typically results from false positives during screening (Aug 2016).  It can result in unnecessary and problematic treatment. 
  of hypothyroidism is under production of thyroxine by the thyroid. 
  is resulting in overtreatment is the application of unnecessary health care.  It is a complex problem:
  • Overtreatment needs to be adaptive.  As people age their medicine levels typically need to be changed.  Often, as in the case of blood pressure, and blood sugar reduction, they should be reduced to avoid inducing falls (Nov 2015).  
  • Patients with chronic diseases, such as type 2 diabetes, often require different treatment settings.  And again these vary with age. 
    
  • Patients who have learned a regime, and been told it was successful, may resist instructions to change it.  Some worry that they will impact their health care provider's treatment performance measures. 
    
  with synthroid (Apr 2017)
• Mis-treatment
• Nov 2015 Many treatments are later found to be ill advised. 
  
• Androgen deprivation therapy lowers the levels of male sex hormones.  These hormones stimulate the growth of prostrate cancer cells.  But the treatment: Bicalutamide, Lupron; is associated with increased rates of: Depression (Apr 2016), Dementia (Oct 2016) including Alzheimer's disease (Dec 2015).   for prostate cancer is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  Research in mice may explain a link between obesity and prostate cancer (Jan 2018).  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
  • Sarcomas
  • Small cell carcinomas
  • Neuroendocrine tumors
  • Transitional cell carcinomas
  associated with increased: Depression is a debilitating episodic state of extreme sadness, typically beginning in late teens or early twenties. This is accompanied by a lack of energy and emotion, which is facilitated by genetic predisposition - for example genes coding for relatively low serotonin levels, estrogen sensitive CREB-1 gene which increases women's incidence of depression at puberty; and an accumulation of traumatic events.  There is a significant risk of suicide: depression is involved in 50% of the 43,000 suicides in the US, and 15% of people with depression commit suicide.  Depression is the primary cause of disability with about 20 million Americans impacted by depression at any time.  There is evidence of shifts in the sleep/wake cycle in affected individuals (Dec 2015).  The affected person will experience a pathological sense of loss of control, prolonged sadness with feelings of hopelessness, helplessness & worthlessness, irritability, sleep disturbances, loss of appetite, and inability to experience pleasure.  Michael Pollan concludes depression is fear of the past.  It affects 12% of men and 20% of women.  It appears to be associated with androgen deprivation therapy treatment for prostate cancer (Apr 2016).  Chronic stress depletes the nucleus accumbens of dopamine, biasing humans towards depression.  Depression easily leads to following unhealthy pathways: drinking, overeating; which increase the risk of heart disease.   It has been associated with an aging related B12 deficiency (Sep 2016).  During depression, stress mediates inhibition of dopamine signalling.  Both depression and stress activate the adrenal glands' release of cortisol, which will, over the long term, impact the PFC.  There is an association between depression and additional brain regions: Enlarged & more active amygdala, Hippocampal dendrite and spine number reductions & in longer bouts hippocampal volume reductions and memory problems, Dorsal raphe nucleus linked to loneliness, Defective functioning of the hypothalamus undermining appetite and sex drive, Abnormalities of the ACC.  Mayberg notes ACC area 25: serotonin transporters are particularly active in depressed people and lower the serotonin in area 25 impacting the emotion circuit it hubs, inducing bodily sensations that patients can't place or consciously do anything about; and right anterior insula: which normally generates emotions from internal feelings instead feel dead inside; are critical in depression.  Childhood adversity can increase depression risk by linking recollections of uncontrollable situations to overgeneralizations that life will always be terrible and uncontrollable.  Sufferers of mild autism often develop depression.  Treatments include: CBT which works well for cases with below average activity of the right anterior insula (mild and moderate depression), UMHS depression management, deep-brain stimulation of the anterior insula to slow firing of area 25.  Drug treatments are required for cases with above average activity of the right anterior insula.  As of 2010 drug treatments: SSRIs (Prozac), MAO, monoamine reuptake inhibitors; take weeks to facilitate a response & many patients do not respond to the first drug applied, often prolonging the agony.  By 2018, Kandel notes, Ketamine is being tested as a short term treatment, as it acts much faster, reversing the effect of cortisol in stimulating glutamate signalling, and because it reverses the atrophy induced by chronic stress.   Genomic predictions of which treatment will be effective have not been possible because: Not all clinical depressions are the same, a standard definition of drug response is difficult; (Apr 2016), Dementia is a classification of memory impairment, constrained feelings and enfeebled or extinct intellect.  The most common form for people under 60 is FTD.  Dementia has multiple causes including: vascular disease (inducing VCI) including strokes, head trauma, syphilis and mercury poisoning for treating syphilis, alcoholism, B12 deficiency (Sep 2016), privation, Androgen deprivation therapy (Oct 2016), stress, Parkinson's disease, Alzheimer's disease, and prion infections such as CJD and kuru.  The condition is typically chronic and treatment long term (Laguna Honda ward) and is predicted by Stanley Prusiner to become a major burden on the health system.  It may be possible to constrain the development some forms of dementia by: physical activity, hypertension management, and ongoing cognitive training.  Dementia appears to develop faster in women than men.   including Alzheimer's disease is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and declarative memory and thinking problems (MCI).  Specific cells within the hippocampal circuitry and its gateway, the entorhinal cortex, are damaged.  The amygdala, cerebelum and other areas supporting implicit memory are not impacted during the early stages of the disease.  Grid cell destruction results in a sense of being lost.  The default mode network is disrupted.  Variants include: late-onset sporadic; with risk factors - ApoE4 for late onset Alzheimer's, presenilin, androgen deprivation therapy (Dec 2015), type 2 diabetes.  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation, Neurons of sporadic Alzheimer's sufferers show greater APP gene diversity due to somatic recombination; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form.  These are seen in fMRIs 10 to 15 years prior to detecting memory and thinking changes.  APP deployed in the cell membrane is cut into three parts.  The external part becomes amyloid-beta peptide which aggregates into Amyloid plaques, external to the neurons, if too much is generated or it is not removed fast enough. 
    
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016). 
    
  • Encouraging the garbage collection of amyloid and tau with gamma rhythms stimulation retards Alzheimer's in mice studies (Mar 2019)
    
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • Mutation driven misfolded Tau proteins can form tangles within the cytoplasm of neurons.  The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    
  • The brain becomes inflamed resulting in the killing of many more nerve cells.  The hippocampus disintegrates and the brain loses critical functions and memory loss becomes noticeable. 
    
  (Oct 2016);
• NSAID is a nonsteroidal anti-inflammatory drug, such as ibuprofen.  They inhibit the production of prostaglandins.  They are often used to treat pain and inflammation.  Since prostaglandins are involved in collagen production NSAIDs can undermine healing.  They are also associated with increased risk of heart attacks (May 2017). 
  s associated with increased risk, is an assessment of the likelihood of an independent problem occurring.  It can be assigned an accurate probability since it is independent of other variables in the system.  As such it is different from uncertainty. 
  of heart attacks is an AMI. It can induce cardiac arrest.  Blocking the formation of clots with platelet aggregation inhibitors, can help with treating and avoiding AMI.  Risk factors include: taking NSAID pain killers (May 2017).  There is uncertainty about why AMI occur.  Alternative hypotheses include:
  
  • Plaques started to gather in the coronary arteries and grew until no blood flow was possible.  If this is true it makes sense to preventatively treat the buildup with angioplasty. 
    
  • Plaques form anywhere in the body due to atherosclerosis and then break up and get lodged in the coronary artery and start to clot.  If this is true it makes sense to preventatively limit the buildup of plaques with drugs like statins or PCSK9 inhibitors. 
    
  after just one week (May 2017)
  
• Dec 2015 Cardiac arrest is a sudden halt in the effective blood circulation due to the heart not contracting effectively.  This prevents delivery of oxygen and glucose to the body.  It can be caused by a heart attack.  CHF in contrast, typically has substandard circulation but the heart is still pumping sufficient blood to sustain life.  Cardiac arrest may be reversed with effective treatment.  The treatment regime and effectiveness vary significantly.  They can include:
  • CPR which needs endurance training to sustain for at least 45 minutes of deployment needed for success.  If no pulse is detected after 20 minutes more powerful treatments should be deployed. 
    
  • ECMO which is more widely used in Japan and South Korea than in the US.  
  • Once circulation is restored additional interventions are required for success, but their application is not benchmarked, standardized or regulated:
  • Therapeutic hypothermia - people who remain comatose after being in cardiac arrest should be cooled for at least 24 hours to a temperature between 89.6 and 96.8 F. 
    
  • Avoiding toxic amounts of oxygen
  • Maintaining normal co2 levels
  • Maintaining high blood pressure
  • If needed cardiac catheterization. 
    
  treatment varies significantly.  
• Medication adherence is focused on improving how effectively patients take their medicines.  In the US in 2017 the problem is huge and costly (Apr 2017).  Chronic diseases such as Malaria illustrate the complexity of the task.  A coherent medical network with shared access to EHR should help.  So do blister packs with the days of the week marked.  M-health glow caps with a wireless transmitter that lights up if medication has not been taken as expected.  An improved prescription label is less open to confusion.  Codes on drugs can be scanned by smartphones to initiate download of an informational video.  Smart pillboxes control when pills are dispensed.  Measuring the contents of a medication bottle can alert for intervention if too much or too little is in the bottle.  Drug manufacturers see ways to get closer to the patient: Sanofi Toujeo deployment; Pharmacies are implementing VDS to support medication adherence: Connected Care;
  
  
• Nonadherence is focused on improving how effectively patients take their medicines.  In the US in 2017 the problem is huge and costly (Apr 2017).  Chronic diseases such as Malaria illustrate the complexity of the task.  A coherent medical network with shared access to EHR should help.  So do blister packs with the days of the week marked.  M-health glow caps with a wireless transmitter that lights up if medication has not been taken as expected.  An improved prescription label is less open to confusion.  Codes on drugs can be scanned by smartphones to initiate download of an informational video.  Smart pillboxes control when pills are dispensed.  Measuring the contents of a medication bottle can alert for intervention if too much or too little is in the bottle.  Drug manufacturers see ways to get closer to the patient: Sanofi Toujeo deployment; Pharmacies are implementing VDS to support medication adherence: Connected Care;
  is a huge problem in US agree National Jewish's Bender, Brigham & Women's hospital's Rosenbaum, Pittsburgh Health Plan's Shrank & Aetna (Apr 2017)
• F.D.A. Food and Drug Administration.   approves NDA is new drug application for F.D.A. approval.  Every drug has to obtain NDA approval before it can be commercialized in the US.  INDs along with the data from higher animal studies and human clinical trials are evaluated to assess if the drug is safe and effective for the proposed use, that the labeling is appropriate, and the methods and quality control procedures for manufacture are adequate. 
  for: Otsuka, Proteus Digital Health (Novartis, Medtronic); digital pill Abilify MyCite, which can monitor for adherence is focused on improving how effectively patients take their medicines.  In the US in 2017 the problem is huge and costly (Apr 2017).  Chronic diseases such as Malaria illustrate the complexity of the task.  A coherent medical network with shared access to EHR should help.  So do blister packs with the days of the week marked.  M-health glow caps with a wireless transmitter that lights up if medication has not been taken as expected.  An improved prescription label is less open to confusion.  Codes on drugs can be scanned by smartphones to initiate download of an informational video.  Smart pillboxes control when pills are dispensed.  Measuring the contents of a medication bottle can alert for intervention if too much or too little is in the bottle.  Drug manufacturers see ways to get closer to the patient: Sanofi Toujeo deployment; Pharmacies are implementing VDS to support medication adherence: Connected Care;
  and report findings (Nov 2017)
• Microbiome , the trillions of bacteria and viruses that live inside higher animals' guts, on their skin etc.  These bacteria and viruses seem to play a role in: immune responses, digesting food, making nutrients, controlling mental health and maintaining a healthy weight.  The signals from the gut microbiota are relayed by major nerve fibers: vagus; to the central nervous system.  The symbiotic relationship must be actively managed.  Human armpits include glands which provide food favoring certain symbionts who build a defensive shield above the skin.  In the human gut: Barriers are setup: Mucus secretions form a physical constraint and provide sites for bacteriophages to anchor and attack pathogenic bacteria; Symbiont tailored nourishment: Plant-heavy food creates opportunities for fibre specialists like Bacteroides thetaiotaomicron; is provided, Selective binding sites are provided, Poisons are deployed against the unwelcome, and Temperature, acidity and oxygenation are managed.    High throughput sequencing allows the characterization of bacterial populations inside guts.  Beginning at birth, as they pass down the birth canal infants are supplied with a microbiome from their mothers.  If they are borne via cesarean they never receive some of the key bacteria: Bifidobaterium infantis which is also dependent on oligosaccharides in breast milk; from their mothers.  A variety of diseases may be caused by changes in the microbiome:
  • Eczema can be related to changes in the skin microbiome. 
    
  • Obesity can be induced by changes to the gut microbiome.  
  • Chronic inflammation
    
  • Allergies
    
  • Type 1 diabetes
    
  
  
• University of Pennsylvania SOM's Dr. Mark Khan shows a brain defect in the condition FCCM is familial cerebral cavernous malformation syndrome, a hereditary condition where blood-filled bubbles protrude from veins in the brain and may leak blood or burst at any time.  University of Pennsylvania's SOM professor Mark Kahn identified a link to bacteria in the gut microbiome (May 2017). 
  is linked to bacteria of the gut microbiome, the trillions of bacteria and viruses that live inside higher animals' guts, on their skin etc.  These bacteria and viruses seem to play a role in: immune responses, digesting food, making nutrients, controlling mental health and maintaining a healthy weight.  The signals from the gut microbiota are relayed by major nerve fibers: vagus; to the central nervous system.  The symbiotic relationship must be actively managed.  Human armpits include glands which provide food favoring certain symbionts who build a defensive shield above the skin.  In the human gut: Barriers are setup: Mucus secretions form a physical constraint and provide sites for bacteriophages to anchor and attack pathogenic bacteria; Symbiont tailored nourishment: Plant-heavy food creates opportunities for fibre specialists like Bacteroides thetaiotaomicron; is provided, Selective binding sites are provided, Poisons are deployed against the unwelcome, and Temperature, acidity and oxygenation are managed.    High throughput sequencing allows the characterization of bacterial populations inside guts.  Beginning at birth, as they pass down the birth canal infants are supplied with a microbiome from their mothers.  If they are borne via cesarean they never receive some of the key bacteria: Bifidobaterium infantis which is also dependent on oligosaccharides in breast milk; from their mothers.  A variety of diseases may be caused by changes in the microbiome:
  • Eczema can be related to changes in the skin microbiome. 
    
  • Obesity can be induced by changes to the gut microbiome.  
  • Chronic inflammation
    
  • Allergies
    
  • Type 1 diabetes
    
  (May 2017)
• Dana-Farber's Matthew Meyerson & University of British Columbia's Robert Holt found Fusobacterium, always in mouth, is found with colon cancer is a major hereditary cancer also called colorectal cancer.  It:
  
  • Follows a slow, many yearlong, progression from a benign polyp to a localized cancer to an invasive one.  Two bacteria: Bacteroides fragilis, Escherichia coli variant; from the gut microbiome have been implicated in the early stages of tumor induction (Feb 2018).  It
    
  • Is often associated with Ras mutations and the high risk allele TCF7L2.  30 to 50% of colon cancers have KRAS mutations.  Intensive medical surveillance and removal of polyps can be lifesaving for those at high risk.  Types of colon cancer include the single gene mutation hereditary: FAP, HNPCC; 
  • Is linked to obesity. 
    
  tumors including metastatic.  If the bacterium is killed with antibiotics are compounds which kill bacteria, molds, etc.  Sulfur dye stuffs were found to be effective antibiotics.  The first evolved antibiotic discovered was penicillin.  Antibiotics are central to modern health care supporting the processes of: Surgery, Wound management, Infection control; which makes the development of antibiotic resistance worrying.  Antibiotics are:
  • Economically problematic to develop and sell. 
    
  • Congress enacted GAIN to encourage development of new antibiotics.  But it has not developed any market-entry award scheme, which seems necessary to encourage new antibiotic R&D. 
    
  • Medicare has required hospitals and SNFs to execute plans to ensure correct use of antibiotics & prevent the spread of drug-resistant infections.  
  • C.D.C. is acting to stop the spread of resistant infections and reduce unnecessary use of antibiotics.  
    
  • F.D.A. has simplified approval standards.  It is working with industry to limit use of antibiotics in livestock. 
    
  • BARDA is promoting public-private partnerships to support promising research.
    
  • Impacting the microbiome of the recipient.  Stool banking is a solution  (Sloan-Kettering stool banking).  
  • Associated with obesity, although evidence suggests childhood obesity relates to the infections not the antibiotic treatments (Nov 2016). 
    
  • Monitored globally by W.H.O.
    
  • Regulated in the US by the F.D.A. who promote voluntary labeling by industry to discourage livestock fattening (Dec 2013).  
  • Customer demands have more effect - Perdue shifts to no antibiotics in premier chickens (Aug 2015). 
    
  the tumor growth slows (Nov 2017)
• Johns Hopkins Cynthia Sears & Drew Pardoll report gut microbiome, the trillions of bacteria and viruses that live inside higher animals' guts, on their skin etc.  These bacteria and viruses seem to play a role in: immune responses, digesting food, making nutrients, controlling mental health and maintaining a healthy weight.  The signals from the gut microbiota are relayed by major nerve fibers: vagus; to the central nervous system.  The symbiotic relationship must be actively managed.  Human armpits include glands which provide food favoring certain symbionts who build a defensive shield above the skin.  In the human gut: Barriers are setup: Mucus secretions form a physical constraint and provide sites for bacteriophages to anchor and attack pathogenic bacteria; Symbiont tailored nourishment: Plant-heavy food creates opportunities for fibre specialists like Bacteroides thetaiotaomicron; is provided, Selective binding sites are provided, Poisons are deployed against the unwelcome, and Temperature, acidity and oxygenation are managed.    High throughput sequencing allows the characterization of bacterial populations inside guts.  Beginning at birth, as they pass down the birth canal infants are supplied with a microbiome from their mothers.  If they are borne via cesarean they never receive some of the key bacteria: Bifidobaterium infantis which is also dependent on oligosaccharides in breast milk; from their mothers.  A variety of diseases may be caused by changes in the microbiome:
  • Eczema can be related to changes in the skin microbiome. 
    
  • Obesity can be induced by changes to the gut microbiome.  
  • Chronic inflammation
    
  • Allergies
    
  • Type 1 diabetes
    
  : Bacteriodes fragilis & Escherichia coli; stimulate colon cancer is a major hereditary cancer also called colorectal cancer.  It:
  
  • Follows a slow, many yearlong, progression from a benign polyp to a localized cancer to an invasive one.  Two bacteria: Bacteroides fragilis, Escherichia coli variant; from the gut microbiome have been implicated in the early stages of tumor induction (Feb 2018).  It
    
  • Is often associated with Ras mutations and the high risk allele TCF7L2.  30 to 50% of colon cancers have KRAS mutations.  Intensive medical surveillance and removal of polyps can be lifesaving for those at high risk.  Types of colon cancer include the single gene mutation hereditary: FAP, HNPCC; 
  • Is linked to obesity. 
    
  by invading the mucus is used to cover tissues that are exposed.  It is made from mucins.  Mucous membranes may secrete mucus to generate a robust barrier. 
  epithelium is a core cell type that lines cavities and surfaces of blood vessels and organs.  All glands are constructed from epithelial cells.  Epithelial cells: secrete, absorb, protect, transport and sense.  They have no blood supply so they are nourished via diffusion through the basement membrane from underlying connective tissue.  Epithelial cell differentiation potency makes these significant cancer agents.  of the colon, developing biofilms is a sheet of bacteria that have invaded the mucus epithelium covering an organ. 
  , and damaging the DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used.   (Feb 2018)
  
• Battle starts between doctors and pharmaceutical companies: Finch Therapeutics, Rebiotix, Seres Therapeutics, Vedanta Biosciences; over the impending F.D.A. Food and Drug Administration.   decision about how to regulate the development and use of FMT is fecal microbiota transplants, where human gut microbiome, fecal matter, is transferred from a donor's bowel to another person. 
  medicines, as a: drug, giving power to pharmaceutical companies, or some other regime, helping doctors and patients.  Currently OpenBiome, founded by microbiologist Dr. Mark Smith & Ms. Carolyn Edelstein, is the sole provider, and only for Clostridium difficile usually competes with other bacteria in the human gut microbiome.  But antibiotic treatments provide it with an advantage where it becomes the predominant gut bacteria causing diarrhea, abdominal pain, and toxic megacolon.  Repeated treatments select for infections that are progressively more difficult to treat.  C. difficile infections kill more than 25,000 people a year in the US.  Fecal transplants, especially enabled by stool-banking, reintroduce competitive bacteria that limit the success of C. difficile and cure patients with previously recurrent infections.  But the F.D.A. has not approved such transplants as a treatment and the procedure is not covered by insurance. 
  
  infections (Mar 2019)
• Infections and antibiotics are compounds which kill bacteria, molds, etc.  Sulfur dye stuffs were found to be effective antibiotics.  The first evolved antibiotic discovered was penicillin.  Antibiotics are central to modern health care supporting the processes of: Surgery, Wound management, Infection control; which makes the development of antibiotic resistance worrying.  Antibiotics are:
  • Economically problematic to develop and sell. 
    
  • Congress enacted GAIN to encourage development of new antibiotics.  But it has not developed any market-entry award scheme, which seems necessary to encourage new antibiotic R&D. 
    
  • Medicare has required hospitals and SNFs to execute plans to ensure correct use of antibiotics & prevent the spread of drug-resistant infections.  
  • C.D.C. is acting to stop the spread of resistant infections and reduce unnecessary use of antibiotics.  
    
  • F.D.A. has simplified approval standards.  It is working with industry to limit use of antibiotics in livestock. 
    
  • BARDA is promoting public-private partnerships to support promising research.
    
  • Impacting the microbiome of the recipient.  Stool banking is a solution  (Sloan-Kettering stool banking).  
  • Associated with obesity, although evidence suggests childhood obesity relates to the infections not the antibiotic treatments (Nov 2016). 
    
  • Monitored globally by W.H.O.
    
  • Regulated in the US by the F.D.A. who promote voluntary labeling by industry to discourage livestock fattening (Dec 2013).  
  • Customer demands have more effect - Perdue shifts to no antibiotics in premier chickens (Aug 2015). 
    
   
• May 2016 Colistin is an old antibiotic that is held in reserve in the US to treat especially dangerous infections (CREs) that are resistant to carbapenems.   resistant bacteria found in US.  
• W.H.O. is World Health Organization a United Nations organization.   supports world leaders aims to develop plans and strategies which ensure effective coordination to improve the common good of the in-group.  John Adair developed a leadership methodology based on the three-circles model. 
  ' UN is the United Nations.   plan to curb drug resistance (Oct 2016). 
• Limiting antibiotics are compounds which kill bacteria, molds, etc.  Sulfur dye stuffs were found to be effective antibiotics.  The first evolved antibiotic discovered was penicillin.  Antibiotics are central to modern health care supporting the processes of: Surgery, Wound management, Infection control; which makes the development of antibiotic resistance worrying.  Antibiotics are:
  • Economically problematic to develop and sell. 
    
  • Congress enacted GAIN to encourage development of new antibiotics.  But it has not developed any market-entry award scheme, which seems necessary to encourage new antibiotic R&D. 
    
  • Medicare has required hospitals and SNFs to execute plans to ensure correct use of antibiotics & prevent the spread of drug-resistant infections.  
  • C.D.C. is acting to stop the spread of resistant infections and reduce unnecessary use of antibiotics.  
    
  • F.D.A. has simplified approval standards.  It is working with industry to limit use of antibiotics in livestock. 
    
  • BARDA is promoting public-private partnerships to support promising research.
    
  • Impacting the microbiome of the recipient.  Stool banking is a solution  (Sloan-Kettering stool banking).  
  • Associated with obesity, although evidence suggests childhood obesity relates to the infections not the antibiotic treatments (Nov 2016). 
    
  • Monitored globally by W.H.O.
    
  • Regulated in the US by the F.D.A. who promote voluntary labeling by industry to discourage livestock fattening (Dec 2013).  
  • Customer demands have more effect - Perdue shifts to no antibiotics in premier chickens (Aug 2015). 
    
  curbs resistant results from evolutionary pressure of antibiotics, supported by plasmids and R factors: NDN1; which encode resistance properties for otherwise lethal antibiotics.  World leaders hope cooperation can preserve the power of last resort antibiotics: Carbapenems, Colistin (Oct 2016).  Worrying trends include: C. auris resistance to medical antifungals: itraconazole; as well as azole agricultural fungicides (Apr 2019), CRE (May 2016), C. diff (May 2015), MDR & XDR TB; resulting in increased risk of sepsis and death.  The World Bank estimates full resistance would reduce the global economy in 2050 by between 1.1 and 3.8%. 
  Clostridium difficile usually competes with other bacteria in the human gut microbiome.  But antibiotic treatments provide it with an advantage where it becomes the predominant gut bacteria causing diarrhea, abdominal pain, and toxic megacolon.  Repeated treatments select for infections that are progressively more difficult to treat.  C. difficile infections kill more than 25,000 people a year in the US.  Fecal transplants, especially enabled by stool-banking, reintroduce competitive bacteria that limit the success of C. difficile and cure patients with previously recurrent infections.  But the F.D.A. has not approved such transplants as a treatment and the procedure is not covered by insurance. 
  
  infections (Jan 2017)
• XDR typhoid is extrensively drug-resistant typhoid.  It has developed in Pakistan (Apr 2018)
  epidemic is the rapid spread of infectious disease: AIDS (Oct 2016), Cholera (2010), Clostridium difficile (May 2015), Ebola, Influenza, Polio, SARS, Tuberculosis, Typhoid (Apr 2018), Malaria, Yellow fever, Zika; to large numbers of people in a population within a short period of time -- two weeks or less.  Epidemics are studied and monitored by: NIAID, CDC, WHO; but are managed by states in the US.  Infection control escalation is supported by biocontainment units: Emory, Nebraska.  Once memes are included in the set of infectious schematic materials, human addictions can present as epidemics concludes Dr. Nora Volkow of the NIDA.  CEPI aims to ensure public health networks are effectively prepared for epidemics.  PHCPI aims to strengthen PCPs globally to improve responsiveness to epidemics.  GAVI helps catalyze the development and deployment of vaccines.  Sporadic investment in public health enables development of conditions for vector development: Mosquitos.  The increasing demands of the global population are altering the planet: Climate change is shifting mosquito bases, Forests are being invaded bringing wildlife and their diseases in contact with human networks.  Globalized travel acts as an infection amplifier: Ebola to Texas.  Health clinics have also acted as amplifiers: AIDS in Haiti, C. diff & MRSA infections enabled & amplified by hospitals.  Haiti earthquake support from the UN similarly introduced Cholera. 
  in Sindh, Pakistan, due to multi drug resistant strain H58 & a plasmid provide bacteria with a way to transfer parts of their DNA complement with one another.  The effect is to ensure that useful mutations can become rapidly distributed within a population of bacteria.  Because the plasmid reproduces asexually beneficial mutations will result in competition between hosts containing different plasmid variants through clonal interference. 
  carrying ceftriaxone (Rocephin) is a cephalosporin antibiotic. 
  resistance, is expected to spread to other endemic typhoid is an acute bacterial infection from Salmonella typhimurium.  It is transmitted by the fecal-oral route from contaminated water or food.  It grows in the intestines and blood.  Vaccine exists and is 30 to 70% effective.  It is treated with azithromycin, fluoroquinolones or cephalosporins.  As of 2018 about 21 million people suffer from typhoid infections each year with 161,000 deaths. 
  areas and is a global concern, the CDC is the HHS's center for disease control and prevention based in Atlanta Georgia.  
  warns.  Public health officials have started vaccinating are a core strategy of public health and have significantly extended global wellbeing over 200 years.  Smallpox & polio were virtually eradicated.  Recent successes include: HPV vaccine: Gardasil.  They induce active acquired immunity to a particular disease.  But the development and deployment of vaccines is complex:
  • The business model for vaccine development has been failing (Aug 2015): 
    
  • No Zika vaccine was available as the epidemic grew (Mar 2016).  No vaccine for: CMV;
    
  • Major foundations: Michael J. Fox, Gates, Wellcome; are working to improve the situation including sponsorship of the GAVI alliance.  A geographic cluster is forming in Seattle including PATH (Apr 2016). 
    
  • Commercial developers include: Affiris, Cell Genesis, Chiron, CSL, Sanofi, Valeant;
    
  • Vaccine deployment traditionally benefited from centrally managed vertical health programs.  But political issues are now constraining success with less than 95-99% coverage required for herd immunity (Aug 2015, Sep 2015, Nov 2015, Nov 2016, Jul 2018).  
  • Where clinics have been driven into local neighborhoods health improves (Apr 2016).  
  • Retail clinics (Mar 2016): CVS Minute Clinics focus on vaccination. 
    
  • NNT is a useful metric for vaccine benefit.  Influenza vaccine has an NNT of between 37 and 77, is cheap and causes little harm, so it is very beneficial. 
    
  • Key vaccines include: BCG, C. difficile (May 2015), Cholera (El Tor), Cervical Cancer (Gardasil HPV Jun 2018, Oct 2018), Dengvaxia (Mexico Dec 2015), Gvax, Influenza, Malaria vaccine, Provenge, Typbar-TCV (XDR typhoid Pakistan Apr 2018);
  • Regulation involves: FDA (CBER), with CMS monitoring (star ratings, PACE (Aug 2016), Report cards (Sep 2015)) & CDC promoting vaccines: as a sepsis measure, To control C. difficile (May 2015);  
  • Coding : CVX, MVX;
    
  • Research on vaccines includes: 
  • NIH: AIDS vaccines (AVRC), Focus on using genetic analysis to improve vaccine response.  
  • NCI:
  • Roswell Park clinical trial of immuno-oncology vaccine cimavax. 
    
  • Geisinger: effective process leverage in treatment. 
    
  • Stanford Edge immuno-oncology for cancer vaccines.  
  • P53-driven-cancer focused, gene therapy (Jun 2015). 
    
  in Hydrabad with Typbar-TCV is Bharat Biotech's typhoid conjugate vaccine.  The Vi capsular polysaccharide is conjugated to a protein to help induce the immune system to respond.  The vaccine provides long term protection to adults and infants, 6 months or older.  These new vaccines are part of a strategy to use immunization to counter the over-deployment of antibiotics and antibiotic resistance. 
  and GAVI funding help (Apr 2018). 
  
• Soil fungus, Candida auris is a fungus resident in soils, which has developed resistance to medical antifungals: itraconazole; as well as azole agricultural fungicides.  90% of C. auris infections are resistant to an antifungal.  30% are resistant to two of the drugs.  Genome analysis indicates four ancient strains persist.  It has been assisted by the widespread use of fungicides enabling it to opportunistically migrate to niches cleared of its normal competitors.  C. auris was first identified in an ear infection of a Japanese patient in 2009.  But it had subsequently colonized all proximate surfaces and was detected in the air.  It infects the very ill and those with weakened immune systems.  50% of those infected die within 90 days. 
  , has grown globally resistant results from evolutionary pressure of antibiotics, supported by plasmids and R factors: NDN1; which encode resistance properties for otherwise lethal antibiotics.  World leaders hope cooperation can preserve the power of last resort antibiotics: Carbapenems, Colistin (Oct 2016).  Worrying trends include: C. auris resistance to medical antifungals: itraconazole; as well as azole agricultural fungicides (Apr 2019), CRE (May 2016), C. diff (May 2015), MDR & XDR TB; resulting in increased risk of sepsis and death.  The World Bank estimates full resistance would reduce the global economy in 2050 by between 1.1 and 3.8%. 
  to azole agricultural fungicides and primary medical antifungals: itraconazole is an antifungal medication, classified by the WHO as an essential medicine.  It is a triazole which stops fungal growth by undermining metabolism and cell membrane integrity.  Effectiveness is being undermined by global agricultural deployment of equivalent azole fungicides on crops. 
  ; grows on most cleaned hospital and human surfaces.  Half the patients infected with C. auris, are already seriously ill at that point and die within 90 days.  C.D.C. is the HHS's center for disease control and prevention based in Atlanta Georgia.  
  monitors C. auris, but does not tell the public, to avoid panic and blacklisting of hospitals: Royal Brompton ICU is intensive care unit.  It is now being realized that the procedures and environment of the ICU is highly stressful for the patients.  In particular sedation with benzodiazepines is suspected to enhance the risk of inducing PTSD.  Intubation and catheterization are also traumatic.  Sometimes seperated into MICU and SICU.  eICU skill centralization may bring down costs. 
  , London, Mount Sinai, Universitari Politecnic La Fe, Valencia, Weill Cornell Medical Center (Apr 2019)
  
• Chicago Northwestern Memorial AMC is Academic medical center.  They perform education, research and patient care.  They include one or more health professions schools, such as a medical school and a hospital.  The major AMCs are represented by the United HealthSystem Consortium.   The costly strategies of the AMCs and increased difficulty of finding enough targeted patients for research studies (Aug 2017) is forcing integration with larger hospital systems.  AMCs offer researchers clinical research support: Virus vectors (Nov 2017);
  lupus is a chronic autoimmune disease, in which many parts of the body can be attacked: joints, skin, kidneys, blood cells, brain, heart, lungs.  Its cause is unknown, there is little linkage within families, but women are affected 4 to 12 times as often as men - especially those of childbearing age.  There are various types: SLE, cutaneous lupus, drug-induced lupus, Neonatal lupus.  It is treated with Belimumab, prednisone corticosteroid;
  patient, Ms. Spoor, collapsed after a lung biopsy resulting in cardiac arrest is a sudden halt in the effective blood circulation due to the heart not contracting effectively.  This prevents delivery of oxygen and glucose to the body.  It can be caused by a heart attack.  CHF in contrast, typically has substandard circulation but the heart is still pumping sufficient blood to sustain life.  Cardiac arrest may be reversed with effective treatment.  The treatment regime and effectiveness vary significantly.  They can include:
  • CPR which needs endurance training to sustain for at least 45 minutes of deployment needed for success.  If no pulse is detected after 20 minutes more powerful treatments should be deployed. 
    
  • ECMO which is more widely used in Japan and South Korea than in the US.  
  • Once circulation is restored additional interventions are required for success, but their application is not benchmarked, standardized or regulated:
  • Therapeutic hypothermia - people who remain comatose after being in cardiac arrest should be cooled for at least 24 hours to a temperature between 89.6 and 96.8 F. 
    
  • Avoiding toxic amounts of oxygen
  • Maintaining normal co2 levels
  • Maintaining high blood pressure
  • If needed cardiac catheterization. 
    
  , provided ECMO is extracorporeal membrane oxygenation where blood is drawn from the patient and passed through an oxygenator and then back into the body. 
  breathing assists, subsequently found by blood test to be infected with Candida auris is a fungus resident in soils, which has developed resistance to medical antifungals: itraconazole; as well as azole agricultural fungicides.  90% of C. auris infections are resistant to an antifungal.  30% are resistant to two of the drugs.  Genome analysis indicates four ancient strains persist.  It has been assisted by the widespread use of fungicides enabling it to opportunistically migrate to niches cleared of its normal competitors.  C. auris was first identified in an ear infection of a Japanese patient in 2009.  But it had subsequently colonized all proximate surfaces and was detected in the air.  It infects the very ill and those with weakened immune systems.  50% of those infected die within 90 days. 
  , possibly HAC is Hospital-Acquired Condition.   from one of the tubes, which proved to be multiple drug resistant results from evolutionary pressure of antibiotics, supported by plasmids and R factors: NDN1; which encode resistance properties for otherwise lethal antibiotics.  World leaders hope cooperation can preserve the power of last resort antibiotics: Carbapenems, Colistin (Oct 2016).  Worrying trends include: C. auris resistance to medical antifungals: itraconazole; as well as azole agricultural fungicides (Apr 2019), CRE (May 2016), C. diff (May 2015), MDR & XDR TB; resulting in increased risk of sepsis and death.  The World Bank estimates full resistance would reduce the global economy in 2050 by between 1.1 and 3.8%. 
  and she died.  She is one of 158 C. auris cases in Illinois since 2016 (Apr 2019)
• Infectious disease specialists are poorly reimbursed is the payment process for much of US health care.  Reimbursement is the centralizing mechanism in the US Health care network.  It associates reward flows with central planning requirements such as HITECH.  Different payment methods apportion risk differently between the payer and the provider.  The payment methods include:
  • Fee-for-service,
    
  • Per Diem,
    
  • Episode of Care Payment, 
  • Multi-provider bundled EPC,
    
  • Condition-specific capitation,
    
  • Full capitation.  
  , by payers include four types:
  • From the 1930s the insurers Blue Cross and Blue Shield catalyzed health care activity by paying a daily per diem to hospitals for the diagnoses and treatments the hospital's dispensed.  At their inception in 1966 Medicare and Medicaid followed this reimbursement model. 
  • From 1983 Medicare and Medicaid switched to the PPS reimbursement mechanism.  This forced alignment of the supplier, diagnosis, treatment, billing and reimbursement processes.  The health care network is still structurally aligned around PPS.  Under scrutiny of ProPAC and its successor MedPAC,  as well as pressure of the BBA after 1997, the payments per DRG have been steadily reduced until it was below the cost of care, forcing hospitals to seek margin from their other payers.  Medicare outlier payments benefited hospitals that inflated charges and thus became eligible. 
    
  • Employers as they experienced cost shifting from the hospital's increased product charges moved their employees over to managed care based payment. 
  • Private payers pay hospitals directly for their diagnosis and treatment.  Typically this group has little power.  There are default rates for private payers - typically 40% of billed charges that are not covered by a fixed payment or a fee schedule.  For the uninsured poor until 2004 they obtained little discount on the hospital's chargemaster list price, because insurers and CMS required to be charged the lowest value offered to any patients.  Medicare has now relaxed this constraint. 
  , for what they do, and the specialty is failing to attract enough trainees to respond to antibiotic resistance results from evolutionary pressure of antibiotics, supported by plasmids and R factors: NDN1; which encode resistance properties for otherwise lethal antibiotics.  World leaders hope cooperation can preserve the power of last resort antibiotics: Carbapenems, Colistin (Oct 2016).  Worrying trends include: C. auris resistance to medical antifungals: itraconazole; as well as azole agricultural fungicides (Apr 2019), CRE (May 2016), C. diff (May 2015), MDR & XDR TB; resulting in increased risk of sepsis and death.  The World Bank estimates full resistance would reduce the global economy in 2050 by between 1.1 and 3.8%. 
  and leverage infection control works to prevent healthcare-associated infections.  It monitors & supports associated hospital processes: Anti-microbial surfaces, Barrier clothing, Cleaning, Disinfection, Hand washing: North shore; Patient access during epidemics, Sterilization; to contain cross infection.  The CDC provides support: Ebola process; and works closely with the primary biocontainment unit at Emory University Hospital. 
  (Apr 2019)
• Oct 2016 Copper hospital room equipment limits bacterial growth.  
• H.I.V. is human immunodeficiency virus, an RNA retrovirus which causes AIDS.  It infects T-lymphocytes destroying the host's immune system.  Some HIV's enter the lymphocytes by leveraging the T cells CCR5 protein.  The HIV X4 variant leverages CXCR4. 
  route and infrastructure and evolved amplifiers into the US is the United States of America.   reported (Oct 2016)
• Brazil yellow fever is an infectious disease of primates caused by a flavivirus, yellow fever virus.  The virus is vectored by mosquitos: In the canopies of Rain Forest trees where monkeys are infected, Aedes aegypti in cities; but hunters can act as a reservoir for infection into aegypti.  Monkeys are tracked by public health officials as signals for outbreaks of the disease.  Often asymptomatic but patients who develop severe symptoms die within 10 days.  Symptoms include: Jaundice, High fever and multiple organ failure. 
  outbreak causes alarm.  Limited initial public health is the proactive planning, coordination and execution of strategies to improve and safeguard the wellbeing of the public.  Its global situation is discussed in The Great Escape by Deaton.  Public health in the US is coordinated by the PHS federally but is mainly executed at the state and local levels.  Public health includes:
  • Awareness campaigns about health threatening activities including: Smoking, Over-eating, Alcohol consumption, Contamination with poisons: lead; Joint damage from over-exercise;
    
  • Research, monitoring and control of disease agents, processes and vectors by agencies including the CDC. 
    
  • Monitoring of the public's health by institutes including the NIH.  This includes screening for cancer & heart disease. 
    
  • Development, deployment and maintenance of infrastructure including: sewers, water plants and pipes.  
  • Development, deployment and maintenance of vaccination strategies.  
  • Development, deployment and maintenance of fluoridation. 
    
  • Development, deployment and maintenance of family planning services. 
    
  • Regulation and constraint of foods, drugs and devices by agencies including the FDA.  
  response blamed.  NIAID is the national institute of allergy and infectious diseases, a part of the NIH.   is worried about disease penetrating US is the United States of America.   via Puerto Rico.  W.H.O. is World Health Organization a United Nations organization.   has supplied Brazil with vaccine are a core strategy of public health and have significantly extended global wellbeing over 200 years.  Smallpox & polio were virtually eradicated.  Recent successes include: HPV vaccine: Gardasil.  They induce active acquired immunity to a particular disease.  But the development and deployment of vaccines is complex:
  • The business model for vaccine development has been failing (Aug 2015): 
    
  • No Zika vaccine was available as the epidemic grew (Mar 2016).  No vaccine for: CMV;
    
  • Major foundations: Michael J. Fox, Gates, Wellcome; are working to improve the situation including sponsorship of the GAVI alliance.  A geographic cluster is forming in Seattle including PATH (Apr 2016). 
    
  • Commercial developers include: Affiris, Cell Genesis, Chiron, CSL, Sanofi, Valeant;
    
  • Vaccine deployment traditionally benefited from centrally managed vertical health programs.  But political issues are now constraining success with less than 95-99% coverage required for herd immunity (Aug 2015, Sep 2015, Nov 2015, Nov 2016, Jul 2018).  
  • Where clinics have been driven into local neighborhoods health improves (Apr 2016).  
  • Retail clinics (Mar 2016): CVS Minute Clinics focus on vaccination. 
    
  • NNT is a useful metric for vaccine benefit.  Influenza vaccine has an NNT of between 37 and 77, is cheap and causes little harm, so it is very beneficial. 
    
  • Key vaccines include: BCG, C. difficile (May 2015), Cholera (El Tor), Cervical Cancer (Gardasil HPV Jun 2018, Oct 2018), Dengvaxia (Mexico Dec 2015), Gvax, Influenza, Malaria vaccine, Provenge, Typbar-TCV (XDR typhoid Pakistan Apr 2018);
  • Regulation involves: FDA (CBER), with CMS monitoring (star ratings, PACE (Aug 2016), Report cards (Sep 2015)) & CDC promoting vaccines: as a sepsis measure, To control C. difficile (May 2015);  
  • Coding : CVX, MVX;
    
  • Research on vaccines includes: 
  • NIH: AIDS vaccines (AVRC), Focus on using genetic analysis to improve vaccine response.  
  • NCI:
  • Roswell Park clinical trial of immuno-oncology vaccine cimavax. 
    
  • Geisinger: effective process leverage in treatment. 
    
  • Stanford Edge immuno-oncology for cancer vaccines.  
  • P53-driven-cancer focused, gene therapy (Jun 2015). 
    
  .  CDC is the HHS's center for disease control and prevention based in Atlanta Georgia.  
  warns of limited vaccine in US (May 2017)
• Nov 2016 Infection, not antibiotics are compounds which kill bacteria, molds, etc.  Sulfur dye stuffs were found to be effective antibiotics.  The first evolved antibiotic discovered was penicillin.  Antibiotics are central to modern health care supporting the processes of: Surgery, Wound management, Infection control; which makes the development of antibiotic resistance worrying.  Antibiotics are:
  • Economically problematic to develop and sell. 
    
  • Congress enacted GAIN to encourage development of new antibiotics.  But it has not developed any market-entry award scheme, which seems necessary to encourage new antibiotic R&D. 
    
  • Medicare has required hospitals and SNFs to execute plans to ensure correct use of antibiotics & prevent the spread of drug-resistant infections.  
  • C.D.C. is acting to stop the spread of resistant infections and reduce unnecessary use of antibiotics.  
    
  • F.D.A. has simplified approval standards.  It is working with industry to limit use of antibiotics in livestock. 
    
  • BARDA is promoting public-private partnerships to support promising research.
    
  • Impacting the microbiome of the recipient.  Stool banking is a solution  (Sloan-Kettering stool banking).  
  • Associated with obesity, although evidence suggests childhood obesity relates to the infections not the antibiotic treatments (Nov 2016). 
    
  • Monitored globally by W.H.O.
    
  • Regulated in the US by the F.D.A. who promote voluntary labeling by industry to discourage livestock fattening (Dec 2013).  
  • Customer demands have more effect - Perdue shifts to no antibiotics in premier chickens (Aug 2015). 
    
  tied to child obesity is an addictive disorder where the brain is induced to require more eating, often because of limits to the number of fat cells available to report satiation (Jul 2016).  Brain images of drug-addicted people and obese people have found similar changes in the brain.  Obese people's reward network tends to be less responsive to dopamine and have a lower density of dopamine receptors.  Obesity spreads like a virus through a social network with a 171% likelihood that a friend of someone who becomes obese will also become so.  Obesity is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes, asthma and heart disease.  It is suspected that this is contributing to the increase in maternal deaths in the US (Sep 2016).  Obesity is a complex condition best viewed as representing many different diseases, which is affected by the: Amount of brown adipose tissue (Oct 2016), Asprosin signalling by white adipose tissue (Nov 2016), Genetic alleles including 25 which guarantee an obese outcome, side effects of some pharmaceuticals for: Psychiatric disorders, Diabetes, Seizure, Hypertension, Auto-immunity; Acute diseases: Hypothyroidism, Cushing's syndrome, Hypothalamus disorders; State of the gut microbiome.  Infections, but not antibiotics, appear associated with childhood obesity (Nov 2016). 
  
  
• Ethics and transparency
• Dec 2015 Health care innovation & marketing arms-race: Memorial Sloan-Kettering Outpatient Surgery Center; and patient transparency.  
• Sep 2015, Oct 2016 Soda companies' sponsorships produce public health is the proactive planning, coordination and execution of strategies to improve and safeguard the wellbeing of the public.  Its global situation is discussed in The Great Escape by Deaton.  Public health in the US is coordinated by the PHS federally but is mainly executed at the state and local levels.  Public health includes:
  • Awareness campaigns about health threatening activities including: Smoking, Over-eating, Alcohol consumption, Contamination with poisons: lead; Joint damage from over-exercise;
    
  • Research, monitoring and control of disease agents, processes and vectors by agencies including the CDC. 
    
  • Monitoring of the public's health by institutes including the NIH.  This includes screening for cancer & heart disease. 
    
  • Development, deployment and maintenance of infrastructure including: sewers, water plants and pipes.  
  • Development, deployment and maintenance of vaccination strategies.  
  • Development, deployment and maintenance of fluoridation. 
    
  • Development, deployment and maintenance of family planning services. 
    
  • Regulation and constraint of foods, drugs and devices by agencies including the FDA.  
  conflicts of interest for non-profits
  
• Mylan coordinates and funds academics and lobbyists to remove EpiPen user's copayment is a fixed payment for a covered service after any deductible has been met.  It is a key strategy of the ACA to make subscribers aware of the costs of treatment and to put pressure on high cost health services.  As such suppliers and providers are keen to undermine the copayment: value based health insurance, Paying the copayment (Oct 2015), Place on the USPSTF list of preventative services (Sep 2016);
  (Sep 2016)
• Drug prices cause conflicts of interest for most patient advocacy groups (Sep 2016)
• Harvard school of public health/D.O.A. - U.S. Department of Agriculture. 
  academics were financed clandestinely by the sugar association to shift blame for obesity is an addictive disorder where the brain is induced to require more eating, often because of limits to the number of fat cells available to report satiation (Jul 2016).  Brain images of drug-addicted people and obese people have found similar changes in the brain.  Obese people's reward network tends to be less responsive to dopamine and have a lower density of dopamine receptors.  Obesity spreads like a virus through a social network with a 171% likelihood that a friend of someone who becomes obese will also become so.  Obesity is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes, asthma and heart disease.  It is suspected that this is contributing to the increase in maternal deaths in the US (Sep 2016).  Obesity is a complex condition best viewed as representing many different diseases, which is affected by the: Amount of brown adipose tissue (Oct 2016), Asprosin signalling by white adipose tissue (Nov 2016), Genetic alleles including 25 which guarantee an obese outcome, side effects of some pharmaceuticals for: Psychiatric disorders, Diabetes, Seizure, Hypertension, Auto-immunity; Acute diseases: Hypothyroidism, Cushing's syndrome, Hypothalamus disorders; State of the gut microbiome.  Infections, but not antibiotics, appear associated with childhood obesity (Nov 2016). 
  from sugar to fat in the 1960s (Sep 2016)
• Internal NIH is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.   investigation concludes MACH study was tainted, with NIAAA is the national institute on alcohol abuse and alcoholism, a part of the NIH. 
  staff and Beth Israel Deaconess/Harvard School of public health's Mukamal breaking many rules in seeking industry funding, and hiding problems from Dr. Collins and his staff.  So Collins cancelled MACH (Jun 2018)

Technology contents

• Applied AI
• Can a computer replace your doctor? (Sep 2014)
• Tech companies race to bring AI platforms to Market (Mar 2016)
• Alphabet Going Neural (Dec 2016) 
• Sundar Pichai - Google CEO leverages OKR is objectives and key results, Intel CEO Andy Grove's methodology for leveraging goals and strategies.  Key results are: specific, time-bound, measurable & verifiable.  They are expected to change as the actions proceed.  The OKR framework is a main subject of John Doerr's book Measure What Matters. 
  s
  
• Google uses Android to drive Chrome installations into the market, abusing its market position, EU is European Union, the 1992 Maastricht Council of Ministers meeting agreed evolution of the ECSC & CAP cartels to include:
  • A single market across the members' countries supporting the transformation of the ECSC.  It maintained the CAP transfers assisting French farmers. 
    
  • A fixed currency 'snake' that allowed the ECSC to operate, binding the deutschmark to the other currencies of participating members: a mini Bretton Woods exchange rate mechanism; that became a single currency, the euro, managed by an independent ECB (based on the independent German Bundesbank). 
    
  commission is the policy initiating & executive arm: implementing already agreed policies; of the EU.  Policy proposals are legislated by the Council of Ministers.  The European Commission is led by the president who is supported by commissioners, and staffed by a large bureaucracy.  The president is appointed for five years nominated by the Council of Ministers and approved by the European Parliament.  The commissioners are appointed by the Council of Ministers for a five year term, with consultation from the president & ratified by a vote of the European Parliament.  France, Germany, Italy, Spain and, until Brexit, the UK appoint two commissioners each, while the other members appoint one each. 
  
  judges & fines Google $5.1 billion (Jul 2018)
  
• Google secretly develops a censored version of their search engine.  Employees want to know about it.  China continues to block Google, Facebook etc. from its network (Aug 2018)
  
• Doug Lenat's Cyc - common sense rule engine used by Cleveland Clinic, Goldman Sachs; features of interest to Allen Institute & needed by Deepmind AlphaGo's deep learning is an artificial intelligence approach where engineers deploy data into deep neural networks. 
  & IBM's Watson (Mar 2016)
• Deepmind wins protein, a relatively long chain (polymer) of peptides.  Shorter chains of peptides are termed polypeptides.   folding modelling competition at Critical Assessment of Structure Prediction contest.  Pharmaceutical giants are seen lagging in applying deep learning is an artificial intelligence approach where engineers deploy data into deep neural networks. 
  to protein structure work (Feb 2019)
• Verily deploys deep neural networks are representational models that achieve high performance on difficult pattern recognition problems in vision and speech.  But they need specialized training methods such as greedy layerwise pre-training or HF optimization.  Researchers are gaining access to the participation of the individual 'neurons' using: visualization, attribution, dimensionality reduction, interpretability; (Mar 2018)
  to detect diabetic retinopathy is damage to the blood vessels of the retina due to high blood sugar levels associated with type 2 diabetes. 
  with retinal scan assistance.  W.H.O. is World Health Organization a United Nations organization.   reports 70 million Indians have diabetes includes type 1 and type 2.  Common side effects include: increased heart disease, hypertension, kidney disease, vision loss, nerve damage, and infections. 
  .  Used in Indian hospitals: Avarind Eye Hospital; and clinics, it supports the very low levels of trained doctors: 11 eye doctors per million people, so an A.I. system may massively improve screening.  Currently needs a clear lens for the neural networks to detect problems.  Europe's regulators have allowed the Verily system on to the market.  The US is the United States of America.   F.D.A. Food and Drug Administration.   also approved a system, but Verily's is still awaiting approval (Mar 2019)
• Google demonstrates decision making integrates situational context, state and signals to prioritize among strategies and respond in a timely manner.  It occurs in all animals, including us and our organizations: 
  
  • Individual human decision making includes conscious and unconscious aspects.  Situational context is highly influential: supplying meaning to our general mechanisms, & for robots too.  Emotions are important in providing a balanced judgement.  The adaptive unconscious interprets percepts quickly supporting 'fast' decision making.  Conscious decision making, supported by the: DLPFC, vmPFC and limbic system; can use slower autonomy.  The amygdala, during unsettling or uncertain social situations, signals the decision making regions of the frontal lobe, including the orbitofrontal cortex.  The BLA supports rejecting unacceptable offers.  Moral decisions are influenced by a moral decision switch.  Sleeping before making an important decision is useful in obtaining the support of the unconscious in developing a preference.  Word framing demonstrates the limitations of our fast intuitive decision making processes.  And prior positive associations detected by the hippocampus, can be reactivated with the support of the striatum linking it to the memory of a reward, inducing a bias into our choices.  Prior to the development of the PFC, the ventral striatum supports adolescent decision making.  Neurons involved in decision making in the association areas of the cortex are active for much longer than neurons participating in the sensory areas of the cortex.  This allows them to link perceptions with a provisional action plan.  Association neurons can track probabilities connected to a choice.  As evidence is accumulated and a threshold is reached a choice is made, making fast thinking highly adaptive.  Diseases including: schizophrenia and anorexia; highlight aspects of human decision making. 
    
  • Organisations often struggle to balance top down and distributed decision making: parliamentry government must use a process, health care is attempting to improve the process: checklists, end-to-end care; and include more participants, but has systemic issues, business leaders struggle with strategy. 
    
  in hidden layers of a visual neural network are representational models that achieve high performance on difficult pattern recognition problems in vision and speech.  But they need specialized training methods such as greedy layerwise pre-training or HF optimization.  Researchers are gaining access to the participation of the individual 'neurons' using: visualization, attribution, dimensionality reduction, interpretability; (Mar 2018)
  (Mar 2018)
  
• Allen Institute's project Alexandria will explore common sense (Mar 2018)  
• Alphabet's Google Duplex critiqued by NYU's Gary Marcus & Ernest Davis, for being tied to deep learning is an artificial intelligence approach where engineers deploy data into deep neural networks. 
  neural networks are representational models that achieve high performance on difficult pattern recognition problems in vision and speech.  But they need specialized training methods such as greedy layerwise pre-training or HF optimization.  Researchers are gaining access to the participation of the individual 'neurons' using: visualization, attribution, dimensionality reduction, interpretability; (Mar 2018)
  , that can only cope with very small domains of conversation.  Marcus & Davis argue the strategy has failed as a general A.I. approach and that work must shift back to knowledge engineering includes the technical, scientific and social strategies required to build, maintain and use knowledge-based computing systems.  The technical infrastructure includes a set of rules about the domain, a user interface & an inference engine. 
  to cope with the infinite flexibility of language (May 2018)
  
• Computer brain interfaces to robotic limbs
• UOM's He Mind-controlled robotic arm (Spring 2017)
  

• Antibiotics
  
• Mar 2014 The fat drug (fructose contribution)
• Nov 2016 Childhood obesity linked to infections, not the antibiotic are compounds which kill bacteria, molds, etc.  Sulfur dye stuffs were found to be effective antibiotics.  The first evolved antibiotic discovered was penicillin.  Antibiotics are central to modern health care supporting the processes of: Surgery, Wound management, Infection control; which makes the development of antibiotic resistance worrying.  Antibiotics are:
  • Economically problematic to develop and sell. 
    
  • Congress enacted GAIN to encourage development of new antibiotics.  But it has not developed any market-entry award scheme, which seems necessary to encourage new antibiotic R&D. 
    
  • Medicare has required hospitals and SNFs to execute plans to ensure correct use of antibiotics & prevent the spread of drug-resistant infections.  
  • C.D.C. is acting to stop the spread of resistant infections and reduce unnecessary use of antibiotics.  
    
  • F.D.A. has simplified approval standards.  It is working with industry to limit use of antibiotics in livestock. 
    
  • BARDA is promoting public-private partnerships to support promising research.
    
  • Impacting the microbiome of the recipient.  Stool banking is a solution  (Sloan-Kettering stool banking).  
  • Associated with obesity, although evidence suggests childhood obesity relates to the infections not the antibiotic treatments (Nov 2016). 
    
  • Monitored globally by W.H.O.
    
  • Regulated in the US by the F.D.A. who promote voluntary labeling by industry to discourage livestock fattening (Dec 2013).  
  • Customer demands have more effect - Perdue shifts to no antibiotics in premier chickens (Aug 2015). 
    
  treatment
  
• Sep 2015 Antibiotics associated with diabetes is the leading cause of blindness, limb amputations and kidney failure.  It is a risk factor for Alzheimer's disease.  Insulin and glucose levels are regulated by the pancreas, liver, muscle, brain and fat.  Diabetes occurs when the insulin level is insufficient to regulate the glucose in the system.  As we age our muscles become less sensitive to insulin and the pancreas responds by increasing the amount generated.  Increased fat levels in obesity demand more insulin overloading the pancreas.  Persistent high glucose levels are also toxic to the pancreas beta cells.  High glucocorticoid levels have been associated with type 2 diabetes.  There are genetic risk factors since siblings of someone with the disease have three times the baseline risk (about 50% of the risk of getting type 2 diabetes is genetic).  The inheritance is polygenic.  More than 20 genes have been identified as risk factors, but that is too few to account for the 50% weighting so many more will be identified.  Of those identified so far many are associated with the beta cells.  The one with the strongest relative risk is TCF7L2.  The disease can be effectively controlled through a diligent application of treatments and regular checkups.  Doctors are monitored for how under control their patients' diabetes is (Sep 2015).  Treatments include:
  • Metformin - does not change the course of pre-diabetes - if you stop taking it, it is as if it hasn't been taken. 
    
  • Diet
  • Exercise
  
  
• May 2015 Clostridium difficile usually competes with other bacteria in the human gut microbiome.  But antibiotic treatments provide it with an advantage where it becomes the predominant gut bacteria causing diarrhea, abdominal pain, and toxic megacolon.  Repeated treatments select for infections that are progressively more difficult to treat.  C. difficile infections kill more than 25,000 people a year in the US.  Fecal transplants, especially enabled by stool-banking, reintroduce competitive bacteria that limit the success of C. difficile and cure patients with previously recurrent infections.  But the F.D.A. has not approved such transplants as a treatment and the procedure is not covered by insurance. 
  
  infections catalyzed by health care's use of antibiotics.  
• Oct 2015 Microbiome stores 
• May 2016 Last resort antibiotic (Colistin) resistant bacteria found in USA 
• Oct 2016 Copper hospital room equipment associated with reduced infections 
• Apr 2019 Soil fungus, Candida auris is a fungus resident in soils, which has developed resistance to medical antifungals: itraconazole; as well as azole agricultural fungicides.  90% of C. auris infections are resistant to an antifungal.  30% are resistant to two of the drugs.  Genome analysis indicates four ancient strains persist.  It has been assisted by the widespread use of fungicides enabling it to opportunistically migrate to niches cleared of its normal competitors.  C. auris was first identified in an ear infection of a Japanese patient in 2009.  But it had subsequently colonized all proximate surfaces and was detected in the air.  It infects the very ill and those with weakened immune systems.  50% of those infected die within 90 days. 
  , has grown globally resistant results from evolutionary pressure of antibiotics, supported by plasmids and R factors: NDN1; which encode resistance properties for otherwise lethal antibiotics.  World leaders hope cooperation can preserve the power of last resort antibiotics: Carbapenems, Colistin (Oct 2016).  Worrying trends include: C. auris resistance to medical antifungals: itraconazole; as well as azole agricultural fungicides (Apr 2019), CRE (May 2016), C. diff (May 2015), MDR & XDR TB; resulting in increased risk of sepsis and death.  The World Bank estimates full resistance would reduce the global economy in 2050 by between 1.1 and 3.8%. 
  to azole agricultural fungicides and primary medical antifungals: itraconazole is an antifungal medication, classified by the WHO as an essential medicine.  It is a triazole which stops fungal growth by undermining metabolism and cell membrane integrity.  Effectiveness is being undermined by global agricultural deployment of equivalent azole fungicides on crops. 
  ; grows on most cleaned hospital and human surfaces.  Half the patients infected with C. auris, are already seriously ill at that point and die within 90 days.  C.D.C. is the HHS's center for disease control and prevention based in Atlanta Georgia.  
  monitors C. auris, but does not tell the public, to avoid panic and blacklisting of hospitals: Royal Brompton ICU is intensive care unit.  It is now being realized that the procedures and environment of the ICU is highly stressful for the patients.  In particular sedation with benzodiazepines is suspected to enhance the risk of inducing PTSD.  Intubation and catheterization are also traumatic.  Sometimes seperated into MICU and SICU.  eICU skill centralization may bring down costs. 
  , London, Mount Sinai, Universitari Politecnic La Fe, Valencia, Weill Cornell Medical Center 
• Chicago Northwestern Memorial AMC is Academic medical center.  They perform education, research and patient care.  They include one or more health professions schools, such as a medical school and a hospital.  The major AMCs are represented by the United HealthSystem Consortium.   The costly strategies of the AMCs and increased difficulty of finding enough targeted patients for research studies (Aug 2017) is forcing integration with larger hospital systems.  AMCs offer researchers clinical research support: Virus vectors (Nov 2017);
  lupus is a chronic autoimmune disease, in which many parts of the body can be attacked: joints, skin, kidneys, blood cells, brain, heart, lungs.  Its cause is unknown, there is little linkage within families, but women are affected 4 to 12 times as often as men - especially those of childbearing age.  There are various types: SLE, cutaneous lupus, drug-induced lupus, Neonatal lupus.  It is treated with Belimumab, prednisone corticosteroid;
  patient, Ms. Spoor, collapsed after a lung biopsy resulting in cardiac arrest is a sudden halt in the effective blood circulation due to the heart not contracting effectively.  This prevents delivery of oxygen and glucose to the body.  It can be caused by a heart attack.  CHF in contrast, typically has substandard circulation but the heart is still pumping sufficient blood to sustain life.  Cardiac arrest may be reversed with effective treatment.  The treatment regime and effectiveness vary significantly.  They can include:
  • CPR which needs endurance training to sustain for at least 45 minutes of deployment needed for success.  If no pulse is detected after 20 minutes more powerful treatments should be deployed. 
    
  • ECMO which is more widely used in Japan and South Korea than in the US.  
  • Once circulation is restored additional interventions are required for success, but their application is not benchmarked, standardized or regulated:
  • Therapeutic hypothermia - people who remain comatose after being in cardiac arrest should be cooled for at least 24 hours to a temperature between 89.6 and 96.8 F. 
    
  • Avoiding toxic amounts of oxygen
  • Maintaining normal co2 levels
  • Maintaining high blood pressure
  • If needed cardiac catheterization. 
    
  , provided ECMO is extracorporeal membrane oxygenation where blood is drawn from the patient and passed through an oxygenator and then back into the body. 
  breathing assists, subsequently found by blood test to be infected with Candida auris is a fungus resident in soils, which has developed resistance to medical antifungals: itraconazole; as well as azole agricultural fungicides.  90% of C. auris infections are resistant to an antifungal.  30% are resistant to two of the drugs.  Genome analysis indicates four ancient strains persist.  It has been assisted by the widespread use of fungicides enabling it to opportunistically migrate to niches cleared of its normal competitors.  C. auris was first identified in an ear infection of a Japanese patient in 2009.  But it had subsequently colonized all proximate surfaces and was detected in the air.  It infects the very ill and those with weakened immune systems.  50% of those infected die within 90 days. 
  , possibly from one of the tubes, which proved to be multiple drug resistant results from evolutionary pressure of antibiotics, supported by plasmids and R factors: NDN1; which encode resistance properties for otherwise lethal antibiotics.  World leaders hope cooperation can preserve the power of last resort antibiotics: Carbapenems, Colistin (Oct 2016).  Worrying trends include: C. auris resistance to medical antifungals: itraconazole; as well as azole agricultural fungicides (Apr 2019), CRE (May 2016), C. diff (May 2015), MDR & XDR TB; resulting in increased risk of sepsis and death.  The World Bank estimates full resistance would reduce the global economy in 2050 by between 1.1 and 3.8%. 
  and she died.  She is one of 158 cases in Illinois since 2016 (Apr 2019)
  
• Personalized medicines
  
• AML inhibitor
• AG-221 
• NIH is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.   allows stem cell is a biological cell which is partly or wholly undifferentiated.  A totipotent cell can generate a complete embryo and placenta.  Embryos include pluripotent cells which can generate any tissue in the body.  Adult humans' cells have turned off this ability but still include multipotent stem cells that differentiate into multiple cell types.   Typically a cell's local environment will have the signals required for it to obtain context and differentiate appropriately.  This will include both the external environment and the internal state of the cell which has replicated from a parent and obtained its epi-genetic state.   So introduction of undifferentiated stem cells into an injured area is not likely to have either aspect of the environment suitable.  Consequently development is aiming to encourage differentiation to progenitor cells for the damaged region.  This requires delivering the cells to the appropriate part of the body.  To avoid rejection by the immune system techniques aim to use cell lines developed from the patient's cells.  The techniques to generate these cell lines include: SCNT, iPS.  Possible mechanisms of stem cell therapy are: Generation of new differentiated cells, Stimulation of growth of new blood vessels to repopulate damaged regions, Secretion of growth factors, Treatment of diabetes (1 and 2) with addition of pancreatic cells, Assistance of other mechanisms; research to grow human parts in animals (Aug 2016)
  
• Juno halts CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers (Aug 2016, Jul 2017, Oct 2017, Nov 2017).  But there are severe side effects.  -T cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016). 
  trial after three deaths (Jul 2016) 
• CAR-T development process (Aug 2016)
• Kite Pharma is a close partner of the NCI is the national cancer institute. 
  leveraging public research investments in CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers (Aug 2016, Jul 2017, Oct 2017, Nov 2017).  But there are severe side effects.  s (Dec 2016)
• Gilead to acquire Kite Pharma for $11.9 billion (Aug 2017)
• Kite Pharma (Gilead)'s CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers (Aug 2016, Jul 2017, Oct 2017, Nov 2017).  But there are severe side effects.  -T gene therapy is the deployment of genes into patient's cells to treat or prevent diseases.  It can be performed outside the body (ex vivo) or in place (in vivo).  It requires a vector such as a: Virus, Ligandal style nanoparticle, electric field (Jul 2018); to perform the deployment.  But viruses are: Difficult to sanitize (bringing in oncogenes etc.) and hard to target as needed,  Unable to target where the DNA is deployed into the target cell chromosomes, Key targets of the immune system.  The process is disease specific:
  • Blood cancers: NHL; can be treated with ex vivo CAR-T (Jul 2017, Oct 2017)
  • Cystic fibrosis requires a virus that infects the airways and then deploys a non-cystic fibrosis allele into the nucleus of the patient's cells.  The obstacles to this process have been challenging: 
    
  • The virus must not have any problematic effects.  In the case of cystic fibrosis one virus activated a cancer gene leaving several trial subjects with leukemia. 
    
  • Efficiency of delivery has to be very high and this has not proved possible as of 2015. 
    
  • The newly delivered DNA must remain intact and be replicated and transcribed.  This has not proved to be the case. 
    
  • The process has not been able to avoid an immune response.  Gene therapy has consequently been of limited value for cystic fibrosis.  
  • Hemophilia A and B; virus delivered in vivo therapies enter final stage trials (Aug 2018)
    
  • ADA based SCID was the first human treatment with gene therapy.  A normal ADA gene was inserted ex vivo into immune system cells.  Initially the updated cells did not live as long as needed. 
    
  • Sickle-cell anemia requires a non-sickle-cell trait allele of the hemoglobin gene to be vectored into the bone marrow of the affected person.  
  • T-lymphocyte DNA updates for: mutation induced autoimmune diseases, melanoma treatment; using gene editing delivered with an electric field. 
    
  Yescarta, is approved is a $6.3 billion bill to increase funding for research into cancer, Alzheimer's disease and other disease, support mental health networks and adjust regulations for drugs and medical devices.  The act does not constrain drug prices.  It is funded with money taken from a preventative health care fund.  It aims to:
  • Expand the funding of the NIH.  
  • Allocates an additional $4.8 billion over 10 years.  Much of the expanded funding is focused on Alzheimer's and cancer.  This funding will still have to be appropriated by Congress. 
    
  • Empowers the NIH:
    
  • Provides them with authority to finance high-risk, high-reward research using special procurement procedures instead of grants and contracts, 
  • Requires the director to establish "Eureka prizes" for biomedical research and treatment improvements. 
    
  • Advances the Precision Medicine Initiative,
    
  • Support the moonshot to cure cancer. 
    
  • Align the federal drug regulatory structure with the processes of the biotechnology industry.  Critics argue it lowers drug and device approval standards, and raises the influence of surrogate endpoints. 
    
  • The F.D.A. is allocated half a billion dollars to help staff the expedited processes. 
    
  • It provides an expedited pathway for breakthrough medical technologies (offering options for life-threatening conditions with few treatment options). 
    
  • F.D.A. must consider the least burdensome means to show device safety. 
    
  • Streamline the mental health network.  It strengthens the enforcement of the mental health parity law.  
  • Creates the Presidentially appointed position of assistant secretary for mental health and substance use.  
  • Directs federal agencies to step up enforcement of laws that require equal insurance coverage for mental and physical illnesses. 
    
  • Stem the problem of opioid drug abuse with a $1 billion investment that will allow expanded access of treatment programs.  
  by F.D.A. Food and Drug Administration.  , for adults with CD19 expressing aggressive forms of NHL is non-Hodgkin lymphoma, It is:
  • A group of blood cancers that include all (> 60) types of lymphoma except HL.  
  • Risk factors include: poor immune function, autoimmune disease, Helicobacter pylori infection, hepatitis C, obesity, Epstein-Barr virus infection, HIV infection, radiation therapy, chemotherapy, PCBs, dioxin, phenoxy herbicides. 
    
  (Oct 2017)
  
• Novartis's Tisagenlecleucel treatment targets CD19 for unresponsive B-cell acute lymphoblastic leukemia is a group of cancers of blood forming tissues: bone marrow, lymphatic network; where abnormal white blood cells are generated.  One type of leukemia is induced when TAD boundaries near the TAL1 gene fail allowing promotors from across the TAD border to distort the operation of the TAL transcription factor.  Mutation clusters common in leukemia have been identified in CHIP. 
  , developed at University of Pennsylvania & deployed at Children's hospital of Philidelphia & Duke University, based on research part funded by the Leukemia & Lymphoma Society recommended for approval by F.D.A. Food and Drug Administration.   panel (Jul 2017)
• NCI is the national cancer institute. 
  research by Stanford SOM's Dr. Mackall, reported in Nature Medicine, targets tumor: Leukemia is a group of cancers of blood forming tissues: bone marrow, lymphatic network; where abnormal white blood cells are generated.  One type of leukemia is induced when TAD boundaries near the TAL1 gene fail allowing promotors from across the TAD border to distort the operation of the TAL transcription factor.  Mutation clusters common in leukemia have been identified in CHIP. 
  , Lymphoma is when lymphocytes continue reproducing, and do not die - a blood cancer. 
  ; cell surface protein CD22 with CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers (Aug 2016, Jul 2017, Oct 2017, Nov 2017).  But there are severe side effects.  -T, while Stanford & Seattle Children's are testing a CAR-T targeting both CD19 & CD22 (Nov 2017)
• University of Pennsylvania's research version of Novartis CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers (Aug 2016, Jul 2017, Oct 2017, Nov 2017).  But there are severe side effects.  -T treatment Kymriah, manufactured by the university and used at the Children's Hospital of Philadelphia to treat B cell ALL is acute lymphocytic/lymphoblastic leukemia.  The cancer starts in the lymphocytes of the bone marrow.  Too many lymphocytes are produced instead of mature white blood cells.  In 2010 combination chemotherapy, including 6-mercaptopurine, cures 85 to 90% of children suffering from ALL.  , resulted in one leukemia is a group of cancers of blood forming tissues: bone marrow, lymphatic network; where abnormal white blood cells are generated.  One type of leukemia is induced when TAD boundaries near the TAL1 gene fail allowing promotors from across the TAD border to distort the operation of the TAL transcription factor.  Mutation clusters common in leukemia have been identified in CHIP. 
  cell being reengineered along with the T-cells or T lymphocytes, are produced in the thymus & tonsils, and include a T-cell receptor.  Alpha beta T cells participate in the adaptive immune system.  Gamma delta T cells present antigens to other T cells.  CD4+ Helper T cells are activated by MHC class II molecules.  They generate cytokines to regulate the immune response.  Cytotoxic T cells (CD8+ receptor) destroy virus-infected cells and tumor cells.  They can be inactivated to prevent autoimmunity.  Memory T cells are formed when undifferentiated T cells are presented with antigen on MHC molecules located on an APC.  They are long lived and replicate widely when they detect antigen.  Regulatory T cells (suppressor and helper T cells) shut down T cell controlled immunity at the end of an immune reaction.  Natural killer T cells respond to CD1d presented glycolipid antigens.  MAIT cells defend against microbial infection with targeting by MR1.  , and deployed into the patient, who then died from the CAR-T resistant leukemia (Oct 2018)
  
• NCI is the national cancer institute. 
  's Rosenberg's TIL is tumor infiltrating lymphocyte, a class of lymphocyte that is considered to invade tumors and attack them.  TILs are isolated from the patient's tumors and cloned in large numbers.  Once the patient's native lymphocytes have been depleted with chemotherapy the TILs are infused in combination with interleukin-2 to attack the tumor. 
  therapy kills six KRAS is a gene that encodes the GTPase KRas, which is part of many signal transduction pathways that propagate growth factors.  Mutations in KRAS are essential for the development of many cancers. 
  tumors (Dec 2016)
  
• Immunotherapy is indirect treatment of disease by altering the immune system.  Targeted diseases include: cancers -- immuno-oncology, organ transplants. 
  (Jul 2016) with Nivolumab is a PD-1 inhibitor monoclonal antibody.  It is sold branded as Opdivo.  Its mode of action means it is likely to be toxic to a developing fetus.  It is used to treat:
  
  • Inoperable or metastatic melanoma (with no BRAF mutation) in combination with ipilimumab.  
  • As a second-line treatment when the cancer has a BRAF mutation - with an added BRAF inhibitor.  
  • Certain Hodgkin lymphomas. 
    
  • As a second-line treatment for squamous non-small cell lung cancer. 
    
  • As a second-line treatment for renal cell carcinoma. 
    
  offers hope, not certainty (Aug 2016) and fails lung cancer affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
  • Non-small-cell carcinomas are of three sub-types:
  • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
    
  • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
    
  • Large-cell carcinomas (5 to 10% of lung cancers).
    
  • Small-cell carcinomas.
    
  trial (Aug 2016), 
  
• UCSF study finds colorectal is also called colon cancer.  It:
  • Follows a slow, many yearlong, progression from a benign polyp to a localized cancer to an invasive one.  Two bacteria: Bacteroides fragilis, Escherichia coli variant; from the gut microbiome have been implicated in the early stages of tumor induction (Feb 2018).  It
    
  • Is often associated with Ras mutations and the high risk allele TCF7L2.  30 to 50% of colon cancers have KRAS mutations.  Intensive medical surveillance and removal of polyps can be lifesaving for those at high risk.  Types of colon cancer include the single gene mutation hereditary: FAP, HNPCC; 
  • Is linked to obesity. 
    
  and prostate is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  Research in mice may explain a link between obesity and prostate cancer (Jan 2018).  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
  • Sarcomas
  • Small cell carcinomas
  • Neuroendocrine tumors
  • Transitional cell carcinomas
  cancers is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016). 
  remotely inhibiting the immune system has to support and protect an inventory of host cell types, detect and respond to invaders and maintain the symbiont equilibrium within the microbiome.  It detects microbes which have breached the secreted mucus barrier, driving them back and fortifying the barrier.  It culls species within the microbiome that are expanding beyond requirements.  It destroys invaders who make it into the internal transport networks.  As part of its initialization it has immune cells which suppress the main system to allow the microbiome to bootstrap.  The initial microbiome is tailored by the antibodies supplied from the mother's milk while breastfeeding.  The immune system consists of two main parts the older non-adaptive part and the newer adaptive part.  The adaptive part achieves this property by being schematically specified by DNA which is highly variable.  By rapid reproduction the system recombines the DNA variable regions in vast numbers of offspring cells which once they have been shown not to attack the host cell lines are used as templates for interacting with any foreign body (antigen).  When the immune cell's DNA hyper-variable regions are expressed as y-shaped antibody proteins they typically include some receptor like structures which match the surfaces of the typical antigen.  Once the antibody becomes bound to the antigen the immune system cells can destroy the invader. 
  via a PD-L1 is programmed death-ligand 1, is a ligand for PD-1. 
  message, where the signal, is an emergent capability which is used by cooperating agents to support coordination & rival agents to support control and dominance.  In eukaryotic cells signalling is used extensively.  A signal interacts with the exposed region of a receptor molecule inducing it to change shape to an activated form.  Chains of enzymes interact with the activated receptor relaying, amplifying and responding to the signal to change the state of the cell.  Many of the signalling pathways pass through the nuclear membrane and interact with the DNA to change its state.  Enzymes sensitive to the changes induced in the DNA then start to operate generating actions including sending further signals.  Cell signalling is reviewed by Helmreich.  Signalling is a fundamental aspect of CAS theory and is discussed from the abstract CAS perspective in signals and sensors.  In AWF the eukaryotic signalling architecture has been abstracted in a codelet based implementation.  To be credible signals must be hard to fake.  To be effective they must be easily detected by the target recipient.  To be efficient they are low cost to produce and destroy. 
  is not on the surface of the cancer cells, explaining how these cancers have undermined current immunotherapy is indirect treatment of disease by altering the immune system.  Targeted diseases include: cancers -- immuno-oncology, organ transplants. 
  drugs uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
  • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
    
  • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
    
  • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
    
  • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
    
  .  Blocking the PD-L1 release from the cancer resulted in attacks by immune cells (Apr 2019)
  
• Major immuno-oncology uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
  • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
    
  • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
    
  • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
    
  • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
    
  trial of Keytruda, by NYU Langone Perlmutter Cancer Center's Dr. Leena Gandhi, funded by Merck, suggests non-squamous non-small-cell lung cancer affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
  • Non-small-cell carcinomas are of three sub-types:
  • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
    
  • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
    
  • Large-cell carcinomas (5 to 10% of lung cancers).
    
  • Small-cell carcinomas.
    
  patients with a biomarker have improved outcomes with early application of Keytruda and chemotherapy.  Result may change clinical practice (Apr 2018)
• BMS Opdivo treatment of HTLV-1 is human T-cell leukemia virus type 1, a human retrovirus, which causes adult T-cell leukemia/lymphoma and a demyelinating disease.  It infects millions of people in: Japan, Africa, South America, Caribbean, Australia; but only 5% of those infected develop the cancer.  It is transmitted between humans by: sex, breast-feeding, needle-sharing, transfusions, and transplants. 
  virus induced adult T-cell are a type of leukocyte.  They appear mainly in the lymphatic network.  Their are various types:
  • B cells which make antibodies that bind to pathogens, and activate the complement system.  When malignant these cells can produce multiple myeloma. 
    
  • Natural killer cells can kill body cells that do not display MHC class 1 molecules, or do display stress markers including MIC-A. 
    
  • T cells including CD4+ helper cells, Cytotoxic T cells, Gamma 5 T cells; 
    
  leukemia is a group of cancers of blood forming tissues: bone marrow, lymphatic network; where abnormal white blood cells are generated.  One type of leukemia is induced when TAD boundaries near the TAL1 gene fail allowing promotors from across the TAD border to distort the operation of the TAL transcription factor.  Mutation clusters common in leukemia have been identified in CHIP. 
  -lymphoma is when lymphocytes continue reproducing, and do not die - a blood cancer. 
  , an immuno-oncology uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
  • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
    
  • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
    
  • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
    
  • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
    
  checkpoint inhibitor release the immune system's checkpoints: PD-1, CTLA-4; on attacking host cells: by 1) stopping T-cell division and 2) reducing their life spans.  They are used in immuno-oncology where, in 2016: They are approved for treatment of: Advanced melanoma, HL, lung, kidney, liver cancer; They have a general success rate of 20 - 40% and higher for melanoma.   Checkpoint inhibitors work best for tumors that have many mutations: melanomas, lung and bladder cancers.  They are enhanced by adjunct treatments that kill tumor cells generating debris to stimulate the immune system.  The drugs include: ipilimumab (CTLA-4 inhbition), nivolumab, pembrolizumab, atezolizumab (PD-1 inhibitors);  They are costly and often have high copayments.  They cause auto-immune side effects including inflammation, rheumatoid arthritis and damage to glands: Adrenal, Thyroid, Pituitary.  Powerful steroids such as prednisone can help reduce the inflammation.  Damaged glands require sustained hormone treatment.  Checkpoint inhibitor research is funded by the CRI.  treatment, failed (Jun 2018)
  
• Trials suggest dupilumab is first safe and effective treatement for eczma (Oct 2016)
• Checkpoint inhibitors release the immune system's checkpoints: PD-1, CTLA-4; on attacking host cells: by 1) stopping T-cell division and 2) reducing their life spans.  They are used in immuno-oncology where, in 2016: They are approved for treatment of: Advanced melanoma, HL, lung, kidney, liver cancer; They have a general success rate of 20 - 40% and higher for melanoma.   Checkpoint inhibitors work best for tumors that have many mutations: melanomas, lung and bladder cancers.  They are enhanced by adjunct treatments that kill tumor cells generating debris to stimulate the immune system.  The drugs include: ipilimumab (CTLA-4 inhbition), nivolumab, pembrolizumab, atezolizumab (PD-1 inhibitors);  They are costly and often have high copayments.  They cause auto-immune side effects including inflammation, rheumatoid arthritis and damage to glands: Adrenal, Thyroid, Pituitary.  Powerful steroids such as prednisone can help reduce the inflammation.  Damaged glands require sustained hormone treatment.  Checkpoint inhibitor research is funded by the CRI.  found to cause heart damage in rare cases (Nov 2016)
• BMS/NCI is the national cancer institute. 
  funded PD-1 is programmed cell death protein 1 (CD279) is encoded by the PDCD1 gene.  It is a cell surface receptor that belongs to the immunoglobulin superfamily. It is expressed on T-cells and pro-B cells.  It acts as an immune checkpoint preventing the activation of T-cells to help self-tolerance and reduce autoimmunity.  When it fails people can suffer from: Lupus, Crohn's disease, Rheumatoid arthritis.  PD-1 inhibitor drugs activate the immune system to attack tumors.   PD-1 inhibitors are being approved for Melanoma and squamous-cell form of lung cancer.   checkpoint inhibitor release the immune system's checkpoints: PD-1, CTLA-4; on attacking host cells: by 1) stopping T-cell division and 2) reducing their life spans.  They are used in immuno-oncology where, in 2016: They are approved for treatment of: Advanced melanoma, HL, lung, kidney, liver cancer; They have a general success rate of 20 - 40% and higher for melanoma.   Checkpoint inhibitors work best for tumors that have many mutations: melanomas, lung and bladder cancers.  They are enhanced by adjunct treatments that kill tumor cells generating debris to stimulate the immune system.  The drugs include: ipilimumab (CTLA-4 inhbition), nivolumab, pembrolizumab, atezolizumab (PD-1 inhibitors);  They are costly and often have high copayments.  They cause auto-immune side effects including inflammation, rheumatoid arthritis and damage to glands: Adrenal, Thyroid, Pituitary.  Powerful steroids such as prednisone can help reduce the inflammation.  Damaged glands require sustained hormone treatment.  Checkpoint inhibitor research is funded by the CRI.  immuno-oncology uses the immune system to treat cancer.  Cancer cells often have different molecules on their cell surface.  Studies have shown that genetic signatures of tumors can help predict which patients will benefit from treatment with PD-1 checkpoint inhibitors.  Checkpoint inhibitor based treatments aim to make the immune system target these antigens.  Clinical trial results indicate they are prolonging lives - even if only by a few months.  They have reduced side effects relative to generic chemo therapy.  There are three main strategies: cellular, antibody and cytokine.  
  • Antibody therapies target receptors including CD20, CD274, CD279 and CTLA-4.  These therapies include MABs: Alemtuzumab, Ofatumumab, Rituximab; and may induce checkpoint inhibition.
    
  • Cellular therapies have typically involved removing the immune cells from the blood or a tumor, activating, culturing and then returning them to the patient.  Trials of these CAR and TCR therapies are proceeding, with some significant problems (Jul 2016). 
    
  • Cytokine therapies enhance anti-tumor activity through the cytokine's regulation and coordination of the immune system. 
    
  • Vaccines, including Sipuleucel-T for prostate cancer and BCG, classically a vaccine for tuberculosis, which is used for treating bladder cancer. 
    
  study by MD Anderson's Dr. Hussain Tawbi reports Opdivo & Yervoy combination used to treat melanoma is a cancer of the melanocytes.  It is a less common form of skin cancer but is the most deadly once it has invaded deeply into layers of skin.  It is primarily caused by UV light.  It is tied to mutations in the signalling pathway (BRAF) and regulatory genes (P53) with a key dependency on crestin reactivation (Jan 2016).   (and likely other cancers of 200,000 people a year) patients with consequent metastatic brain cancers, at 28 AMC is Academic medical center.  They perform education, research and patient care.  They include one or more health professions schools, such as a medical school and a hospital.  The major AMCs are represented by the United HealthSystem Consortium.   The costly strategies of the AMCs and increased difficulty of finding enough targeted patients for research studies (Aug 2017) is forcing integration with larger hospital systems.  AMCs offer researchers clinical research support: Virus vectors (Nov 2017);
  s, find survival rate expands beyond a year, like Jimmy Carter after he was treated with Keytruda.  But 50% of patients had significant side effects of which 20% quit the treatment (Aug 2018)
  
• MD Anderson's president, scientist & strategist, John Mendelsohn, dies of glioblastoma are a fast growing form of glioma which usually strike older people and have an average survival time of 18 months in 2015.  The reason for the aggressive growth of glioblastomas is due to collapse of the barriers between two DNA islands which integrates a highly active loop with a low activation loop containing a growth promotor (Dec 2015). Researched by the TCGA project. 
  .  Originally a scientist at UC San Diego, where he developed centuximab is an EGF receptor inhibitor.  It is a humanized mouse MAB branded as Erbitux.  It used to treate metastatic cancers: colorectal, non-small cell lung, neck, head.  Cetuximab was developed by John Mendelsohn, at UC San Diego, with ImClone Systems which was later purchased by Eli Lilly.  Being mouse originated, it has induced MMA (Jul 2018). 
  (Erbitux) with ImClone Systems where Mendelson was a director, which was purchased by Eli Lilly.  Mendelson was also a director of Enron, on its audit committee!  Mendelson ramped revenue at MD Anderson to $3 billion (Jan 2019) 
  
• Cuban immunotherapy vaccine are a core strategy of public health and have significantly extended global wellbeing over 200 years.  Smallpox & polio were virtually eradicated.  Recent successes include: HPV vaccine: Gardasil.  They induce active acquired immunity to a particular disease.  But the development and deployment of vaccines is complex:
  • The business model for vaccine development has been failing (Aug 2015): 
    
  • No Zika vaccine was available as the epidemic grew (Mar 2016).  No vaccine for: CMV;
    
  • Major foundations: Michael J. Fox, Gates, Wellcome; are working to improve the situation including sponsorship of the GAVI alliance.  A geographic cluster is forming in Seattle including PATH (Apr 2016). 
    
  • Commercial developers include: Affiris, Cell Genesis, Chiron, CSL, Sanofi, Valeant;
    
  • Vaccine deployment traditionally benefited from centrally managed vertical health programs.  But political issues are now constraining success with less than 95-99% coverage required for herd immunity (Aug 2015, Sep 2015, Nov 2015, Nov 2016, Jul 2018).  
  • Where clinics have been driven into local neighborhoods health improves (Apr 2016).  
  • Retail clinics (Mar 2016): CVS Minute Clinics focus on vaccination. 
    
  • NNT is a useful metric for vaccine benefit.  Influenza vaccine has an NNT of between 37 and 77, is cheap and causes little harm, so it is very beneficial. 
    
  • Key vaccines include: BCG, C. difficile (May 2015), Cholera (El Tor), Cervical Cancer (Gardasil HPV Jun 2018, Oct 2018), Dengvaxia (Mexico Dec 2015), Gvax, Influenza, Malaria vaccine, Provenge, Typbar-TCV (XDR typhoid Pakistan Apr 2018);
  • Regulation involves: FDA (CBER), with CMS monitoring (star ratings, PACE (Aug 2016), Report cards (Sep 2015)) & CDC promoting vaccines: as a sepsis measure, To control C. difficile (May 2015);  
  • Coding : CVX, MVX;
    
  • Research on vaccines includes: 
  • NIH: AIDS vaccines (AVRC), Focus on using genetic analysis to improve vaccine response.  
  • NCI:
  • Roswell Park clinical trial of immuno-oncology vaccine cimavax. 
    
  • Geisinger: effective process leverage in treatment. 
    
  • Stanford Edge immuno-oncology for cancer vaccines.  
  • P53-driven-cancer focused, gene therapy (Jun 2015). 
    
  Cimavax is a non-small cell lung cancer immuno-oncology vaccine.  It is an active vaccine, containing the ligand EGF and P64k and Montanide ISA 51 which together stimulate the immune system to generate antibodies targeted at EGF.  This results in the EGF concentration in the blood dropping.  Many cancers: Lung, Colon, Kidney, Head, Neck; leverage EGFR to stimulate cell growth. 
  is smuggled to US by non-small cell lung cancer affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
  • Non-small-cell carcinomas are of three sub-types:
  • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
    
  • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
    
  • Large-cell carcinomas (5 to 10% of lung cancers).
    
  • Small-cell carcinomas.
    
  sufferers (Nov 2016)
• NK are natural killer cells:
  
  • Are cell killing lymphocytes that participate in the innate and adaptive immune system responses.  
  • Are unusual in recognising stressed cells without signalling from antibodies or MHC.  They consequently respond relatively rapidly.  And they kill cells that T-lymphocytes will not. 
    
  • Attack viral-infected cells and tumor cells.  
  • Express cell surface proteins CD16 & CD56. 
    
  based therapy research at MD Anderson offer possibility of off-the-shelf immunotherapy is indirect treatment of disease by altering the immune system.  Targeted diseases include: cancers -- immuno-oncology, organ transplants. 
  , as CAR is chimeric antigen receptor.  Killer T lymphocytes are genetically engineered to produce a novel protein, composed of pieces from different parts of the immune system such as: antibody components to construct a new receptor binding site on the T cell that targeted an antigen exposed on the cell surface of cancer cells, and two receptor associated signals that switch the T-cell into kill mode and sustain it in that mode.  Small clinical trials of CAR-T cells have shown substantial remissions among patients with various blood cancers (Aug 2016, Jul 2017, Oct 2017, Nov 2017).  But there are severe side effects.  -T increases target tumors treated: Leukemia is a group of cancers of blood forming tissues: bone marrow, lymphatic network; where abnormal white blood cells are generated.  One type of leukemia is induced when TAD boundaries near the TAL1 gene fail allowing promotors from across the TAD border to distort the operation of the TAL transcription factor.  Mutation clusters common in leukemia have been identified in CHIP. 
  (blood) soon and same Novartis Tisagenlecleucel CD19 targeted treatment expanded to lymphoma is when lymphocytes continue reproducing, and do not die - a blood cancer. 
  ; and glioblastoma are a fast growing form of glioma which usually strike older people and have an average survival time of 18 months in 2015.  The reason for the aggressive growth of glioblastomas is due to collapse of the barriers between two DNA islands which integrates a highly active loop with a low activation loop containing a growth promotor (Dec 2015). Researched by the TCGA project. 
  (brain) studied at U. Penn, breast is a variety of different cancerous conditions of the breast tissue.  World wide it is the leading type of cancer in women and is 100 times more common in women than men.  260,000 new cases of breast cancer will occur in the US in 2018 causing 41,000 deaths.  The varieties include: Hormone sensitive tumors that test negative for her2 (the most common type affecting three quarters of breast cancers in the US, BRCA1/2 positive, ductal carcinomas including DCIS, lobular carcinomas including LCIS.  Receptor presence on the cancer cells is used as a classification: Her2+/-, estrogen (ER)+/-, progesterone (PR)+/-.  Metastasis classes the cancer as stage 4.  Genetic risk factors include: BRCA, p53, PTEN, STK11, CHEK2, ATM, GATA3, BRIP1 and PALB2.  Treatments include: Tamoxifen, Raloxifene; where worrying racial disparities have been found (Dec 2013).  International studies indicate early stage breast cancer typed by a genomic test: Oncotype DX, MammaPrint; can be treated without chemotherapy (Aug 2016, Jun 2018), prostate is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  Research in mice may explain a link between obesity and prostate cancer (Jan 2018).  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
  • Sarcomas
  • Small cell carcinomas
  • Neuroendocrine tumors
  • Transitional cell carcinomas
  , ovary is a relatively uncommon disease but is often fatal.  It has been associated with use of talcum powder (May 2016).  , lung affects 200,000 Americans each year.  Inflammation is a driver of lung cancer spread (Aug 2017).  All these cancers are carcinomas.  There are two main hystological types:
  • Non-small-cell carcinomas are of three sub-types:
  • Adenocarcinomas (40% of lung cancers) are typically peripherally situated and mostly induced by smoking.
    
  • Squamous-cell carcinomas (30% of lung cancers) arise in the large bronchi an are highly correlated with smoking. 
    
  • Large-cell carcinomas (5 to 10% of lung cancers).
    
  • Small-cell carcinomas.
    
  & pancreas is most often an exocrine tumor.  Islet cell tumors are less common.  These are rare cancers: less than 200,000 US cases per year, but the five year survival rates are extremely low 3%.  They all have KRAS mutations.  They are associated with obesity.  Diagnostics are starting to leverage genomics and big databases (23 and me).  Treatments include:
  • Avastin
    
  • Tarceva 
  within 5 years (Jul 2017) 
• Study by Brigham & Women's Dr. Ridker of Novartis's rheumatoid arthritis is an autoimmune disorder where the immune system attacks the joints and can generate inflammation around the lungs and heart.  It can be treated with: Enbrel, Humira, Ilaris, Xeljanz;
  drug Ilaris shows by reducing inflammation it also lower cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016). 
  and cardiac is coronary artery disease, also called heart disease or CHD.  It reflects atherosclerosis of the coronary arteries.  risk, is an assessment of the likelihood of an independent problem occurring.  It can be assigned an accurate probability since it is independent of other variables in the system.  As such it is different from uncertainty. 
  but high cost will limit its deployment (Aug 2017)
  
• Personalized medicine is a medical strategy where decisions, practices, and products are tailored to the individual patient.  Research is looking at the impact of providing potentially deleterious genomic testing information to people: The REVEAL study found no increased anxiety induced by hearing that one's genome implied increased risk of developing late onset Alzheimer's disease.  The take-up of personalized medicine benefits from the focus on genomics, enabled by next generation sequencing of DNA, and detailed by the NIH director Francis Collins and includes:
  • NCCN intensive cell therapies
    
  • Direct to consumer genomic testing
    
  • Direct to consumer diagnostics
    
  • Pharmacogenomics tailored drug treatments reducing the risk and cost of adverse drug reactions.   
  & immunotherapy is indirect treatment of disease by altering the immune system.  Targeted diseases include: cancers -- immuno-oncology, organ transplants. 
  clinical trials are constrained by: Limited patient base argue: Yale CC, MSKCC, Genentech; Companies with me-too products requesting trials -- a situation companies with F.D.A. Food and Drug Administration.   approval: Merck; are happy to see (Aug 2017)
• Electric field found to be quick acting replacement for viral delivery platforms, allowing CRISPR is clustered replicating interspersed silent palindromic repeats; a technique for exact targeting, cutting and editing of DNA based on leveraging bacterial enzymatic defenses against viruses generalized to any DNA sequence in a prokaryotic or eukaryotic cell.  It was identified during studies of a bacterial adaptive immune system.  In that system bacterial proteins grab parts of a virus that has infected them and record it within the palindromic structures that mark an array of inserted viral DNA used as a log persisted over generations.  If a new infection occurs the viral DNA is compared with the sequences and if a match exists the CAS proteins break up the viral DNA initiating its destruction.  This bacterial system was then updated and repurposed by the researchers to support targeted genetic engineering.  As explained by Dr. Doudna, the CRISPR proteins and the 20 nucleotide RNA template migrate into the nucleus where they rapidly target DNA which complements the RNA template and the Cas9 enzyme performs the edits.  Being a bacterial system CRISPR Cas9 does not target eukaryotic heterochromatic DNA well.  It is not fully understood how they find the target sequence so quickly.  It has been shown that Cas9 will bind to sites with a 5-8 base match but then it releases rapidly without cutting.  To cut, Cas9 has to reconfigure, which does not occur in the mismatch situations.   introduction to T-cells are a type of leukocyte.  They appear mainly in the lymphatic network.  Their are various types:
  • B cells which make antibodies that bind to pathogens, and activate the complement system.  When malignant these cells can produce multiple myeloma. 
    
  • Natural killer cells can kill body cells that do not display MHC class 1 molecules, or do display stress markers including MIC-A. 
    
  • T cells including CD4+ helper cells, Cytotoxic T cells, Gamma 5 T cells; 
    
  for DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used.   editing, in major scientific advance by UCSF/UC Berkeley Innovative Genomics Institute's Dr. Marson.  In-vitro, T-cells were programmed to: recognize melanoma is a cancer of the melanocytes.  It is a less common form of skin cancer but is the most deadly once it has invaded deeply into layers of skin.  It is primarily caused by UV light.  It is tied to mutations in the signalling pathway (BRAF) and regulatory genes (P53) with a key dependency on crestin reactivation (Jan 2016).   cells, and help children with autoimmune disease include: celiac disease, eczema, IBD, lupus, multiple sclerosis, type-1-diabetes; are often debilitating and life long conditions.  Autoimmune diseases are increasing in prevalence rapidly over two or three generations in advanced societies.  One in thirteen Americans has an autoimmune condition.  Some are associated with gene alleles encoding the immune system.  Stress is associated with increased autoimmune problems (Jan 2017)
  caused by rare mutations.  Therapies may follow shortly including for HIV is human immunodeficiency virus, an RNA retrovirus which causes AIDS.  It infects T-lymphocytes destroying the host's immune system.  Some HIV's enter the lymphocytes by leveraging the T cells CCR5 protein.  The HIV X4 variant leverages CXCR4. 
  (Jul 2018)
• Scientific reprogramming of the immune response, helps with organ transplants.  A patient with NASH is non-alcoholic steatohepatitis. 
  induced liver is an emergent cellular system providing metabolic: Dietary compound metabolism and signalling: After gorging on sugar-rich foods the liver releases FGF21 hormone to dampen further eating activity; Detoxification, Regulation of glucose through glycogen storage (asprosin signalling from white adipose tissue); clotting, immune, exocrine and endocrine functions.  It is supplied with oxygen-rich blood via the hepatic artery and blood rich in semi-processed foodstuffs from the intestines & spleen via the hepatic portal vein.  It is constructed from: Hepatocytes which swim in the blood to process it, BECs, Stromal cells, Hepatic stellate cells, Kupffer cells, and blood vessels.  The embryonic endoderm cells invade the mesoderm to form the liver bud.  Subsequently the liver bud vascularizes and is colonized by hematopoietic cells.  The liver operates on a daily cycle (Aug 2018) allowing it time to recover from the stress of processing toxic substances.  In a healthy adult liver cells do not divide significantly.  But in a damaged liver, the liver cells shift back to a neonatal state to re-enter the cell cycle and rebuild the liver.  There are over 100 disorders of the liver.  Obesity and diabetes are associated with increased prevalence of these liver disorders worldwide. 
  failure becomes an early target for reprogramming.  Liver and kidney provides multiple vital functions.  It: Produces renin which supports negative feedback, Removes excess organic molecules from the blood, Regulates electrolytes in the blood, Maintains pH homeostasis, Regulates fluid balance, Regulates blood pressure, monitors blood oxygen concentration and signals erythropoiesis with EPO, Reabsorbs water, glucose (SGLT2) and amino acids.  Kidney function is monitored with the GFR.  Kidneys can fail acutely or chronically.  Kidneys are affected by a variety of cancers including: advanced kidney cancer, von Hippel Landau; some of which are induced by PFAS.    Multiple myeloma, type 2 diabetes, TB and drug treatments for MDR TB place a strain on the kidneys and can induce failure.   transplants suffer from immune responses and immune supression drug impacts.  Mass. Gen's James Markmann & Dana-Farber's Eva Guinan grow Regulatory T-cells or T lymphocytes, are produced in the thymus & tonsils, and include a T-cell receptor.  Alpha beta T cells participate in the adaptive immune system.  Gamma delta T cells present antigens to other T cells.  CD4+ Helper T cells are activated by MHC class II molecules.  They generate cytokines to regulate the immune response.  Cytotoxic T cells (CD8+ receptor) destroy virus-infected cells and tumor cells.  They can be inactivated to prevent autoimmunity.  Memory T cells are formed when undifferentiated T cells are presented with antigen on MHC molecules located on an APC.  They are long lived and replicate widely when they detect antigen.  Regulatory T cells (suppressor and helper T cells) shut down T cell controlled immunity at the end of an immune reaction.  Natural killer T cells respond to CD1d presented glycolipid antigens.  MAIT cells defend against microbial infection with targeting by MR1.   with donor tissue invitro, then infuse the T-cells back into the patient to reprogram the immune system has to support and protect an inventory of host cell types, detect and respond to invaders and maintain the symbiont equilibrium within the microbiome.  It detects microbes which have breached the secreted mucus barrier, driving them back and fortifying the barrier.  It culls species within the microbiome that are expanding beyond requirements.  It destroys invaders who make it into the internal transport networks.  As part of its initialization it has immune cells which suppress the main system to allow the microbiome to bootstrap.  The initial microbiome is tailored by the antibodies supplied from the mother's milk while breastfeeding.  The immune system consists of two main parts the older non-adaptive part and the newer adaptive part.  The adaptive part achieves this property by being schematically specified by DNA which is highly variable.  By rapid reproduction the system recombines the DNA variable regions in vast numbers of offspring cells which once they have been shown not to attack the host cell lines are used as templates for interacting with any foreign body (antigen).  When the immune cell's DNA hyper-variable regions are expressed as y-shaped antibody proteins they typically include some receptor like structures which match the surfaces of the typical antigen.  Once the antibody becomes bound to the antigen the immune system cells can destroy the invader. 
  to accept the donor's liver cells.  Pittsburg is using regulatory dendritic cells is an APC that is critical to inflammatory state activation and control of the innate and adaptive immune systems and induction of tolerance during the system's steady-state.  Regulatory dendritic cells present environmental antigens to regulatory T-cells to induce immune tolerance.  It is possible to push abundant immature white blood cells to transform into dendritic cells in-vitro.   to support kidney transplants (Jan 2019)
  
• Viral delivery platforms for gene therapy is the deployment of genes into patient's cells to treat or prevent diseases.  It can be performed outside the body (ex vivo) or in place (in vivo).  It requires a vector such as a: Virus, Ligandal style nanoparticle, electric field (Jul 2018); to perform the deployment.  But viruses are: Difficult to sanitize (bringing in oncogenes etc.) and hard to target as needed,  Unable to target where the DNA is deployed into the target cell chromosomes, Key targets of the immune system.  The process is disease specific:
  • Blood cancers: NHL; can be treated with ex vivo CAR-T (Jul 2017, Oct 2017)
  • Cystic fibrosis requires a virus that infects the airways and then deploys a non-cystic fibrosis allele into the nucleus of the patient's cells.  The obstacles to this process have been challenging: 
    
  • The virus must not have any problematic effects.  In the case of cystic fibrosis one virus activated a cancer gene leaving several trial subjects with leukemia. 
    
  • Efficiency of delivery has to be very high and this has not proved possible as of 2015. 
    
  • The newly delivered DNA must remain intact and be replicated and transcribed.  This has not proved to be the case. 
    
  • The process has not been able to avoid an immune response.  Gene therapy has consequently been of limited value for cystic fibrosis.  
  • Hemophilia A and B; virus delivered in vivo therapies enter final stage trials (Aug 2018)
    
  • ADA based SCID was the first human treatment with gene therapy.  A normal ADA gene was inserted ex vivo into immune system cells.  Initially the updated cells did not live as long as needed. 
    
  • Sickle-cell anemia requires a non-sickle-cell trait allele of the hemoglobin gene to be vectored into the bone marrow of the affected person.  
  • T-lymphocyte DNA updates for: mutation induced autoimmune diseases, melanoma treatment; using gene editing delivered with an electric field. 
    
  , are proving difficult to produce: MilliporeSigma, Oxford BioMedica, BioMarin; constraining experimental research (Nov 2017)
• Biomarin, Spark/Pfizer sees success with gene therapy is the deployment of genes into patient's cells to treat or prevent diseases.  It can be performed outside the body (ex vivo) or in place (in vivo).  It requires a vector such as a: Virus, Ligandal style nanoparticle, electric field (Jul 2018); to perform the deployment.  But viruses are: Difficult to sanitize (bringing in oncogenes etc.) and hard to target as needed,  Unable to target where the DNA is deployed into the target cell chromosomes, Key targets of the immune system.  The process is disease specific:
  • Blood cancers: NHL; can be treated with ex vivo CAR-T (Jul 2017, Oct 2017)
  • Cystic fibrosis requires a virus that infects the airways and then deploys a non-cystic fibrosis allele into the nucleus of the patient's cells.  The obstacles to this process have been challenging: 
    
  • The virus must not have any problematic effects.  In the case of cystic fibrosis one virus activated a cancer gene leaving several trial subjects with leukemia. 
    
  • Efficiency of delivery has to be very high and this has not proved possible as of 2015. 
    
  • The newly delivered DNA must remain intact and be replicated and transcribed.  This has not proved to be the case. 
    
  • The process has not been able to avoid an immune response.  Gene therapy has consequently been of limited value for cystic fibrosis.  
  • Hemophilia A and B; virus delivered in vivo therapies enter final stage trials (Aug 2018)
    
  • ADA based SCID was the first human treatment with gene therapy.  A normal ADA gene was inserted ex vivo into immune system cells.  Initially the updated cells did not live as long as needed. 
    
  • Sickle-cell anemia requires a non-sickle-cell trait allele of the hemoglobin gene to be vectored into the bone marrow of the affected person.  
  • T-lymphocyte DNA updates for: mutation induced autoimmune diseases, melanoma treatment; using gene editing delivered with an electric field. 
    
  for hemophilia A is due to problems with clotting factor VIII. 
  and B is due to problems with clotting factor IX. 
  .  The genes are deployed into the livers is an emergent cellular system providing metabolic: Dietary compound metabolism and signalling: After gorging on sugar-rich foods the liver releases FGF21 hormone to dampen further eating activity; Detoxification, Regulation of glucose through glycogen storage (asprosin signalling from white adipose tissue); clotting, immune, exocrine and endocrine functions.  It is supplied with oxygen-rich blood via the hepatic artery and blood rich in semi-processed foodstuffs from the intestines & spleen via the hepatic portal vein.  It is constructed from: Hepatocytes which swim in the blood to process it, BECs, Stromal cells, Hepatic stellate cells, Kupffer cells, and blood vessels.  The embryonic endoderm cells invade the mesoderm to form the liver bud.  Subsequently the liver bud vascularizes and is colonized by hematopoietic cells.  The liver operates on a daily cycle (Aug 2018) allowing it time to recover from the stress of processing toxic substances.  In a healthy adult liver cells do not divide significantly.  But in a damaged liver, the liver cells shift back to a neonatal state to re-enter the cell cycle and rebuild the liver.  There are over 100 disorders of the liver.  Obesity and diabetes are associated with increased prevalence of these liver disorders worldwide. 
  of hemophiliacs, using a virus - which inflammed the immune system has to support and protect an inventory of host cell types, detect and respond to invaders and maintain the symbiont equilibrium within the microbiome.  It detects microbes which have breached the secreted mucus barrier, driving them back and fortifying the barrier.  It culls species within the microbiome that are expanding beyond requirements.  It destroys invaders who make it into the internal transport networks.  As part of its initialization it has immune cells which suppress the main system to allow the microbiome to bootstrap.  The initial microbiome is tailored by the antibodies supplied from the mother's milk while breastfeeding.  The immune system consists of two main parts the older non-adaptive part and the newer adaptive part.  The adaptive part achieves this property by being schematically specified by DNA which is highly variable.  By rapid reproduction the system recombines the DNA variable regions in vast numbers of offspring cells which once they have been shown not to attack the host cell lines are used as templates for interacting with any foreign body (antigen).  When the immune cell's DNA hyper-variable regions are expressed as y-shaped antibody proteins they typically include some receptor like structures which match the surfaces of the typical antigen.  Once the antibody becomes bound to the antigen the immune system cells can destroy the invader. 
  .  After finding an Italian who produced 12 times the normal levels of factor IX, researchers could reduce the amount of virus needed to deploy spark's medication.  Treatment for A had to deploy a huge gene - too big a payload for an adeno-associated virus.  Over 15 years of chopping bits out of the gene that were not found to be essential, the payload has shrunk.  Final stage trials are just beginning.  Biomarin trial for A increased factor VIII for a year but its level dropped in the second year.  Spark's trial only raised factor IX to 35% of normal, but the level has stayed steady for two years.  (Aug 2018)
• Bluebird Bio gene therapy is the deployment of genes into patient's cells to treat or prevent diseases.  It can be performed outside the body (ex vivo) or in place (in vivo).  It requires a vector such as a: Virus, Ligandal style nanoparticle, electric field (Jul 2018); to perform the deployment.  But viruses are: Difficult to sanitize (bringing in oncogenes etc.) and hard to target as needed,  Unable to target where the DNA is deployed into the target cell chromosomes, Key targets of the immune system.  The process is disease specific:
  • Blood cancers: NHL; can be treated with ex vivo CAR-T (Jul 2017, Oct 2017)
  • Cystic fibrosis requires a virus that infects the airways and then deploys a non-cystic fibrosis allele into the nucleus of the patient's cells.  The obstacles to this process have been challenging: 
    
  • The virus must not have any problematic effects.  In the case of cystic fibrosis one virus activated a cancer gene leaving several trial subjects with leukemia. 
    
  • Efficiency of delivery has to be very high and this has not proved possible as of 2015. 
    
  • The newly delivered DNA must remain intact and be replicated and transcribed.  This has not proved to be the case. 
    
  • The process has not been able to avoid an immune response.  Gene therapy has consequently been of limited value for cystic fibrosis.  
  • Hemophilia A and B; virus delivered in vivo therapies enter final stage trials (Aug 2018)
    
  • ADA based SCID was the first human treatment with gene therapy.  A normal ADA gene was inserted ex vivo into immune system cells.  Initially the updated cells did not live as long as needed. 
    
  • Sickle-cell anemia requires a non-sickle-cell trait allele of the hemoglobin gene to be vectored into the bone marrow of the affected person.  
  • T-lymphocyte DNA updates for: mutation induced autoimmune diseases, melanoma treatment; using gene editing delivered with an electric field. 
    
  for sickle-cell anemia is a recessive single gene disease where the sufferer's hemoglobin causes the red blood cells to distort.  It is a side effect of the evolved protection from malaria provided by sickle cell trait.  Potential treatments include gene therapy and drugs that block the sickling of red blood cells.  Carrier screening was undermined by there being no effective prenatal test limiting the benefit of the information and because the white doctors were not trusted by their black patients.  In the future iPS cells could have the problem mutations replaced with ex vivo gene therapy. 
  in trials: Boston Children's; resulting in patients with no symptoms, mid trail.  Red blood stem cells is a biological cell which is partly or wholly undifferentiated.  A totipotent cell can generate a complete embryo and placenta.  Embryos include pluripotent cells which can generate any tissue in the body.  Adult humans' cells have turned off this ability but still include multipotent stem cells that differentiate into multiple cell types.   Typically a cell's local environment will have the signals required for it to obtain context and differentiate appropriately.  This will include both the external environment and the internal state of the cell which has replicated from a parent and obtained its epi-genetic state.   So introduction of undifferentiated stem cells into an injured area is not likely to have either aspect of the environment suitable.  Consequently development is aiming to encourage differentiation to progenitor cells for the damaged region.  This requires delivering the cells to the appropriate part of the body.  To avoid rejection by the immune system techniques aim to use cell lines developed from the patient's cells.  The techniques to generate these cell lines include: SCNT, iPS.  Possible mechanisms of stem cell therapy are: Generation of new differentiated cells, Stimulation of growth of new blood vessels to repopulate damaged regions, Secretion of growth factors, Treatment of diabetes (1 and 2) with addition of pancreatic cells, Assistance of other mechanisms; are removed from the bone marrow, the sickle-cell gene mutation is removed from the DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used.   and the stem-cells are flowed back into the body, where they must reenter the bone marrow for the therapy to work.  Genetic update can use newly discovered large viral vector.   An alternative to gene therapy uses a gene edit using CRISPR is clustered replicating interspersed silent palindromic repeats; a technique for exact targeting, cutting and editing of DNA based on leveraging bacterial enzymatic defenses against viruses generalized to any DNA sequence in a prokaryotic or eukaryotic cell.  It was identified during studies of a bacterial adaptive immune system.  In that system bacterial proteins grab parts of a virus that has infected them and record it within the palindromic structures that mark an array of inserted viral DNA used as a log persisted over generations.  If a new infection occurs the viral DNA is compared with the sequences and if a match exists the CAS proteins break up the viral DNA initiating its destruction.  This bacterial system was then updated and repurposed by the researchers to support targeted genetic engineering.  As explained by Dr. Doudna, the CRISPR proteins and the 20 nucleotide RNA template migrate into the nucleus where they rapidly target DNA which complements the RNA template and the Cas9 enzyme performs the edits.  Being a bacterial system CRISPR Cas9 does not target eukaryotic heterochromatic DNA well.  It is not fully understood how they find the target sequence so quickly.  It has been shown that Cas9 will bind to sites with a 5-8 base match but then it releases rapidly without cutting.  To cut, Cas9 has to reconfigure, which does not occur in the mismatch situations.  .  Another treatment strategy blocks the genetic transition from fetal to adult hemoglobin: fetal does not sickle.  NIH is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.   is launching a funding program 'Cure Sickle-Cell' (Jan 2019)
  
• Statistical failures in prior research causes genetic test to misdiagnose minorities (Aug 2016)
  
• Renaissance RX cash taints gene tests (Jun 2015)
• Active surveillance is an approach to early-stage prostate cancer which replaces treatment, such as surgery or radiation, with monitoring to ensure the cancers aren't growing rapidly.  It started to be used in about 2000 and so will take time to build a predictive history of the success of the regimen (10 year longitudinal study results Sep 2016).  Active surveillance treatements include: Oncotype DX, PSA, STHLM3; helping in treatment for prostate cancer is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  Research in mice may explain a link between obesity and prostate cancer (Jan 2018).  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
  • Sarcomas
  • Small cell carcinomas
  • Neuroendocrine tumors
  • Transitional cell carcinomas
  (Dec 2015)
• 10 year study clarifies some additional risk, is an assessment of the likelihood of an independent problem occurring.  It can be assigned an accurate probability since it is independent of other variables in the system.  As such it is different from uncertainty. 
  of active surveillance of prostate cancer (Sep 2016)
  
• Liquid biopsy uses a tiny blood sample used for diagnostic testing.  Often the testing is based on using DNA sequencing to detect DNA in the blood from cancer cells.  By identifying the mutations in a patient's tumor accurate treatments can be selected, and recurrence can be detected.  But aging generates many similar mutations which could lead to false positives in a broad screening test.  Research and development is ongoing (Jun 2016). 
  study positive on use as diagnostic (Jun 2016)
  
• Fred Hutchinson's Dr. Radich announces paper card can support central diagnosis of CML is chronic myelogenous leukemia.  It is a leukemia characterized by the unregulated growth of myeloid cells in the bone marrow.  The growth is encouraged by the cellular signalling system (gene change that generates a faulty tyrosine kinase) being locked on.  Visual methods allowed Dr. Janet Rowley's team to recognize that most CML includes the Philadelphia chromosome.  It encodes the chimeric always on tyrosine kinase protein seen only in CML.  Targeted treatments such as Gleevec block the pathway for the tyrosine kinase. 
  from dried blood (Nov 2016)
  
• Direct-to-consumer lab tests (Jun 2016)
• Genomic testing uses genomic analysis to diagnose genetic disorders - for example Genomic Health's Oncotype DX & Agendia's MammaPrint.  The desire to see the genetic risk factors identified by such tests should depend on the risk * burden * Possibility of intervention.  Early tests look at only single gene mutations, but big data research tools are showing promise with large gene algorithms (Aug 2018).  Genomic testing can be performed direct-to-consumer.  Data is being collated on the genetic components of most diseases to enable more sophisticated diagnosis in the future such as the OPHG (EGAPP initiative), USPSTF recommendations and NCBI (Genetic test registry).  While there is only limited identification of the significant mutations and limited patient bases misdiagnosis is a problem (Aug 2016). 
  indicates who can avoid chemotherapy is the treatment of cancers by highly cytotoxic chemicals: Paclitaxel, Platinum, 6-mercaptopurine; assuming that cancer cells are unusually active and will be differentially poisoned.  It has been successful in offering treatments when no other course was available, but non-specificity means that healthy cells also get poisoned resulting in side effects which increase with age: Permanent nerve damage, heart failure (4-5%) and leukemia (0.5-1%). 
  (Aug 2016, Jun 2018)
• Massachusetts General Hospital Center for Genomic Medicine director, Dr. Kathiresan, and MGH & Broad Institute cardiologist is the diagnosis and treatment of: Congenital heart defects, CAD, Heart failure, Valvular heart disease; by cardiologists.   Dr. Amit Khera, report, in Nature Genetics, developing a big data encompasses the IT systems and processes necessary to do population based data collection, management and analysis.  The very low cost, robust, data storage organized by infrastructure: HADOOP; allows digital data to be stored en mass.  Data scientists then apply assumptions about the world to the data, analogous to evolved mechanisms in vision, in the form of algorithms: Precision medicine, Protein folding modeling (Feb 2019) assumes coevolutionary methods can be applied to identify contact points in a protein's tertiary structure.  Rather than depending on averages, analysis at Verisk drills down to specifics and then highlights modeling problems by identifying the underlying CAS.  For the analysis to be useful it requires a hierarchy of supporting BI infrastructure:
  • Analytics utilization and integration delivered via SaaS and the Cloud to cope with the silos and data intensive nature. 
    
  • Analytics tools (BI) for PHM will be hard to develop.  
  • Complex data models must include clinical aspects of the patient specific data, including disease state population wide.  
  • A key aspect is providing clear signals about the nature of the data using data visualization. 
    
  • Data communication with the ability to exchange and transact.  HIEs and EMPI alliance approaches are all struggling to provide effective exchange. 
    
  • Data labeling and secure access and retreival.  While HIPAA was initially drafted as a secure MPI the index was removed from the legislation leaving the US without such a tool.  Silos imply that the security architecture will need to be robust. 
    
  • Raw data scrubbing, restructuring and standardization.  Even financial data is having to be restandarized shifting from ICD-9 to -10.  The intent is to transform the unstructured data via OCR and NLP to structured records to support the analytics process. 
    
  • Raw data warehousing is distributed across silos including PCP, Hospital system and network, cloud and SaaS for process, clinical and financial data. 
    
  • Data collection from the patient's proximate environment as well as provider CPOE, EHRs, workflow and process infrastructure.  The integration of the EHR into a big data collection tool is key. 
    
  tool, based on the UK Biobank and then cross checking for validity with: East Asian, South Asian, African American and Hispanics; and 20,000 people from Brigham & Women's, that uses 6.6 million base pair positions to identify increased risk, is an assessment of the likelihood of an independent problem occurring.  It can be assigned an accurate probability since it is independent of other variables in the system.  As such it is different from uncertainty. 
  of: heart disease is cardiovascular disease which refers to:
  • Conditions where narrowed and blocked blood vessels result in angina, hypertension, CHD and heart attacks and hemorrhagic/ischemic strokes.  Mutations of the gene PCSK9 have been implicated in cardiovascular disease.  Rare families with dominant inheritence of the mutations have an overactive protein, very high levels of blood cholesterol and cardiac disease. Other rare PCSK9 mutations result in an 88% reduced risk from heart disease.  Inflammation is associated with cardiovascular disease (Aug 2017). 
    
  , breast cancer is a variety of different cancerous conditions of the breast tissue.  World wide it is the leading type of cancer in women and is 100 times more common in women than men.  260,000 new cases of breast cancer will occur in the US in 2018 causing 41,000 deaths.  The varieties include: Hormone sensitive tumors that test negative for her2 (the most common type affecting three quarters of breast cancers in the US, BRCA1/2 positive, ductal carcinomas including DCIS, lobular carcinomas including LCIS.  Receptor presence on the cancer cells is used as a classification: Her2+/-, estrogen (ER)+/-, progesterone (PR)+/-.  Metastasis classes the cancer as stage 4.  Genetic risk factors include: BRCA, p53, PTEN, STK11, CHEK2, ATM, GATA3, BRIP1 and PALB2.  Treatments include: Tamoxifen, Raloxifene; where worrying racial disparities have been found (Dec 2013).  International studies indicate early stage breast cancer typed by a genomic test: Oncotype DX, MammaPrint; can be treated without chemotherapy (Aug 2016, Jun 2018), Type 2 diabetes is the leading cause of blindness, limb amputations and kidney failure.  It is a risk factor for Alzheimer's disease.  Insulin and glucose levels are regulated by the pancreas, liver, muscle, brain and fat.  Diabetes occurs when the insulin level is insufficient to regulate the glucose in the system.  As we age our muscles become less sensitive to insulin and the pancreas responds by increasing the amount generated.  Increased fat levels in obesity demand more insulin overloading the pancreas.  Persistent high glucose levels are also toxic to the pancreas beta cells.  High glucocorticoid levels have been associated with type 2 diabetes.  There are genetic risk factors since siblings of someone with the disease have three times the baseline risk (about 50% of the risk of getting type 2 diabetes is genetic).  The inheritance is polygenic.  More than 20 genes have been identified as risk factors, but that is too few to account for the 50% weighting so many more will be identified.  Of those identified so far many are associated with the beta cells.  The one with the strongest relative risk is TCF7L2.  The disease can be effectively controlled through a diligent application of treatments and regular checkups.  Doctors are monitored for how under control their patients' diabetes is (Sep 2015).  Treatments include:
  • Metformin - does not change the course of pre-diabetes - if you stop taking it, it is as if it hasn't been taken. 
    
  • Diet
  • Exercise
  , Chronic IBD is inflammatory bowel disease, which is a chronic inflammation of part of the digestive tract.  It includes Crohn's disease and Ulcerative colitis.  Johns Hopkins's Bayless noted it differs from irritable bowel syndrome - they require different treatments.  Symptoms include: Severe diarrhea, Pain, Fatigue & weight loss.  It typically begins in the teens or twenties.  Incidence has increased exponentially since 1945 in developed countries.  160 genes have been associated with IBD.  These genes all relate to: Producing mucus, solidifying the lining of the gut, or regulating the immune system.  The rapid increase in the incidence of IBD can be explained by societal impacts on the gut microbiome which interacts with these genes and their products.  No particular culprit has been found.  It is probably an ecological shift away from symbiosis.  There is a shift from fibre-fermenters: Faecalibaterium prausnitzii, Bacteroides fragilis; to: Fusobacterium nucleatum, Escherichia coli; which are more inflammatory.  The trigger for disease appears complex: Less early infections with tapeworms, bacteria & viruses, Smaller families - which are typically cleaner, More urban environments - resulting in less contact with higher animals, Less pets, Antibiotics, Endocrine disrupters, Caeserean births, Formula fed babies - rather than breast milk; all potentially contributing to the altered setup and operation of the immune system and microbiome.  , AF is atrial fibrillation, an abnormal heart rhythm: rapid, irregular.  It:
  • Can lead to blood clots, stroke, CHF, dementia and other complications.  
  • Fibrillations allow blood to pool in the heart chambers and form small clots which can then lodge in small arteries and block blood flow. 
    
  • Has become much more common being induced by endemic diseases: hypertension, obesity and type-2-diabetes. 
    
  • Cocoa reduces risk of AF (May 2017)
  • Treatments include: digoxin;
    
  ; accessible via a web site (Aug 2018)
  
• Helix sets up network of direct-to-consumer genomic testing uses genomic analysis to diagnose genetic disorders - for example Genomic Health's Oncotype DX & Agendia's MammaPrint.  The desire to see the genetic risk factors identified by such tests should depend on the risk * burden * Possibility of intervention.  Early tests look at only single gene mutations, but big data research tools are showing promise with large gene algorithms (Aug 2018).  Genomic testing can be performed direct-to-consumer.  Data is being collated on the genetic components of most diseases to enable more sophisticated diagnosis in the future such as the OPHG (EGAPP initiative), USPSTF recommendations and NCBI (Genetic test registry).  While there is only limited identification of the significant mutations and limited patient bases misdiagnosis is a problem (Aug 2016). 
  including Geisinger (Oct 2017)
• Companies: Promethease; use 23andMe profile to analyze for disease generating mutations, but the process is not an approved diagnosis: 23andMe legitimately only runs their sequencers describes methods of DNA sequencing, that replace traditional Sanger sequencing, which have been implemented in commercial DNA sequencers after 2000.  The methods include:
  • Base-by-base is stepwise sequencing where there are 3' removable blockers on the DNA arrays. 
    
  • Pyrosequencing,  
  • Sequencing by synthesis,
    
  • Sequencing by ligation,
    
  • SMRT,
    
  • DNA colony sequencing,
  • DNA nanoball, 
  • Nanopore sequencing,
    
  • MPSS was the first of the next generation sequencing methods,
  • Polony sequencing.  
  on limited sequences of the raw DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used.  , to keep the processing time and cost down, the analysis companies then compound the risk, is an assessment of the likelihood of an independent problem occurring.  It can be assigned an accurate probability since it is independent of other variables in the system.  As such it is different from uncertainty. 
  of false positives & negatives, using comparison databases that can contain errors.  While consumers are warned of the situation it is not clear that they understand the implications.  F.D.A. Food and Drug Administration.   approved diagnostic laboratories have to be much more rigorous about the bredth of DNA analysed, the accuracy of the data bases they reference, and the validation steps taken (Jul 2018) 
• Invitae funded study indicates 23andMe consumer test is not effective for BRCA is breast cancer type 1 or 2 susceptibility gene.  The two types provide related cellular functions maintaining the validity of the cell.  If either gene product fails there is an increased likelihood of cancer.  Still individuals with mutations in BRCA1/2 genes account for only 5 to 10 percent of breast cancers.  The:  
  • Type 1 gene codes for a protein that supports DNA repair and where this is not possible can stimulate cell death.  Hence if the protein becomes defective one or both of these key caretaker functions may stop and increase the susceptibility to cancer.  The BRCA1 protein has multiple actions.  It:
    
  • Combines with other tumor suppressors, DNA damage sensors and cellular signal transducers to form the BASC surveillance complex monitoring the health of the cells DNA. 
    
  • Associates with RNA pol II to support transcription. 
    
  • Interacts with histone deacetylase to regulate transcription.  
  • It is a marker of high risk of breast and uterine cancer. 
    
  • It was collaboratively researched by Dr. Mary-Claire King and Francis Collins's labs studying chromosome 17 using genomics.  
  • In 1990 Dr. King had reported to ASHG evidence of 'this' single gene linked to a highly heritable form of breast cancer.  
  • Over the next two years the labs gathered details of BRCA1, allowing families with the mutation to understand their individual risk and plan for their futures.  
  • In 1993 BRCA1 was identified by Mark Skolnick of Myriad Genetics. 
    
  • Type 2 gene codes for a protein that binds both single stranded DNA and the recombinase RAD51 to facilitate homologous recombination.  
  • Advice from Dr. Collins, for families who have a history of breast or ovarian cancer includes:
  • Counselling women with the high risk BRCA mutations, about the risk of breast and ovarian cancer and the treatments available
  • Telling women who choose watchful waiting to have periodic MRIs.  And warn that watchful waiting is unreliable for ovarian cancer allowing metastasis before detection.  
  • Prophylactically removing the ovaries and Fallopian tubes on completion of childbearing.  
  • Teaching about breast reconstruction and recommending prophylactic mastectomy.  
  • Males with BRCA mutations should have careful surveillance for: Prostate, Pancreatic and breast cancer.  
  • No one being given the test without being fully counselled beforehand about the implications of the result.  Negative results may bring survivor guilt while positive results will need careful management.  
  breast cancer is a variety of different cancerous conditions of the breast tissue.  World wide it is the leading type of cancer in women and is 100 times more common in women than men.  260,000 new cases of breast cancer will occur in the US in 2018 causing 41,000 deaths.  The varieties include: Hormone sensitive tumors that test negative for her2 (the most common type affecting three quarters of breast cancers in the US, BRCA1/2 positive, ductal carcinomas including DCIS, lobular carcinomas including LCIS.  Receptor presence on the cancer cells is used as a classification: Her2+/-, estrogen (ER)+/-, progesterone (PR)+/-.  Metastasis classes the cancer as stage 4.  Genetic risk factors include: BRCA, p53, PTEN, STK11, CHEK2, ATM, GATA3, BRIP1 and PALB2.  Treatments include: Tamoxifen, Raloxifene; where worrying racial disparities have been found (Dec 2013).  International studies indicate early stage breast cancer typed by a genomic test: Oncotype DX, MammaPrint; can be treated without chemotherapy (Aug 2016, Jun 2018) analysis, generating false negatives, - only looking for 3 Ashkenazi Jewish mutations instead of thousands that other women may suffer from, conflicting with prior F.D.A. Food and Drug Administration.   approval of the direct to consumer approach (Apr 2019)
  
• Molecular diagnostics
  
• Oxamer DNA chip
  
• Liquid biopsy study positive on use as diagnostic (Jun 2016)
  
• Pregnancy
  
• Microchimerism (Sep 2015)
  

• HIV/AIDS
  
• HIV is human immunodeficiency virus, an RNA retrovirus which causes AIDS.  It infects T-lymphocytes destroying the host's immune system.  Some HIV's enter the lymphocytes by leveraging the T cells CCR5 protein.  The HIV X4 variant leverages CXCR4. 
  entered US in 1971 in New York City from Haiti (Oct 2016)
  
• CVD is cardiovascular disease which refers to:
  • Conditions where narrowed and blocked blood vessels result in angina, hypertension, CHD and heart attacks and hemorrhagic/ischemic strokes.  Mutations of the gene PCSK9 have been implicated in cardiovascular disease.  Rare families with dominant inheritence of the mutations have an overactive protein, very high levels of blood cholesterol and cardiac disease. Other rare PCSK9 mutations result in an 88% reduced risk from heart disease.  Inflammation is associated with cardiovascular disease (Aug 2017). 
    
  
  
• NSAID is a nonsteroidal anti-inflammatory drug, such as ibuprofen.  They inhibit the production of prostaglandins.  They are often used to treat pain and inflammation.  Since prostaglandins are involved in collagen production NSAIDs can undermine healing.  They are also associated with increased risk of heart attacks (May 2017). 
  s associated with increased risk, is an assessment of the likelihood of an independent problem occurring.  It can be assigned an accurate probability since it is independent of other variables in the system.  As such it is different from uncertainty. 
  of heart attacks is an AMI. It can induce cardiac arrest.  Blocking the formation of clots with platelet aggregation inhibitors, can help with treating and avoiding AMI.  Risk factors include: taking NSAID pain killers (May 2017).  There is uncertainty about why AMI occur.  Alternative hypotheses include:
  
  • Plaques started to gather in the coronary arteries and grew until no blood flow was possible.  If this is true it makes sense to preventatively treat the buildup with angioplasty. 
    
  • Plaques form anywhere in the body due to atherosclerosis and then break up and get lodged in the coronary artery and start to clot.  If this is true it makes sense to preventatively limit the buildup of plaques with drugs like statins or PCSK9 inhibitors. 
    
  after just one week (May 2017)
• Baby born after heart attack is an AMI. It can induce cardiac arrest.  Blocking the formation of clots with platelet aggregation inhibitors, can help with treating and avoiding AMI.  Risk factors include: taking NSAID pain killers (May 2017).  There is uncertainty about why AMI occur.  Alternative hypotheses include:
  
  • Plaques started to gather in the coronary arteries and grew until no blood flow was possible.  If this is true it makes sense to preventatively treat the buildup with angioplasty. 
    
  • Plaques form anywhere in the body due to atherosclerosis and then break up and get lodged in the coronary artery and start to clot.  If this is true it makes sense to preventatively limit the buildup of plaques with drugs like statins or PCSK9 inhibitors. 
    
  has heart restored with mitochondrial are the energy molecule generating production functions of eukaryotic cells.  They are vestigial blue-green bacteria with their own DNA and infrastructure.  Unlike stand-alone bacteria they also use the eukaryotic host DNA and infrastructure for some functions.  The high energy molecules are nucleotides with a high energy phosphate bond.  The most used high energy molecule is Adenosine-tri-phosphate.   infusion at Boston Childrens (Jul 2018)
  
• Dementia
  
• Plaque helps predict Alzheimer's is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and declarative memory and thinking problems (MCI).  Specific cells within the hippocampal circuitry and its gateway, the entorhinal cortex, are damaged.  The amygdala, cerebelum and other areas supporting implicit memory are not impacted during the early stages of the disease.  Grid cell destruction results in a sense of being lost.  The default mode network is disrupted.  Variants include: late-onset sporadic; with risk factors - ApoE4 for late onset Alzheimer's, presenilin, androgen deprivation therapy (Dec 2015), type 2 diabetes.  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation, Neurons of sporadic Alzheimer's sufferers show greater APP gene diversity due to somatic recombination; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form.  These are seen in fMRIs 10 to 15 years prior to detecting memory and thinking changes.  APP deployed in the cell membrane is cut into three parts.  The external part becomes amyloid-beta peptide which aggregates into Amyloid plaques, external to the neurons, if too much is generated or it is not removed fast enough. 
    
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016). 
    
  • Encouraging the garbage collection of amyloid and tau with gamma rhythms stimulation retards Alzheimer's in mice studies (Mar 2019)
    
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • Mutation driven misfolded Tau proteins can form tangles within the cytoplasm of neurons.  The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    
  • The brain becomes inflamed resulting in the killing of many more nerve cells.  The hippocampus disintegrates and the brain loses critical functions and memory loss becomes noticeable. 
    
  (May 2015)
• MIT is Massachusetts Institute of Technology.   Picower's Li-Huei Tsai's studies of mice show recovery from Alzheimer's is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and declarative memory and thinking problems (MCI).  Specific cells within the hippocampal circuitry and its gateway, the entorhinal cortex, are damaged.  The amygdala, cerebelum and other areas supporting implicit memory are not impacted during the early stages of the disease.  Grid cell destruction results in a sense of being lost.  The default mode network is disrupted.  Variants include: late-onset sporadic; with risk factors - ApoE4 for late onset Alzheimer's, presenilin, androgen deprivation therapy (Dec 2015), type 2 diabetes.  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation, Neurons of sporadic Alzheimer's sufferers show greater APP gene diversity due to somatic recombination; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form.  These are seen in fMRIs 10 to 15 years prior to detecting memory and thinking changes.  APP deployed in the cell membrane is cut into three parts.  The external part becomes amyloid-beta peptide which aggregates into Amyloid plaques, external to the neurons, if too much is generated or it is not removed fast enough. 
    
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016). 
    
  • Encouraging the garbage collection of amyloid and tau with gamma rhythms stimulation retards Alzheimer's in mice studies (Mar 2019)
    
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • Mutation driven misfolded Tau proteins can form tangles within the cytoplasm of neurons.  The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    
  • The brain becomes inflamed resulting in the killing of many more nerve cells.  The hippocampus disintegrates and the brain loses critical functions and memory loss becomes noticeable. 
    
  symptoms with 40 hertz - gamma rhythm are observed as 40 Hz neural activity waves associated with conscious access.  They link different brain regions during alignment and integration of emergent memories aggregated from models in different cortical regions: occipital, temporal, somatosensory, insula, olfactory; meshing 'images' of sight, smells, taste, feel and sound into a single experience.  Yogi's gamma rhythms can last for over a minute, instead of the more typical fifth of a second explain Goleman and Davidson. 
  aligned - light and clicks, which activate microglia form a subset of glial cells, acting as garbage collectors and the main form of active immune defense in the central nervous system. 
  which garbage collect: tau, amyloid; and support immune has to support and protect an inventory of host cell types, detect and respond to invaders and maintain the symbiont equilibrium within the microbiome.  It detects microbes which have breached the secreted mucus barrier, driving them back and fortifying the barrier.  It culls species within the microbiome that are expanding beyond requirements.  It destroys invaders who make it into the internal transport networks.  As part of its initialization it has immune cells which suppress the main system to allow the microbiome to bootstrap.  The initial microbiome is tailored by the antibodies supplied from the mother's milk while breastfeeding.  The immune system consists of two main parts the older non-adaptive part and the newer adaptive part.  The adaptive part achieves this property by being schematically specified by DNA which is highly variable.  By rapid reproduction the system recombines the DNA variable regions in vast numbers of offspring cells which once they have been shown not to attack the host cell lines are used as templates for interacting with any foreign body (antigen).  When the immune cell's DNA hyper-variable regions are expressed as y-shaped antibody proteins they typically include some receptor like structures which match the surfaces of the typical antigen.  Once the antibody becomes bound to the antigen the immune system cells can destroy the invader. 
  regulation.  Mice memory in the brain includes functionally different types: Declarative, or explicit, (episodic and semantic), Implicit, Procedural, Spatial, Temporal, Verbal; Hebb suggested that glutamate receptive neurons learn by (NMDA channel based) synaptic strengthening: short term memory.  This was shown to happen for explicit memory formation in the hippocampus.  This strengthening is sustained by subsequent LTP.  The non-real-time learning and planning processes operate through consciousness using the working memory structures, and then via sleep, the salient ones are consolidated while the rest are destroyed and garbage collected.   and cognition is the ability to orchestrate thought and action in accordance with internal goals according to Princeton's Jonathan Cohen. 
  improved, with auditory cortex is part of the temporal lobe that processes auditory information.  It is present in both brain hemispheres.  Auditory sensations only reach consciousness once signalled by the auditory cortex.  Final sound processing is performed by the parietal and frontal lobes in humans. 
  and hippocampus is a part of the medial temporal lobe of the brain involved in the temporary storage or coding of long-term episodic memory.  It includes the dentate gyrus.  Memory formation in the cells of the hippocampus uses the MAP kinase signalling network which is impacted by sleep deprivation.  The hippocampus dependent memory system is directly affected by cholinergic changes throughout the wake-sleep cycle.  Increased acetylcholine during REM sleep promotes information attained during wakefulness to be stored in the hippocampus by suppressing previous excitatory connections while facilitating encoding without interference from previously stored information.  During slow-wave sleep low levels of acetylcholine cause the release of the suppression and allow for spontaneous recovery of hippocampal neurons resulting in memory consolidation.  It was initially associated with memory formation by McGill University's Dr. Brenda Milner, via studies of 'HM' Henry Molaison, whose medial temporal lobes had been surgically destroyed leaving him unable to create new explicit memories.  The size of neurons' dendritic trees expands and contracts over a female rat's ovulatory cycle, with the peak in size and cognitive skills at the estrogen high point.  Adult neurogenesis occurs in the hippocampus (3% of neurons are replaced each month) where the new neurons integrate into preexisting circuits.  It is enhanced by learning, exercise, estrogen, antidepressants, environmental enrichment, and brain injury and inhibited by various stressors explains Sapolsky.  Prolonged stress makes the hippocampus atrophy.  He notes the new neurons are essential for integrating new information into preexisting schemas -- learning that two things you thought were the same are actually different.  Specific cells within the hippocampus and its gateway, the entorhinal cortex, are compromised by Alzheimer's disease.  It directly signals area 25. 
  protected by sounds, and sounds with light additionally helping maintain the PFC is prefrontal cortex which is:
  • The front part of the frontal lobe of the cerebral cortex.  It evolved most recently.  During adolescence when the PFC is still deploying, older brain agents provide equivalent strategies: ventral striatum.  The PFC has been implicated in planning, working memory: dorsolateral; decision making: Orbitofrontal cortex; and social behavior.  It regulates feelings.  Different PFC circuits track internal reward driven strategies and externally signalled advice.  The PFC chooses between conflicting options, letting go or restraint, especially between cognition and emotions.  It imposes an overarching strategy for managing working memory.  It is essential for thinking about multiple items with different labels.  It includes neurons that are interested in particular sub-categories: Dog, Cat.  Once it has made a decision it signals the rest of the frontal lobe just behind it.  Glucocorticoids decrease excitability of the PFC.  
  .  Follow on tests will look at the effects in people of such stimulation (Mar 2019)
  
• Research autopsies of Alzheimer's is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and declarative memory and thinking problems (MCI).  Specific cells within the hippocampal circuitry and its gateway, the entorhinal cortex, are damaged.  The amygdala, cerebelum and other areas supporting implicit memory are not impacted during the early stages of the disease.  Grid cell destruction results in a sense of being lost.  The default mode network is disrupted.  Variants include: late-onset sporadic; with risk factors - ApoE4 for late onset Alzheimer's, presenilin, androgen deprivation therapy (Dec 2015), type 2 diabetes.  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation, Neurons of sporadic Alzheimer's sufferers show greater APP gene diversity due to somatic recombination; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form.  These are seen in fMRIs 10 to 15 years prior to detecting memory and thinking changes.  APP deployed in the cell membrane is cut into three parts.  The external part becomes amyloid-beta peptide which aggregates into Amyloid plaques, external to the neurons, if too much is generated or it is not removed fast enough. 
    
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016). 
    
  • Encouraging the garbage collection of amyloid and tau with gamma rhythms stimulation retards Alzheimer's in mice studies (Mar 2019)
    
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • Mutation driven misfolded Tau proteins can form tangles within the cytoplasm of neurons.  The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    
  • The brain becomes inflamed resulting in the killing of many more nerve cells.  The hippocampus disintegrates and the brain loses critical functions and memory loss becomes noticeable. 
    
  victims often indicate multiple problems that induce dementia is a classification of memory impairment, constrained feelings and enfeebled or extinct intellect.  The most common form for people under 60 is FTD.  Dementia has multiple causes including: vascular disease (inducing VCI) including strokes, head trauma, syphilis and mercury poisoning for treating syphilis, alcoholism, B12 deficiency (Sep 2016), privation, Androgen deprivation therapy (Oct 2016), stress, Parkinson's disease, Alzheimer's disease, and prion infections such as CJD and kuru.  The condition is typically chronic and treatment long term (Laguna Honda ward) and is predicted by Stanley Prusiner to become a major burden on the health system.  It may be possible to constrain the development some forms of dementia by: physical activity, hypertension management, and ongoing cognitive training.  Dementia appears to develop faster in women than men.  : silent-strokes is when brain cells are deprived of oxygen and begin to die.  750,000 patients a year suffer strokes in the US.  85% of those strokes are caused by clots.  There are two structural types: Ischemic and hemorrhagic.  Thrombectomy has been found to be a highly effective treatment for some stroke situations (Jan 2018). 
  , Lewy bodies are protein clumps that are a pathological mark of Parkinson's disease and Lewy body dementia.  A major component of the clumps is alpha-synuclein.  , amyloid, hippocampal sclerosis, TDP-43; and the disease is typically associated with reduced blood flow to the cerebrum is a developmental classification of brain areas formed from the embryonic prosencephalon.  These areas include the cerebral cortex, hippocampus, olfactory bulb and the basal ganglia. 
  explains Harvard's Dr. Hofman & Bristol's Dr. Love, age is the most significant risk factor asserts Washington University in St. Louis' Dr. Morris.  A decline of 15% in new cases over 25 years matches: reduced smoking, use of statins are serum cholesterol lowering drugs established as safe and effective at reducing the risk of heart-attacks, hemorrhagic & Ischemic strokes and deaths from atherosclerotic heart disease.  They also reduce inflammation that can induce blood clots.  They appear to stabilize plaque.  About 5% of people, most with a specific allele of SLCO1B1, have muscle aches, and in some blood sugar increases.  Statins inhibit HMG-CoA reductase which produces cholesterol in the liver.  , and hypertension is high blood pressure.  It is directly associated with death rate due to pressure induced damage to the left ventricle and in general to cardiovascular diseases.  Treated with antihypertensives: Diuretics, Calcium channel blockers, Angiotensin receptor blockers or Beta blockers.   management (Apr 2019)
  
• Alzheimer's develops faster in women than in men (Jul 2015)
• Hypertension is high blood pressure.  It is directly associated with death rate due to pressure induced damage to the left ventricle and in general to cardiovascular diseases.  Treated with antihypertensives: Diuretics, Calcium channel blockers, Angiotensin receptor blockers or Beta blockers.   is a high risk, is an assessment of the likelihood of an independent problem occurring.  It can be assigned an accurate probability since it is independent of other variables in the system.  As such it is different from uncertainty. 
  factor for later dementia (Oct 2017)
  
• Alzheimer's develops faster and more often with obesity is an addictive disorder where the brain is induced to require more eating, often because of limits to the number of fat cells available to report satiation (Jul 2016).  Brain images of drug-addicted people and obese people have found similar changes in the brain.  Obese people's reward network tends to be less responsive to dopamine and have a lower density of dopamine receptors.  Obesity spreads like a virus through a social network with a 171% likelihood that a friend of someone who becomes obese will also become so.  Obesity is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes, asthma and heart disease.  It is suspected that this is contributing to the increase in maternal deaths in the US (Sep 2016).  Obesity is a complex condition best viewed as representing many different diseases, which is affected by the: Amount of brown adipose tissue (Oct 2016), Asprosin signalling by white adipose tissue (Nov 2016), Genetic alleles including 25 which guarantee an obese outcome, side effects of some pharmaceuticals for: Psychiatric disorders, Diabetes, Seizure, Hypertension, Auto-immunity; Acute diseases: Hypothyroidism, Cushing's syndrome, Hypothalamus disorders; State of the gut microbiome.  Infections, but not antibiotics, appear associated with childhood obesity (Nov 2016). 
  (Sep 2015)
• Sugary Drinks tied to rapid brain aging and Alzheimer's markers (Apr 2017)
  
• Alzheimer's development slowdown correlates with education and healthy liefstyle (Feb 2016)
  
• B12 deficiency associated with depression, dementia (Sep 2016)
  
• Johns Hopkins study finds the number of chronic inflammatory events in middle age correlates with increased memory loss later in life (Feb 2019)
  
• Alzheimer's ApoE is Apolipoprotein E which is essential for normal catabolism of triglyceride-rich lipoproteins.  It is used by the liver, macrophages, and central nervous system where astrocytes use it to transport cholesterol to neurons via APOE receptors. 
  risk reduced by eating seafood (Feb 2016)
  
• Alzheimer's risk of hormone are signalling molecules: ACTH, TRH, Melanocyte stimulating hormone, Testosterone, Oxytocin, Vasopressin, Insulin, Growth hormone, Estrogen, Progesterone, Angiotensin II, Asprosin, EPO, Irisin, Leptin, FGF21 hormone, Prostaglandins, TSH, Thyroxine, Glococorticoids: Cortisol; that are transported by the circulatory system to interact with target organs having appropriate receptors.  The levels of hormones can fluctuate massively, as in pregnancy. 
  therapy for prostate cancer is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  Research in mice may explain a link between obesity and prostate cancer (Jan 2018).  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
  • Sarcomas
  • Small cell carcinomas
  • Neuroendocrine tumors
  • Transitional cell carcinomas
  (Dec 2015) 
• Alzheimer's during aging initiated by leaky blood-brain barrier and innate immune response to subsequent infections (May 2016)
  
• Stage 2 clinical trial of Eisai/Biogen's BAN2401 is reporting positive results, removing plaques and reducing cognitive decline a bit in early Alzheimer is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and declarative memory and thinking problems (MCI).  Specific cells within the hippocampal circuitry and its gateway, the entorhinal cortex, are damaged.  The amygdala, cerebelum and other areas supporting implicit memory are not impacted during the early stages of the disease.  Grid cell destruction results in a sense of being lost.  The default mode network is disrupted.  Variants include: late-onset sporadic; with risk factors - ApoE4 for late onset Alzheimer's, presenilin, androgen deprivation therapy (Dec 2015), type 2 diabetes.  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation, Neurons of sporadic Alzheimer's sufferers show greater APP gene diversity due to somatic recombination; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form.  These are seen in fMRIs 10 to 15 years prior to detecting memory and thinking changes.  APP deployed in the cell membrane is cut into three parts.  The external part becomes amyloid-beta peptide which aggregates into Amyloid plaques, external to the neurons, if too much is generated or it is not removed fast enough. 
    
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016). 
    
  • Encouraging the garbage collection of amyloid and tau with gamma rhythms stimulation retards Alzheimer's in mice studies (Mar 2019)
    
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • Mutation driven misfolded Tau proteins can form tangles within the cytoplasm of neurons.  The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    
  • The brain becomes inflamed resulting in the killing of many more nerve cells.  The hippocampus disintegrates and the brain loses critical functions and memory loss becomes noticeable. 
    
  's patients (Jul 2018)
  
• Agitation and argression eased by drug combination (Sep 2015)
• LMTX is leucomethylthioninium salts, a second generation tau aggregation inhibitor manufactured by TauRx Therapeutics. 
  falters in trial (Jul 2016)
• Solanezumab fails in trial (Nov 2016)
  
• Dementia rates dropping as population ages (Nov 2016)
• Three hourly walks a week provides benefits for VCI is vascular cognitive impairment, the second most common dementia after Alzheimer's disease, it is due to damaged blood vessels in the brain.  It is often associated with hypertension and heart disease.  Surviving a heart attack results in a 35% increase in risk of VCI (Nov 2017).  In its early stages it makes the brain function less efficiently with more work required to perform a memory, decision-making or attention based task.   (May 2017)
• Heart attack is an AMI. It can induce cardiac arrest.  Blocking the formation of clots with platelet aggregation inhibitors, can help with treating and avoiding AMI.  Risk factors include: taking NSAID pain killers (May 2017).  There is uncertainty about why AMI occur.  Alternative hypotheses include:
  
  • Plaques started to gather in the coronary arteries and grew until no blood flow was possible.  If this is true it makes sense to preventatively treat the buildup with angioplasty. 
    
  • Plaques form anywhere in the body due to atherosclerosis and then break up and get lodged in the coronary artery and start to clot.  If this is true it makes sense to preventatively limit the buildup of plaques with drugs like statins or PCSK9 inhibitors. 
    
  survival associated with later VCI is vascular cognitive impairment, the second most common dementia after Alzheimer's disease, it is due to damaged blood vessels in the brain.  It is often associated with hypertension and heart disease.  Surviving a heart attack results in a 35% increase in risk of VCI (Nov 2017).  In its early stages it makes the brain function less efficiently with more work required to perform a memory, decision-making or attention based task.   (Nov 2017)
  
• Devices
  
• Heart disease is cardiovascular disease which refers to:
  • Conditions where narrowed and blocked blood vessels result in angina, hypertension, CHD and heart attacks and hemorrhagic/ischemic strokes.  Mutations of the gene PCSK9 have been implicated in cardiovascular disease.  Rare families with dominant inheritence of the mutations have an overactive protein, very high levels of blood cholesterol and cardiac disease. Other rare PCSK9 mutations result in an 88% reduced risk from heart disease.  Inflammation is associated with cardiovascular disease (Aug 2017). 
    
  treatment stents is a small wire cage that can be inserted into an artery to prop it open.  They were introduced as an alternative to bypass surgery in the 1990s.  Stents are expensive.  Medicare payments vary depending on what kind of stent is used and how many, but are generally in the range $10,000 to $17,000 in 2015.   Double blind trials show that stents have no effect on chest pain relief (Nov 2017)
  found to provide no relief for chest pain emerged as a mental experience, Damasio asserts, constructed by the mind using mapping structures and events provided by nervous systems.  But feeling pain is supported by older biological functions that support homeostasis.  These capabilities reflect the organism's underlying emotive processes that respond to wounds: antibacterial and analgesic chemical deployment, flinching and evading actions; that occur in organisms without nervous systems.  Later in evolution, after organisms with nervous systems were able to map non-neural events, the components of this complex response were 'imageable'.  Today, a wound induced by an internal disease is reported by old, unmyelinated C nerve fibers.  A wound created by an external cut is signalled by evolutionarily recent myelinated fibers that result in a sharp well-localized report, that initially flows to the dorsal root ganglia, then to the spinal cord, where the signals are mixed within the dorsal and ventral horns, and then are transmitted to the brain stem nuclei, thalamus and cerebral cortex.  The pain of a cut is located, but it is also felt through an emotive response that stops us in our tracks.  Pain amplifies the aggression response of people by interoceptive signalling of brain regions providing social emotions including the PAG projecting to the amygdala; making aggressive people more so and less aggressive people less so.  Fear of pain is a significant contributor to female anxiety.  Pain is the main reason people visit the ED in the US.  Pain is mediated by the thalamus and nucleus accumbens, unless undermined by sleep deprivation. 
  (Nov 2017) 
• Heart failure is congestive heart failure which occurs when the heart is unable to generate enough blood flow to meet the body's demands.  There are two main types: failure due to left ventricular dysfunction and abnormal diastolic function increasing the stiffness of the left ventricle and decreasing its relaxation.  Heart expansion in CHF distorts the mitral valve which exacerbates the problems.  MitraClip surgery trials found effective in correcting the mitral valve damage (Sep 2018).  Treatments include: digoxin; now has a powerful treatment, Abbott labs's MitraClip, a small device that improves the efficiency of the mitral valve allows blood to flow from the heart's left atrium to the left ventricle.  If it fails the heart will have trouble pumping blood around the body resulting in CHF.   that has been damaged by a heart attack is an AMI. It can induce cardiac arrest.  Blocking the formation of clots with platelet aggregation inhibitors, can help with treating and avoiding AMI.  Risk factors include: taking NSAID pain killers (May 2017).  There is uncertainty about why AMI occur.  Alternative hypotheses include:
  
  • Plaques started to gather in the coronary arteries and grew until no blood flow was possible.  If this is true it makes sense to preventatively treat the buildup with angioplasty. 
    
  • Plaques form anywhere in the body due to atherosclerosis and then break up and get lodged in the coronary artery and start to clot.  If this is true it makes sense to preventatively limit the buildup of plaques with drugs like statins or PCSK9 inhibitors. 
    
  , a 614 patient trial showed.  The device still needs F.D.A. Food and Drug Administration.   approval (Sep 2018)
• TAVR is transcatheter aortic valve replacement, where MIS is used to deploy a valve replacement device through an incision in the groin (Mar 2019). 
  found in large clinical trials by: Columbia's Leon + Baylor Scott and White's Mack, Beth Israel Deaconess's Popma; funded by Edwards Lifesciences & Medtronic; to be safe and effective replacement for open heart surgery, for a broad range of patients.  It is not yet known how long such devices operate before failing (Mar 2019)
  
• Diet
• Changing recommendations (Feb 2015)
• Cocoa associated with reduced risk, is an assessment of the likelihood of an independent problem occurring.  It can be assigned an accurate probability since it is independent of other variables in the system.  As such it is different from uncertainty. 
  of AF is atrial fibrillation, an abnormal heart rhythm: rapid, irregular.  It:
  • Can lead to blood clots, stroke, CHF, dementia and other complications.  
  • Fibrillations allow blood to pool in the heart chambers and form small clots which can then lodge in small arteries and block blood flow. 
    
  • Has become much more common being induced by endemic diseases: hypertension, obesity and type-2-diabetes. 
    
  • Cocoa reduces risk of AF (May 2017)
  • Treatments include: digoxin;
    
  (May 2017)
  
• Boston University & Tufts study shows fast-food is defined by Nhanes as any item obtained from a fast-food/pizza establishment.  Gordon discusses the development of fast-food restaurants in the US.  Michael Pollan compares the industrial processed food supply chain with organic and hunter gatherer equivalents. 
  at: Arby's, Burger King, Carl's Jr., Dairy Queen, Hardees, Jack in the Box, KFC, Long John Silver's, McDonald's, Wendy's; has got bigger and saltier over the last 20 years (Mar 2019)
  
• Salt's effects on the body (May 2017) 
• Salt's impact on wellbeing indicates the state of an organism is within homeostatic balance.  It is described by Angus Deaton as all the things that are good for a person:
  • Material wellbeing includes income and wealth and its measures: GDP, personal income and consumption.  It can be traded for goods and services which recapture time.  Material wellbeing depends on investments in:
  • Infrastructure
    
  • Physical
    
  • Property rights, contracts and dispute resolution
    
  • People and their education
    
  • Capturing of basic knowledge via science.  
  • Engineering to turn science into goods and services and then continuously improve them. 
    
  • Physical and psychological wellbeing are represented by health and happiness; and education and the ability to participate in civil society through democracy and the rule of law.  University of Wisconsin's Ryff focuses on Aristotle's flourishing.  Life expectancy as a measure of population health, highly weights reductions in child mortality. 
    
  , hypertension is high blood pressure.  It is directly associated with death rate due to pressure induced damage to the left ventricle and in general to cardiovascular diseases.  Treated with antihypertensives: Diuretics, Calcium channel blockers, Angiotensin receptor blockers or Beta blockers.   leading to: kidney failure or CKD is
  
  • Where there is permanent damage to the Kidneys.  Diabetes and high blood pressure are the leading causes of CKD.  This has driven up the percentage of American's suffering from CKD. 
    
  •  CKD is diagnosed via a GFR of less than 60, or another marker such as protein in the urine, for atleast three months. 
    
  • The disease, classed as having five stages, causes no symptoms until the later stages.  The fifth stage of CKD is ESRD.  CKD is associated with: Atherosclerosis, Cardiovascular disease, Iron deficiency anemia from reduced EPO synthesis, Fluid volume overload, Hyperphosphatemia, Hypertension, Metabolic acidosis, Mineral bone disorder, Potassium accumulation, & Urea accumulation. 
    
  , heart attack is an AMI. It can induce cardiac arrest.  Blocking the formation of clots with platelet aggregation inhibitors, can help with treating and avoiding AMI.  Risk factors include: taking NSAID pain killers (May 2017).  There is uncertainty about why AMI occur.  Alternative hypotheses include:
  
  • Plaques started to gather in the coronary arteries and grew until no blood flow was possible.  If this is true it makes sense to preventatively treat the buildup with angioplasty. 
    
  • Plaques form anywhere in the body due to atherosclerosis and then break up and get lodged in the coronary artery and start to clot.  If this is true it makes sense to preventatively limit the buildup of plaques with drugs like statins or PCSK9 inhibitors. 
    
  , strokes is when brain cells are deprived of oxygen and begin to die.  750,000 patients a year suffer strokes in the US.  85% of those strokes are caused by clots.  There are two structural types: Ischemic and hemorrhagic.  Thrombectomy has been found to be a highly effective treatment for some stroke situations (Jan 2018). 
  ; (Nov 2017)
  
• Study associates hypertension is high blood pressure.  It is directly associated with death rate due to pressure induced damage to the left ventricle and in general to cardiovascular diseases.  Treated with antihypertensives: Diuretics, Calcium channel blockers, Angiotensin receptor blockers or Beta blockers.   with diet not age: Yanomamo is a tribe of contemporary Venezuelan hunter gatherers.  They are still isolated from modern societies (Nov 2018).  They have been a popular model of historic hunter gatherers: discussed in Behave, and in The Origin of Wealth. 
  (are still isolated) and Yekwana (get western food) compared as they age.  Yanomamo average blood pressure 95/63 remains same as they age to 60.  Yekwana 104/66 increases with age to 114/73.  Johns Hopkins's epidemiologist studies patterns, causes and effects of health and disease in populations.  It identifies risk factors for disease and focuses on preventative health care.  Being observational it suffers from a core limitation.  It can only show association, not causation.  It can suggest hypothesis but it can not disprove them.   Noel Mueller concludes cutting salt intake in half will prevent 15 million cases of US is the United States of America.   hypertension (Nov 2018)
  
• Weight hysterisis supported by sensory osteocytes in the bones of animals (Jan 2018)
  
• NIH is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.   funded Harvard School of Public Health study concludes eating nuts is associated with a lowered risk of heart disease is cardiovascular disease which refers to:
  • Conditions where narrowed and blocked blood vessels result in angina, hypertension, CHD and heart attacks and hemorrhagic/ischemic strokes.  Mutations of the gene PCSK9 have been implicated in cardiovascular disease.  Rare families with dominant inheritence of the mutations have an overactive protein, very high levels of blood cholesterol and cardiac disease. Other rare PCSK9 mutations result in an 88% reduced risk from heart disease.  Inflammation is associated with cardiovascular disease (Aug 2017). 
    
  (Nov 2017)
• Swedish researchers found lowered risk, is an assessment of the likelihood of an independent problem occurring.  It can be assigned an accurate probability since it is independent of other variables in the system.  As such it is different from uncertainty. 
  of: heart attack is an AMI. It can induce cardiac arrest.  Blocking the formation of clots with platelet aggregation inhibitors, can help with treating and avoiding AMI.  Risk factors include: taking NSAID pain killers (May 2017).  There is uncertainty about why AMI occur.  Alternative hypotheses include:
  
  • Plaques started to gather in the coronary arteries and grew until no blood flow was possible.  If this is true it makes sense to preventatively treat the buildup with angioplasty. 
    
  • Plaques form anywhere in the body due to atherosclerosis and then break up and get lodged in the coronary artery and start to clot.  If this is true it makes sense to preventatively limit the buildup of plaques with drugs like statins or PCSK9 inhibitors. 
    
  , heart failure is congestive heart failure which occurs when the heart is unable to generate enough blood flow to meet the body's demands.  There are two main types: failure due to left ventricular dysfunction and abnormal diastolic function increasing the stiffness of the left ventricle and decreasing its relaxation.  Heart expansion in CHF distorts the mitral valve which exacerbates the problems.  MitraClip surgery trials found effective in correcting the mitral valve damage (Sep 2018).  Treatments include: digoxin; , stroke is when brain cells are deprived of oxygen and begin to die.  750,000 patients a year suffer strokes in the US.  85% of those strokes are caused by clots.  There are two structural types: Ischemic and hemorrhagic.  Thrombectomy has been found to be a highly effective treatment for some stroke situations (Jan 2018). 
  , AF is atrial fibrillation, an abnormal heart rhythm: rapid, irregular.  It:
  • Can lead to blood clots, stroke, CHF, dementia and other complications.  
  • Fibrillations allow blood to pool in the heart chambers and form small clots which can then lodge in small arteries and block blood flow. 
    
  • Has become much more common being induced by endemic diseases: hypertension, obesity and type-2-diabetes. 
    
  • Cocoa reduces risk of AF (May 2017)
  • Treatments include: digoxin;
    
  ; was due to: youth, exercise, higher education level, lower BMI is body mass index.  , less likely to smoke, ate fruits and vegitables; not due to nuts (Apr 2018)
• Asians, and South Asians in particular, are much more likely to have heart attacks is an AMI. It can induce cardiac arrest.  Blocking the formation of clots with platelet aggregation inhibitors, can help with treating and avoiding AMI.  Risk factors include: taking NSAID pain killers (May 2017).  There is uncertainty about why AMI occur.  Alternative hypotheses include:
  
  • Plaques started to gather in the coronary arteries and grew until no blood flow was possible.  If this is true it makes sense to preventatively treat the buildup with angioplasty. 
    
  • Plaques form anywhere in the body due to atherosclerosis and then break up and get lodged in the coronary artery and start to clot.  If this is true it makes sense to preventatively limit the buildup of plaques with drugs like statins or PCSK9 inhibitors. 
    
  .  The UCSF Northwestern MASALA is a research study of Mediators of Atherosclerosis in South Asians Living in America.  Researchers at UCSF & Northwestern University followed 900 South Asians in Chicago and the San Francisco Bay Area for 9 years, noting a tendency to develop hypertension, high cholesterol and triglycerides and type 2 diabetes at lower body weights than other groups.  South Asians have four times more risk of heart disease.  The research suggests this is partly due to the increased amounts of ectopic fats in Asian bodies, relative to Europeans, but diet also plays a role with consumption of fried snacks, sweetened beverages, & high-fat dairy products.   study suggests this is partly due to the increased amounts of ectopic fats is triglyceride stored in non adipose tissue: liver, skeletal muscle, heart, pancreas; where it can interfere with cellular and organ function. 
  in Asian bodies, relative to Europeans, but diet also plays a role with consumption of fried snacks, sweetened beverages, high-fat dairy products (Feb 2019)
  
• Obesity is an addictive disorder where the brain is induced to require more eating, often because of limits to the number of fat cells available to report satiation (Jul 2016).  Brain images of drug-addicted people and obese people have found similar changes in the brain.  Obese people's reward network tends to be less responsive to dopamine and have a lower density of dopamine receptors.  Obesity spreads like a virus through a social network with a 171% likelihood that a friend of someone who becomes obese will also become so.  Obesity is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes, asthma and heart disease.  It is suspected that this is contributing to the increase in maternal deaths in the US (Sep 2016).  Obesity is a complex condition best viewed as representing many different diseases, which is affected by the: Amount of brown adipose tissue (Oct 2016), Asprosin signalling by white adipose tissue (Nov 2016), Genetic alleles including 25 which guarantee an obese outcome, side effects of some pharmaceuticals for: Psychiatric disorders, Diabetes, Seizure, Hypertension, Auto-immunity; Acute diseases: Hypothyroidism, Cushing's syndrome, Hypothalamus disorders; State of the gut microbiome.  Infections, but not antibiotics, appear associated with childhood obesity (Nov 2016). 
  linked to cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016). 
  (Aug 2016)
  
• Pancreatic cancer is most often an exocrine tumor.  Islet cell tumors are less common.  These are rare cancers: less than 200,000 US cases per year, but the five year survival rates are extremely low 3%.  They all have KRAS mutations.  They are associated with obesity.  Diagnostics are starting to leverage genomics and big databases (23 and me).  Treatments include:
  • Avastin
    
  • Tarceva 
  will trend to the 2nd most deadly in the US is the United States of America.   by 2030.  Given the drop in smoking, research has been seeking a cause for the rise: obesity is an addictive disorder where the brain is induced to require more eating, often because of limits to the number of fat cells available to report satiation (Jul 2016).  Brain images of drug-addicted people and obese people have found similar changes in the brain.  Obese people's reward network tends to be less responsive to dopamine and have a lower density of dopamine receptors.  Obesity spreads like a virus through a social network with a 171% likelihood that a friend of someone who becomes obese will also become so.  Obesity is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes, asthma and heart disease.  It is suspected that this is contributing to the increase in maternal deaths in the US (Sep 2016).  Obesity is a complex condition best viewed as representing many different diseases, which is affected by the: Amount of brown adipose tissue (Oct 2016), Asprosin signalling by white adipose tissue (Nov 2016), Genetic alleles including 25 which guarantee an obese outcome, side effects of some pharmaceuticals for: Psychiatric disorders, Diabetes, Seizure, Hypertension, Auto-immunity; Acute diseases: Hypothyroidism, Cushing's syndrome, Hypothalamus disorders; State of the gut microbiome.  Infections, but not antibiotics, appear associated with childhood obesity (Nov 2016). 
  , type 2 diabetes is the leading cause of blindness, limb amputations and kidney failure.  It is a risk factor for Alzheimer's disease.  Insulin and glucose levels are regulated by the pancreas, liver, muscle, brain and fat.  Diabetes occurs when the insulin level is insufficient to regulate the glucose in the system.  As we age our muscles become less sensitive to insulin and the pancreas responds by increasing the amount generated.  Increased fat levels in obesity demand more insulin overloading the pancreas.  Persistent high glucose levels are also toxic to the pancreas beta cells.  High glucocorticoid levels have been associated with type 2 diabetes.  There are genetic risk factors since siblings of someone with the disease have three times the baseline risk (about 50% of the risk of getting type 2 diabetes is genetic).  The inheritance is polygenic.  More than 20 genes have been identified as risk factors, but that is too few to account for the 50% weighting so many more will be identified.  Of those identified so far many are associated with the beta cells.  The one with the strongest relative risk is TCF7L2.  The disease can be effectively controlled through a diligent application of treatments and regular checkups.  Doctors are monitored for how under control their patients' diabetes is (Sep 2015).  Treatments include:
  • Metformin - does not change the course of pre-diabetes - if you stop taking it, it is as if it hasn't been taken. 
    
  • Diet
  • Exercise
  , metabolic syndrome is an inadequate ability to store fat.  The body aims to store excess energy in the form of fats in adipose tissue.  It there is not enough the fat is stored in other organs: liver, heart, muscles and pancreas where it poisons the organs resulting in metabolic syndrome.  Obese people do not have enough adipose tissue to cope and so develop metabolic syndrome.  Ceramide and diacylglycerol buildup in tissues appear to inhibit insulin signalling.  They are suspected to be the poisons in metabolic syndrome.  Modified dinitrophenol may safely inhibit diacylglycerol buildup, stopping type-2-diabetes and fatty liver development.  ; are all epidemics is the rapid spread of infectious disease: AIDS (Oct 2016), Cholera (2010), Clostridium difficile (May 2015), Ebola, Influenza, Polio, SARS, Tuberculosis, Typhoid (Apr 2018), Malaria, Yellow fever, Zika; to large numbers of people in a population within a short period of time -- two weeks or less.  Epidemics are studied and monitored by: NIAID, CDC, WHO; but are managed by states in the US.  Infection control escalation is supported by biocontainment units: Emory, Nebraska.  Once memes are included in the set of infectious schematic materials, human addictions can present as epidemics concludes Dr. Nora Volkow of the NIDA.  CEPI aims to ensure public health networks are effectively prepared for epidemics.  PHCPI aims to strengthen PCPs globally to improve responsiveness to epidemics.  GAVI helps catalyze the development and deployment of vaccines.  Sporadic investment in public health enables development of conditions for vector development: Mosquitos.  The increasing demands of the global population are altering the planet: Climate change is shifting mosquito bases, Forests are being invaded bringing wildlife and their diseases in contact with human networks.  Globalized travel acts as an infection amplifier: Ebola to Texas.  Health clinics have also acted as amplifiers: AIDS in Haiti, C. diff & MRSA infections enabled & amplified by hospitals.  Haiti earthquake support from the UN similarly introduced Cholera. 
  (Jul 2018)
  
• High fat diet appears to enable operation of prostate cancer is cancer of the prostate gland.  Genomics detected several common DNA variants associated with increased risk of prostate cancer.  Dr. Francis Collins explains that a cluster of these risk variants lies in a stretch of 1 million DNA base pairs on chromosome 8.  The cluster contains seven or more risk variants, each of which can raise the risk of prostate cancer by 10 to 30%.  The high risk variants occur more frequently in African-American men than European or Asians.  African-Americans die from prostate cancer at more than twice the rate of Europeans.  Research in mice may explain a link between obesity and prostate cancer (Jan 2018).  The average diagnosis is at age 66.  Worldwide in 2012 there were 1.1 million cases from which 307,000 died.  A common life-saving (Feb 2017) treatment is androgen deprivation therapy, but it has worrying side effects.  Various classically defined types of cancer can occur.  The most common is adenocarcinoma associated with the epithelial gland cells that generate seminal fluid.  Epithelial cell differentiation potency makes these significant cancer agents.  Other very rare types of cancer that can start in the prostate are:
  • Sarcomas
  • Small cell carcinomas
  • Neuroendocrine tumors
  • Transitional cell carcinomas
  cells and support metastasis reports Beth Israel Deconesses researchers (Jan 2018)
  
• Obesity and diabetes includes type 1 and type 2.  Common side effects include: increased heart disease, hypertension, kidney disease, vision loss, nerve damage, and infections. 
  linked to cancers (Dec 2017)
• Nhanes is the National Health and Nutrition Examination Survey, a program that continuously monitors the health and nutritional status of Americans. 
  finds obesity is an addictive disorder where the brain is induced to require more eating, often because of limits to the number of fat cells available to report satiation (Jul 2016).  Brain images of drug-addicted people and obese people have found similar changes in the brain.  Obese people's reward network tends to be less responsive to dopamine and have a lower density of dopamine receptors.  Obesity spreads like a virus through a social network with a 171% likelihood that a friend of someone who becomes obese will also become so.  Obesity is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes, asthma and heart disease.  It is suspected that this is contributing to the increase in maternal deaths in the US (Sep 2016).  Obesity is a complex condition best viewed as representing many different diseases, which is affected by the: Amount of brown adipose tissue (Oct 2016), Asprosin signalling by white adipose tissue (Nov 2016), Genetic alleles including 25 which guarantee an obese outcome, side effects of some pharmaceuticals for: Psychiatric disorders, Diabetes, Seizure, Hypertension, Auto-immunity; Acute diseases: Hypothyroidism, Cushing's syndrome, Hypothalamus disorders; State of the gut microbiome.  Infections, but not antibiotics, appear associated with childhood obesity (Nov 2016). 
  rates increasing in the US is the United States of America.   for adults, correlating with a rise in the sale of fast-food is defined by Nhanes as any item obtained from a fast-food/pizza establishment.  Gordon discusses the development of fast-food restaurants in the US.  Michael Pollan compares the industrial processed food supply chain with organic and hunter gatherer equivalents. 
  (Mar 2018)
  
• Heights declining (Jul 2016) 
• Evolutionary biology
  
• Yale/Arizona study of Hadza is a Tanzanian hunter gatherer tribe that subsists by hunting and foraging.  They forage for berries, honey, baobab fruit and tubers. 
  shows high daily mobility (Nov 2016) 
• Medication adherence is focused on improving how effectively patients take their medicines.  In the US in 2017 the problem is huge and costly (Apr 2017).  Chronic diseases such as Malaria illustrate the complexity of the task.  A coherent medical network with shared access to EHR should help.  So do blister packs with the days of the week marked.  M-health glow caps with a wireless transmitter that lights up if medication has not been taken as expected.  An improved prescription label is less open to confusion.  Codes on drugs can be scanned by smartphones to initiate download of an informational video.  Smart pillboxes control when pills are dispensed.  Measuring the contents of a medication bottle can alert for intervention if too much or too little is in the bottle.  Drug manufacturers see ways to get closer to the patient: Sanofi Toujeo deployment; Pharmacies are implementing VDS to support medication adherence: Connected Care;
  
  
• Nonadherence is focused on improving how effectively patients take their medicines.  In the US in 2017 the problem is huge and costly (Apr 2017).  Chronic diseases such as Malaria illustrate the complexity of the task.  A coherent medical network with shared access to EHR should help.  So do blister packs with the days of the week marked.  M-health glow caps with a wireless transmitter that lights up if medication has not been taken as expected.  An improved prescription label is less open to confusion.  Codes on drugs can be scanned by smartphones to initiate download of an informational video.  Smart pillboxes control when pills are dispensed.  Measuring the contents of a medication bottle can alert for intervention if too much or too little is in the bottle.  Drug manufacturers see ways to get closer to the patient: Sanofi Toujeo deployment; Pharmacies are implementing VDS to support medication adherence: Connected Care;
  is a huge problem in US (Apr 2017)
  
• F.D.A. Food and Drug Administration.   NDA is new drug application for F.D.A. approval.  Every drug has to obtain NDA approval before it can be commercialized in the US.  INDs along with the data from higher animal studies and human clinical trials are evaluated to assess if the drug is safe and effective for the proposed use, that the labeling is appropriate, and the methods and quality control procedures for manufacture are adequate. 
  approved for: Otsuka, Proteus Digital Health; digital pill Abilify MyCite, which can monitor for adherence is focused on improving how effectively patients take their medicines.  In the US in 2017 the problem is huge and costly (Apr 2017).  Chronic diseases such as Malaria illustrate the complexity of the task.  A coherent medical network with shared access to EHR should help.  So do blister packs with the days of the week marked.  M-health glow caps with a wireless transmitter that lights up if medication has not been taken as expected.  An improved prescription label is less open to confusion.  Codes on drugs can be scanned by smartphones to initiate download of an informational video.  Smart pillboxes control when pills are dispensed.  Measuring the contents of a medication bottle can alert for intervention if too much or too little is in the bottle.  Drug manufacturers see ways to get closer to the patient: Sanofi Toujeo deployment; Pharmacies are implementing VDS to support medication adherence: Connected Care;
  and report findings (Nov 2017)
  

• Studies on environment affecting heritability (Dec 2015)
• Brain tumors grow fast because DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used.   islands become linked (Dec 2015)
• Human genome is divided into TAD is topalogically associating domain, an aspect of the way chromosomes fold up into compact chromatin. In humans there are approximately 2,000 TADs of varying sizes.  TAD borders act as folding instructions and specify rules for genetic operations.  Genetic operations do not normally cross TAD boundaries.  Cohesin and CTCF are found clustered at the TAD borders.  Failure of the TAD borders is associated with cancers of the: colon, esophagus, brain and blood. 
  s.  Failure of the boundaries associated with malformations and cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016). 
  : Leukemia is a group of cancers of blood forming tissues: bone marrow, lymphatic network; where abnormal white blood cells are generated.  One type of leukemia is induced when TAD boundaries near the TAL1 gene fail allowing promotors from across the TAD border to distort the operation of the TAL transcription factor.  Mutation clusters common in leukemia have been identified in CHIP. 
  (Jan 2017)
  

• Brain tumor diagnosis & treatment should use genetic details (Jun 2015)
• Elephants use p53 is a tumor suppressor which improves the specificity of transcription's DNA binding and promotes the transcriptional activity of E2F.  P53's activity is controlled by phosphorylation by cyclin Cdk complexes allowing indirect control of the cell cycle.  Among the many genes controlled by p53 are cyclin genes, genes for an inhibitor of cyclin-dependent kinases (Cdk), and the bax gene, which promotes apoptosis.  p53 can thus promote cell proliferation.  It can drive cells into apoptosis.  But it can also stop cell proliferation by arresting the cell cycle.  Normally there is a dynamic balance between proliferation of cells and their death.  In cancer proliferation may become unregulated due to oncogenic mutations or over expression of key regulatory signalling G proteins such as Ras.  Mutations of the p53 suppressor gene are the most frequent suppressor gene mutations in human cancers.  Elephants like humans, have a relatively low buildup of cancer with age.  Elephant's cells have twenty copies of p53 gene pairs which ensure cells with damaged DNA go into apoptosis blocking cancer onset.  P53 has been shown to be involved in irregular brain cell activity in epilepsy and ASD. 
  copies to limit cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016). 
  onset by apoptosis, programmed cell death is a signal initiated DNA controlled process which results in eukaryotic cells self-destructing.   (Oct 2015)
• Aging analyzed by tissue regeneration (Dec 2016)
  
• Octopuses and aging (Dec 2016) 
• Calico aging process researchers, Kenyon & Bohnert identify sperm signalled, is an emergent capability which is used by cooperating agents to support coordination & rival agents to support control and dominance.  In eukaryotic cells signalling is used extensively.  A signal interacts with the exposed region of a receptor molecule inducing it to change shape to an activated form.  Chains of enzymes interact with the activated receptor relaying, amplifying and responding to the signal to change the state of the cell.  Many of the signalling pathways pass through the nuclear membrane and interact with the DNA to change its state.  Enzymes sensitive to the changes induced in the DNA then start to operate generating actions including sending further signals.  Cell signalling is reviewed by Helmreich.  Signalling is a fundamental aspect of CAS theory and is discussed from the abstract CAS perspective in signals and sensors.  In AWF the eukaryotic signalling architecture has been abstracted in a codelet based implementation.  To be credible signals must be hard to fake.  To be effective they must be easily detected by the target recipient.  To be efficient they are low cost to produce and destroy. 
  oocyte protein repair processes (Nov 2017)
  
• Database search identifies healthy adults with mutations that typically kill in childhood (Apr 2016). 
  
• CHIP is:
  
  • The Children's Health Insurance Program started in 1997 as part of the BBA as SCHIP.  It provides health insurance coverage for children in families with income below 200 percent of the poverty line.  The coverage is focused on care specialized for children including: developmental delays, chronic conditions including asthma and obesity.  CHIP's funding must be iteratively re-authorized by Congress.  CHIP is financed federally, but states must enroll eligible children.  In many states one agency administers CHIP and Medicaid.  CHIP is leveraged by families that have employer based insurance with costly premiums, so the families only cover the adults.  
  • Clonal Hematopoiesis of Indeterminate Potential, where stem cells develop a somatic mutation cluster pair often found in leukemia, which is expressed in white blood cells they produce.  The mutation clusters give these stem cells a competitive advantage and they accumulate over time.  The white blood cells form inflammatory plaques.  CHIP increases with age, increasing the risk of dying, of clot fragment induced heart attacks and stroke, over the subsequent 10 years by 54%
  mechanism identified: somatic, Schematic structures which are used to support the operation of the agent.  They are modified as the agent's state changes unlike the germ-line schemata.   mutated stem cells is a biological cell which is partly or wholly undifferentiated.  A totipotent cell can generate a complete embryo and placenta.  Embryos include pluripotent cells which can generate any tissue in the body.  Adult humans' cells have turned off this ability but still include multipotent stem cells that differentiate into multiple cell types.   Typically a cell's local environment will have the signals required for it to obtain context and differentiate appropriately.  This will include both the external environment and the internal state of the cell which has replicated from a parent and obtained its epi-genetic state.   So introduction of undifferentiated stem cells into an injured area is not likely to have either aspect of the environment suitable.  Consequently development is aiming to encourage differentiation to progenitor cells for the damaged region.  This requires delivering the cells to the appropriate part of the body.  To avoid rejection by the immune system techniques aim to use cell lines developed from the patient's cells.  The techniques to generate these cell lines include: SCNT, iPS.  Possible mechanisms of stem cell therapy are: Generation of new differentiated cells, Stimulation of growth of new blood vessels to repopulate damaged regions, Secretion of growth factors, Treatment of diabetes (1 and 2) with addition of pancreatic cells, Assistance of other mechanisms;, with certain leukemia is a group of cancers of blood forming tissues: bone marrow, lymphatic network; where abnormal white blood cells are generated.  One type of leukemia is induced when TAD boundaries near the TAL1 gene fail allowing promotors from across the TAD border to distort the operation of the TAL transcription factor.  Mutation clusters common in leukemia have been identified in CHIP. 
  mutations, accumulate in bone marrow and generate white blood cells that are highly inflammatory; encouraging: arthritis, clot formation or coagulation is formation of a clot:
  • Platlets become activated, adhere and aggregate supported by
  • Fibrin polymerization, deposition and maturation.  
  and collapse resulting in high incidence of heart attack is an AMI. It can induce cardiac arrest.  Blocking the formation of clots with platelet aggregation inhibitors, can help with treating and avoiding AMI.  Risk factors include: taking NSAID pain killers (May 2017).  There is uncertainty about why AMI occur.  Alternative hypotheses include:
  
  • Plaques started to gather in the coronary arteries and grew until no blood flow was possible.  If this is true it makes sense to preventatively treat the buildup with angioplasty. 
    
  • Plaques form anywhere in the body due to atherosclerosis and then break up and get lodged in the coronary artery and start to clot.  If this is true it makes sense to preventatively limit the buildup of plaques with drugs like statins or PCSK9 inhibitors. 
    
  and stroke is when brain cells are deprived of oxygen and begin to die.  750,000 patients a year suffer strokes in the US.  85% of those strokes are caused by clots.  There are two structural types: Ischemic and hemorrhagic.  Thrombectomy has been found to be a highly effective treatment for some stroke situations (Jan 2018). 
  ; Dana-Farber's Ebert, Broad Institute/Massachusetts General's Kathiresan conclude (Jan 2018)
  
• Zebra fish with human BRAF is a human gene that codes for the protein B-Raf. 
  and P53 in all melanocytes signal cancer identifying requirement for crestin to reactivate (Jan 2016). 
  
• Genetic engineering of photosynthesis to improve plant yields (Nov 2016).  
• Rare gene mutation of ANGPTL3 is angiopoietin-like 3, a protein encoded by the ANGPTL3 gene, that participates in angiogenesis in the liver.  The preprotein is proteolytically processed into active proteins which inhibit triglyceride metabolism.  Gene knockouts result in reduced plasma lipid concentrations. 
  that stops inhibition of triglyceride metabolism in angiogenesis is the formation of new blood vessels from existing vessels.  It is important in growth, development and wound healing.  To become malignant many tumors stimulate angiogenesis. 
  found associated with reduced CVD is cardiovascular disease which refers to:
  • Conditions where narrowed and blocked blood vessels result in angina, hypertension, CHD and heart attacks and hemorrhagic/ischemic strokes.  Mutations of the gene PCSK9 have been implicated in cardiovascular disease.  Rare families with dominant inheritence of the mutations have an overactive protein, very high levels of blood cholesterol and cardiac disease. Other rare PCSK9 mutations result in an 88% reduced risk from heart disease.  Inflammation is associated with cardiovascular disease (Aug 2017). 
    
  .  Prompts medical studies: Massachusetts General Hospital, University of Pennsylvania, Washington University; & commercial research & development: Regeneron, Ionis; for blockbuster drug (May 2017)
  
• Obesity is an addictive disorder where the brain is induced to require more eating, often because of limits to the number of fat cells available to report satiation (Jul 2016).  Brain images of drug-addicted people and obese people have found similar changes in the brain.  Obese people's reward network tends to be less responsive to dopamine and have a lower density of dopamine receptors.  Obesity spreads like a virus through a social network with a 171% likelihood that a friend of someone who becomes obese will also become so.  Obesity is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes, asthma and heart disease.  It is suspected that this is contributing to the increase in maternal deaths in the US (Sep 2016).  Obesity is a complex condition best viewed as representing many different diseases, which is affected by the: Amount of brown adipose tissue (Oct 2016), Asprosin signalling by white adipose tissue (Nov 2016), Genetic alleles including 25 which guarantee an obese outcome, side effects of some pharmaceuticals for: Psychiatric disorders, Diabetes, Seizure, Hypertension, Auto-immunity; Acute diseases: Hypothyroidism, Cushing's syndrome, Hypothalamus disorders; State of the gut microbiome.  Infections, but not antibiotics, appear associated with childhood obesity (Nov 2016). 
  explained through lipodystrophy is a rare genetic disorder, characterized by an abnormal lack of fatty tissue but the symptoms of obesity.  It results in reduced production of leptin. 
  mechanism by NIDDK is the National Institute of Diabetes and Digestive and Kidney Diseases. 
  (Jul 2016)
• Thin gene FBN1 is a gene which encodes fibrillin and in white adipose tissue the hormone asprosin. 
  asprosin is a protein based hormone produced in white adipose tissue that signals the brain and liver to release glucose into the blood stream.  It is encoded by the FBN1 gene.  cAMP is the second messenger in the signalling network. 
  signalling, is an emergent capability which is used by cooperating agents to support coordination & rival agents to support control and dominance.  In eukaryotic cells signalling is used extensively.  A signal interacts with the exposed region of a receptor molecule inducing it to change shape to an activated form.  Chains of enzymes interact with the activated receptor relaying, amplifying and responding to the signal to change the state of the cell.  Many of the signalling pathways pass through the nuclear membrane and interact with the DNA to change its state.  Enzymes sensitive to the changes induced in the DNA then start to operate generating actions including sending further signals.  Cell signalling is reviewed by Helmreich.  Signalling is a fundamental aspect of CAS theory and is discussed from the abstract CAS perspective in signals and sensors.  In AWF the eukaryotic signalling architecture has been abstracted in a codelet based implementation.  To be credible signals must be hard to fake.  To be effective they must be easily detected by the target recipient.  To be efficient they are low cost to produce and destroy. 
  viewed as an experimental probe for obesity is an addictive disorder where the brain is induced to require more eating, often because of limits to the number of fat cells available to report satiation (Jul 2016).  Brain images of drug-addicted people and obese people have found similar changes in the brain.  Obese people's reward network tends to be less responsive to dopamine and have a lower density of dopamine receptors.  Obesity spreads like a virus through a social network with a 171% likelihood that a friend of someone who becomes obese will also become so.  Obesity is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes, asthma and heart disease.  It is suspected that this is contributing to the increase in maternal deaths in the US (Sep 2016).  Obesity is a complex condition best viewed as representing many different diseases, which is affected by the: Amount of brown adipose tissue (Oct 2016), Asprosin signalling by white adipose tissue (Nov 2016), Genetic alleles including 25 which guarantee an obese outcome, side effects of some pharmaceuticals for: Psychiatric disorders, Diabetes, Seizure, Hypertension, Auto-immunity; Acute diseases: Hypothyroidism, Cushing's syndrome, Hypothalamus disorders; State of the gut microbiome.  Infections, but not antibiotics, appear associated with childhood obesity (Nov 2016). 
  (Nov 2016)
  
• Cholera from 1849 pandemic decoded.  Pandemics driven by shipping and enabled by poor sewage treatment. 
  
• P53 is a tumor suppressor which improves the specificity of transcription's DNA binding and promotes the transcriptional activity of E2F.  P53's activity is controlled by phosphorylation by cyclin Cdk complexes allowing indirect control of the cell cycle.  Among the many genes controlled by p53 are cyclin genes, genes for an inhibitor of cyclin-dependent kinases (Cdk), and the bax gene, which promotes apoptosis.  p53 can thus promote cell proliferation.  It can drive cells into apoptosis.  But it can also stop cell proliferation by arresting the cell cycle.  Normally there is a dynamic balance between proliferation of cells and their death.  In cancer proliferation may become unregulated due to oncogenic mutations or over expression of key regulatory signalling G proteins such as Ras.  Mutations of the p53 suppressor gene are the most frequent suppressor gene mutations in human cancers.  Elephants like humans, have a relatively low buildup of cancer with age.  Elephant's cells have twenty copies of p53 gene pairs which ensure cells with damaged DNA go into apoptosis blocking cancer onset.  P53 has been shown to be involved in irregular brain cell activity in epilepsy and ASD. 
  blocks Crispr is clustered replicating interspersed silent palindromic repeats; a technique for exact targeting, cutting and editing of DNA based on leveraging bacterial enzymatic defenses against viruses generalized to any DNA sequence in a prokaryotic or eukaryotic cell.  It was identified during studies of a bacterial adaptive immune system.  In that system bacterial proteins grab parts of a virus that has infected them and record it within the palindromic structures that mark an array of inserted viral DNA used as a log persisted over generations.  If a new infection occurs the viral DNA is compared with the sequences and if a match exists the CAS proteins break up the viral DNA initiating its destruction.  This bacterial system was then updated and repurposed by the researchers to support targeted genetic engineering.  As explained by Dr. Doudna, the CRISPR proteins and the 20 nucleotide RNA template migrate into the nucleus where they rapidly target DNA which complements the RNA template and the Cas9 enzyme performs the edits.  Being a bacterial system CRISPR Cas9 does not target eukaryotic heterochromatic DNA well.  It is not fully understood how they find the target sequence so quickly.  It has been shown that Cas9 will bind to sites with a 5-8 base match but then it releases rapidly without cutting.  To cut, Cas9 has to reconfigure, which does not occur in the mismatch situations.   action, detecting DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used.   changes and blocking DNA synthesis and invoking apoptosis, programmed cell death is a signal initiated DNA controlled process which results in eukaryotic cells self-destructing.  .  Gene editing companies: Crispr therapeutics, Intellia Therapeutics, Editas Medicine; take a beating (Jun 2018)
  
• Crispr leverage clears pig chromosomes of viruses (Oct 2015) and with gene drive generates concerns about evolutionary consequences (Nov 2015)
• Crispr is clustered replicating interspersed silent palindromic repeats; a technique for exact targeting, cutting and editing of DNA based on leveraging bacterial enzymatic defenses against viruses generalized to any DNA sequence in a prokaryotic or eukaryotic cell.  It was identified during studies of a bacterial adaptive immune system.  In that system bacterial proteins grab parts of a virus that has infected them and record it within the palindromic structures that mark an array of inserted viral DNA used as a log persisted over generations.  If a new infection occurs the viral DNA is compared with the sequences and if a match exists the CAS proteins break up the viral DNA initiating its destruction.  This bacterial system was then updated and repurposed by the researchers to support targeted genetic engineering.  As explained by Dr. Doudna, the CRISPR proteins and the 20 nucleotide RNA template migrate into the nucleus where they rapidly target DNA which complements the RNA template and the Cas9 enzyme performs the edits.  Being a bacterial system CRISPR Cas9 does not target eukaryotic heterochromatic DNA well.  It is not fully understood how they find the target sequence so quickly.  It has been shown that Cas9 will bind to sites with a 5-8 base match but then it releases rapidly without cutting.  To cut, Cas9 has to reconfigure, which does not occur in the mismatch situations.   and Talen is transcription activator-like effector nuclease.  These are restriction enzymes that function as a dimer with unique DNA binding domains. 
  gene editing by:Cellectis, DuPont Pioneer, Monsanto, Recombinetics; to produce new foods not currently considered a genetic modification by 2016 labeling law of 2016 specifies what foods must declare on a label as genetically modified.  It replaces all state labeling laws.  , the U.S.D.A. - U.S. Department of Agriculture.  or F.D.A. Food and Drug Administration.   (Jan 2017)
• F.D.A. Food and Drug Administration.   constraints on leghemoglobin, loved by VCs: Khosla Ventures, Bill Gates; Impossible Foods burger ingredient may become complex to certify (Aug 2017)
• study of genome deltas
  
• Perlegen finds genetic recombinations in human primate differences 
• Regeneron studies clinical collection of DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used.   exomes is the 1 ot 2 percent of the genome which codes for the proteins. 
  with Geisinger - stored in EHR refers to electronic health records which are a synonym of EMR.  EHR analysis suggests strengths and weaknesses:
  • The EHR provides an integrated record of the health systems notes on a patient including: Diagnosis and Treatment plans and protocols followed, Prescribed drugs with doses, Adverse drug reactions;
  • The EHR does not necessarily reflect the patient's situation accurately. 
    
  • The EHR often acts as a catch-all.  There is often little time for a doctor, newly attending the patient, to review and validate the historic details. 
    
  • The meaningful use requirements of HITECH and Medicare/Medicaid specify compliance of an EHR system or EHR module for specific environments such as an ambulatory or hospital in-patient setting. 
    
  • As of 2016 interfacing with the EHR is cumbersome and undermines face-to-face time between doctor and patient.  Doctors are allocated 12 minutes to interact with a patient of which less than five minutes was used for recording hand written notes.  With the EHR 12 minutes may be required to update the record!
    
  ; NHGRI is the NIH's national human genome research institute which aims to advance human health through genomics research. 
  argues the approach is significant (Jan 2014) 
• HGP is the human genome project an international research project to determine the sequence of DNA base pairs of humans and identify and map physically and functionally all the genes in the human genome.  The HapMap project proved very helpful for discovering the SNPs. 
  2: The Human Genome Synthesis Project (May 2016)
  
• Synthetic Biology is the design and construction of biological systems, modules and machines for research or industry leverage by the integration of disciplines from biology and engineering including:
  • Biotechnology: PCR enables phage display;
    
  • Evolutionary biology allowed directed evolution to build enzymes with desired functional properties. 
    
  • Genetic engineering
  • Molecular biology
  • Molecular engineering
  • Systems biology
    
  • Biophysics
  • Computer engineering. 
    
   
• Synthego raises $41 million from Founders Fund, Menlo Ventures, 8VC, Jennifer Doudna (Jan 2017)
  
• National academies criticized for biotechnology (synthetic biology is the design and construction of biological systems, modules and machines for research or industry leverage by the integration of disciplines from biology and engineering including:
  • Biotechnology: PCR enables phage display;
    
  • Evolutionary biology allowed directed evolution to build enzymes with desired functional properties. 
    
  • Genetic engineering
  • Molecular biology
  • Molecular engineering
  • Systems biology
    
  • Biophysics
  • Computer engineering. 
    
  ) panel committee academics: Steven Bradbury, Farren Isaacs, Richard Amasino, Jeffrey Wolt; and EBRC board members, links to industry (Dec 2016)

• Microbiome, the trillions of bacteria and viruses that live inside higher animals' guts, on their skin etc.  These bacteria and viruses seem to play a role in: immune responses, digesting food, making nutrients, controlling mental health and maintaining a healthy weight.  The signals from the gut microbiota are relayed by major nerve fibers: vagus; to the central nervous system.  The symbiotic relationship must be actively managed.  Human armpits include glands which provide food favoring certain symbionts who build a defensive shield above the skin.  In the human gut: Barriers are setup: Mucus secretions form a physical constraint and provide sites for bacteriophages to anchor and attack pathogenic bacteria; Symbiont tailored nourishment: Plant-heavy food creates opportunities for fibre specialists like Bacteroides thetaiotaomicron; is provided, Selective binding sites are provided, Poisons are deployed against the unwelcome, and Temperature, acidity and oxygenation are managed.    High throughput sequencing allows the characterization of bacterial populations inside guts.  Beginning at birth, as they pass down the birth canal infants are supplied with a microbiome from their mothers.  If they are borne via cesarean they never receive some of the key bacteria: Bifidobaterium infantis which is also dependent on oligosaccharides in breast milk; from their mothers.  A variety of diseases may be caused by changes in the microbiome:
  • Eczema can be related to changes in the skin microbiome. 
    
  • Obesity can be induced by changes to the gut microbiome.  
  • Chronic inflammation
    
  • Allergies
    
  • Type 1 diabetes
    
  
  
• Brain defect linked to gut microbiome, the trillions of bacteria and viruses that live inside higher animals' guts, on their skin etc.  These bacteria and viruses seem to play a role in: immune responses, digesting food, making nutrients, controlling mental health and maintaining a healthy weight.  The signals from the gut microbiota are relayed by major nerve fibers: vagus; to the central nervous system.  The symbiotic relationship must be actively managed.  Human armpits include glands which provide food favoring certain symbionts who build a defensive shield above the skin.  In the human gut: Barriers are setup: Mucus secretions form a physical constraint and provide sites for bacteriophages to anchor and attack pathogenic bacteria; Symbiont tailored nourishment: Plant-heavy food creates opportunities for fibre specialists like Bacteroides thetaiotaomicron; is provided, Selective binding sites are provided, Poisons are deployed against the unwelcome, and Temperature, acidity and oxygenation are managed.    High throughput sequencing allows the characterization of bacterial populations inside guts.  Beginning at birth, as they pass down the birth canal infants are supplied with a microbiome from their mothers.  If they are borne via cesarean they never receive some of the key bacteria: Bifidobaterium infantis which is also dependent on oligosaccharides in breast milk; from their mothers.  A variety of diseases may be caused by changes in the microbiome:
  • Eczema can be related to changes in the skin microbiome. 
    
  • Obesity can be induced by changes to the gut microbiome.  
  • Chronic inflammation
    
  • Allergies
    
  • Type 1 diabetes
    
  (May 2017)
• Fusobacterium, always in mouth, is found with colon cancer is a major hereditary cancer also called colorectal cancer.  It:
  
  • Follows a slow, many yearlong, progression from a benign polyp to a localized cancer to an invasive one.  Two bacteria: Bacteroides fragilis, Escherichia coli variant; from the gut microbiome have been implicated in the early stages of tumor induction (Feb 2018).  It
    
  • Is often associated with Ras mutations and the high risk allele TCF7L2.  30 to 50% of colon cancers have KRAS mutations.  Intensive medical surveillance and removal of polyps can be lifesaving for those at high risk.  Types of colon cancer include the single gene mutation hereditary: FAP, HNPCC; 
  • Is linked to obesity. 
    
  tumors including metastatic.  If the bacterium is killed with antibiotics are compounds which kill bacteria, molds, etc.  Sulfur dye stuffs were found to be effective antibiotics.  The first evolved antibiotic discovered was penicillin.  Antibiotics are central to modern health care supporting the processes of: Surgery, Wound management, Infection control; which makes the development of antibiotic resistance worrying.  Antibiotics are:
  • Economically problematic to develop and sell. 
    
  • Congress enacted GAIN to encourage development of new antibiotics.  But it has not developed any market-entry award scheme, which seems necessary to encourage new antibiotic R&D. 
    
  • Medicare has required hospitals and SNFs to execute plans to ensure correct use of antibiotics & prevent the spread of drug-resistant infections.  
  • C.D.C. is acting to stop the spread of resistant infections and reduce unnecessary use of antibiotics.  
    
  • F.D.A. has simplified approval standards.  It is working with industry to limit use of antibiotics in livestock. 
    
  • BARDA is promoting public-private partnerships to support promising research.
    
  • Impacting the microbiome of the recipient.  Stool banking is a solution  (Sloan-Kettering stool banking).  
  • Associated with obesity, although evidence suggests childhood obesity relates to the infections not the antibiotic treatments (Nov 2016). 
    
  • Monitored globally by W.H.O.
    
  • Regulated in the US by the F.D.A. who promote voluntary labeling by industry to discourage livestock fattening (Dec 2013).  
  • Customer demands have more effect - Perdue shifts to no antibiotics in premier chickens (Aug 2015). 
    
  the tumor growth slows (Nov 2017)
• Johns Hopkins Cynthia Sears & Drew Pardoll report gut microbiome, the trillions of bacteria and viruses that live inside higher animals' guts, on their skin etc.  These bacteria and viruses seem to play a role in: immune responses, digesting food, making nutrients, controlling mental health and maintaining a healthy weight.  The signals from the gut microbiota are relayed by major nerve fibers: vagus; to the central nervous system.  The symbiotic relationship must be actively managed.  Human armpits include glands which provide food favoring certain symbionts who build a defensive shield above the skin.  In the human gut: Barriers are setup: Mucus secretions form a physical constraint and provide sites for bacteriophages to anchor and attack pathogenic bacteria; Symbiont tailored nourishment: Plant-heavy food creates opportunities for fibre specialists like Bacteroides thetaiotaomicron; is provided, Selective binding sites are provided, Poisons are deployed against the unwelcome, and Temperature, acidity and oxygenation are managed.    High throughput sequencing allows the characterization of bacterial populations inside guts.  Beginning at birth, as they pass down the birth canal infants are supplied with a microbiome from their mothers.  If they are borne via cesarean they never receive some of the key bacteria: Bifidobaterium infantis which is also dependent on oligosaccharides in breast milk; from their mothers.  A variety of diseases may be caused by changes in the microbiome:
  • Eczema can be related to changes in the skin microbiome. 
    
  • Obesity can be induced by changes to the gut microbiome.  
  • Chronic inflammation
    
  • Allergies
    
  • Type 1 diabetes
    
  : Bacteriodes fragilis & Escherichia coli; stimulate colon cancer is a major hereditary cancer also called colorectal cancer.  It:
  
  • Follows a slow, many yearlong, progression from a benign polyp to a localized cancer to an invasive one.  Two bacteria: Bacteroides fragilis, Escherichia coli variant; from the gut microbiome have been implicated in the early stages of tumor induction (Feb 2018).  It
    
  • Is often associated with Ras mutations and the high risk allele TCF7L2.  30 to 50% of colon cancers have KRAS mutations.  Intensive medical surveillance and removal of polyps can be lifesaving for those at high risk.  Types of colon cancer include the single gene mutation hereditary: FAP, HNPCC; 
  • Is linked to obesity. 
    
  by invading the mucus is used to cover tissues that are exposed.  It is made from mucins.  Mucous membranes may secrete mucus to generate a robust barrier. 
  epithelium is a core cell type that lines cavities and surfaces of blood vessels and organs.  All glands are constructed from epithelial cells.  Epithelial cells: secrete, absorb, protect, transport and sense.  They have no blood supply so they are nourished via diffusion through the basement membrane from underlying connective tissue.  Epithelial cell differentiation potency makes these significant cancer agents.  of the colon, developing biofilms is a sheet of bacteria that have invaded the mucus epithelium covering an organ. 
  , and damaging the DNA (DNA), a polymer composed of a chain of deoxy ribose sugars with purine or pyrimidine side chains.  DNA naturally forms into helical pairs with the side chains stacked in the center of the helix.  It is a natural form of schematic string.  The purines and pyrimidines couple so that AT and GC pairs make up the stackable items.  A code of triplets of base pairs (enabling 64 separate items to be named) has evolved which now redundantly represents each of the 20 amino-acids that are deployed into proteins, along with triplets representing the termination sequence.  Chemical modifications and histone binding (chromatin) allow cells to represent state directly on the DNA schema.  To cope with inconsistencies in the cell wide state second messenger and evolved amplification strategies are used.   (Feb 2018)
  

• Cellular pathway models
  
• Exercise
  
• Oct 2016 Irisin is a hormone which stimulates white adipose (fat) tissue to turn brown.  Irisin is created in working muscles in mice.  After entering the bloodstream it migrates to other tissues, in particular adipose cells where it signals a pathway that promotes UCP1 generation and causes some of the white adipose cells to turn brown.  Brown adipose: Burns calories, Controls insulin and blood sugar; and reduces the risk of type-2-diabetes.   Irisin signals white adipose stem cells to become bone cells.  Irisin has no apparent effect on brown adipose cells.  When irisin was injected into mice being fed a high fat, high calorie diet it inhibited them becoming obese. 
  stimulated in workouts model of exercise suggests. 
  
• Predictive health analytics 
• Jun 2014 NYT When a health Plan Knows How You Shop
• Sep 2014 To Gather Drug Data use Consumer surveys
  
• PTSD
  
• Aug 2014 Combat stress found to persist since Vietnam
• Post-hospital syndrome
  
• Impacts of hospital stays on the elderly: disrupted sleep facilitates salient memory formation and removal of non-salient memories.  The five different stages of the nightly sleep cycles support different aspects of memory formation.  The sleep stages follow Pre-sleep and include: Stage one characterized by light sleep and lasting 10 minutes, Stage two where theta waves and sleep spindles occur, Stage three and Stage four together represent deep slow-wave sleep (SWS) with delta waves, Stage five is REM sleep; sleep cycles last between 90-110 minutes each and as the night progresses SWS times reduce and REM times increase.   Sleep includes the operation of synapse synthesis and maintenance through DNA based activity including membrane trafficking, synaptic vesicle recycling, myelin structural protein formation and cholesterol and protein synthesis.  Sleep also controls inflammation (Jan 2019)  Sleep deprivation undermines the thalamus & nucleus accumbens management of pain. 
  , unappetizing meal impacts, reduced muscle mass, poor balance, additional medicine complications, delirium, pain emerged as a mental experience, Damasio asserts, constructed by the mind using mapping structures and events provided by nervous systems.  But feeling pain is supported by older biological functions that support homeostasis.  These capabilities reflect the organism's underlying emotive processes that respond to wounds: antibacterial and analgesic chemical deployment, flinching and evading actions; that occur in organisms without nervous systems.  Later in evolution, after organisms with nervous systems were able to map non-neural events, the components of this complex response were 'imageable'.  Today, a wound induced by an internal disease is reported by old, unmyelinated C nerve fibers.  A wound created by an external cut is signalled by evolutionarily recent myelinated fibers that result in a sharp well-localized report, that initially flows to the dorsal root ganglia, then to the spinal cord, where the signals are mixed within the dorsal and ventral horns, and then are transmitted to the brain stem nuclei, thalamus and cerebral cortex.  The pain of a cut is located, but it is also felt through an emotive response that stops us in our tracks.  Pain amplifies the aggression response of people by interoceptive signalling of brain regions providing social emotions including the PAG projecting to the amygdala; making aggressive people more so and less aggressive people less so.  Fear of pain is a significant contributor to female anxiety.  Pain is the main reason people visit the ED in the US.  Pain is mediated by the thalamus and nucleus accumbens, unless undermined by sleep deprivation. 
  , internal bleeding, anemia is a decrease in the number of red blood cells or the amount of hemoglobin in the blood.  There are various types: Fanconia anemia, Iron-deficiency anemia, Pernicious anemia, Sickle-cell anemia;
  , ED is emergency department.  Pain is the main reason (75%) patients go to an E.D.  It has traditionally been part of an acute care hospital but recently is being deployed standalone as a catchment funnel to the owning hospital.  The EMTALA legislation requires E.D. treatment to stabilize every person seeking treatment by most hospitals.  Unreimbursed care is supported from federal government funds.  E. D. profitability has been helped by hospitals contracting with 3rd party companies who are able to improve margins through surprise billing.  The standalone E.D. competes with the positioning and brand power of lower cost urgent care clinics.  Commercial nature of care requires walk-ins to register to gain access to care.  With the focus on treatment of pain, E.D.s are a major distributor of opioids (5% of opioid prescriptions) and a major starting point of addiction in patients but are cutting back (Jun 2016). 
  crowding/chaos induced PTSD is post-traumatic stress disorder, an induced level of stress that is so troubling to the brain that it avoids processing it, change that is necessary if the stress is to be dissipated by the normal brain processes.  The hippocampus loses volume.  The damage to the hippocampus results in: flashbacks, becoming emotionally numb and withdrawn from other people, irritability, jumpiness, being more aggressive, having trouble sleeping and avoidance of the sensory experiences associated with the initial event.  The amygdala responds to overwhelming trauma by repeatedly grabbing attention to encourage response to the emergency, increases in volume and is hyperactive and anxious.  As a result it remains in a heightened state, resulting in fear of recall and further stress.  PTSD is often accompanied by depression and substance abuse.  It is now being realized that PTSD can be introduced into patients by traumatic treatment regimens such as ICU procedures.  Traumatic head injuries, seen in athletes and soldiers can be reflected in PTSD and can subsequently become associated with prion based dementia.  Some people are genetically predisposed to PTSD, with identical twins responding similarly.  Another risk factor for PTSD is childhood trauma which can induce epi-genetic changes to stress processing.  PTSD can be managed with CBT, and it also responds to propranolol while recalling the traumatic event, where the drug undermines the memory reconsolidation process. 
  , forced to walk in hospital gowns; results in post-hospital syndrome, after discharge - have costly handoff problems reviewed by project BOOST.  When discharge takes too long it ties up acute bed space which can result in adding up to 30% more (unnecessary) capacity when improved discharge would translate into additional revenue.  Various interventions aim to improve the execution of the process including: CTI, TCN and RED for discharge to outpatient; InterAct for discharge to SNFs and BPIP to HHAs.  Discharge information can include:
  • Patient info
    
  • Behavioral summary
  • Treatment history
  • Medical history
  • Treatment objectives
  • Insurance policy
  • Discharge plans
  , Yale's Harlam Krumholz concluded, based on readmission have become a source of increased revenue for hospitals.  But with government interested in reducing the US health care cost curve ACA's HRRP (pay-for-performance), BPCI and CTI and Interact discharge initiative have all increased the focus on unnecessary readmissions.  Now the end-to-end process is under scrutiny with hospitals reengineering discharge (RED) and PAC providers using RAI and TCN. 
  being for unrelated problems to the initial cause of hospitalization (Aug 2018)
  
• Virtual Reality 
• Aug 2014 Forum on Oculus Rift and Jaunt cinematic VR with Stanford researcher reviewing use in Surgery, PTSD is post-traumatic stress disorder, an induced level of stress that is so troubling to the brain that it avoids processing it, change that is necessary if the stress is to be dissipated by the normal brain processes.  The hippocampus loses volume.  The damage to the hippocampus results in: flashbacks, becoming emotionally numb and withdrawn from other people, irritability, jumpiness, being more aggressive, having trouble sleeping and avoidance of the sensory experiences associated with the initial event.  The amygdala responds to overwhelming trauma by repeatedly grabbing attention to encourage response to the emergency, increases in volume and is hyperactive and anxious.  As a result it remains in a heightened state, resulting in fear of recall and further stress.  PTSD is often accompanied by depression and substance abuse.  It is now being realized that PTSD can be introduced into patients by traumatic treatment regimens such as ICU procedures.  Traumatic head injuries, seen in athletes and soldiers can be reflected in PTSD and can subsequently become associated with prion based dementia.  Some people are genetically predisposed to PTSD, with identical twins responding similarly.  Another risk factor for PTSD is childhood trauma which can induce epi-genetic changes to stress processing.  PTSD can be managed with CBT, and it also responds to propranolol while recalling the traumatic event, where the drug undermines the memory reconsolidation process. 
  , 
• Nov 2015 Artificial Patients, Real Learning
  

• Alzheimer's is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and declarative memory and thinking problems (MCI).  Specific cells within the hippocampal circuitry and its gateway, the entorhinal cortex, are damaged.  The amygdala, cerebelum and other areas supporting implicit memory are not impacted during the early stages of the disease.  Grid cell destruction results in a sense of being lost.  The default mode network is disrupted.  Variants include: late-onset sporadic; with risk factors - ApoE4 for late onset Alzheimer's, presenilin, androgen deprivation therapy (Dec 2015), type 2 diabetes.  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation, Neurons of sporadic Alzheimer's sufferers show greater APP gene diversity due to somatic recombination; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form.  These are seen in fMRIs 10 to 15 years prior to detecting memory and thinking changes.  APP deployed in the cell membrane is cut into three parts.  The external part becomes amyloid-beta peptide which aggregates into Amyloid plaques, external to the neurons, if too much is generated or it is not removed fast enough. 
    
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016). 
    
  • Encouraging the garbage collection of amyloid and tau with gamma rhythms stimulation retards Alzheimer's in mice studies (Mar 2019)
    
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • Mutation driven misfolded Tau proteins can form tangles within the cytoplasm of neurons.  The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    
  • The brain becomes inflamed resulting in the killing of many more nerve cells.  The hippocampus disintegrates and the brain loses critical functions and memory loss becomes noticeable. 
    
  as a behavioral disorder (Jul 2016)
• Mount Sinai Icahn SOM's Dr. Joel Dudley's precision medicine is the integration of molecular research: genomics, proteomics, transcriptomics, metabolomics, cell signalling; and clinical data through a taxonomy based on CAS modeling overlaid on an information commons.  It aims to support treatment of disease and remove the organ and symptom based methodological flaws in the ICD.  Supporters of the D.S.M. note the aggressive shift to precision medicine at the NIMH under Dr. Insel, constrained useful clinical research (Nov 2015). 
  (Big Data encompasses the IT systems and processes necessary to do population based data collection, management and analysis.  The very low cost, robust, data storage organized by infrastructure: HADOOP; allows digital data to be stored en mass.  Data scientists then apply assumptions about the world to the data, analogous to evolved mechanisms in vision, in the form of algorithms: Precision medicine, Protein folding modeling (Feb 2019) assumes coevolutionary methods can be applied to identify contact points in a protein's tertiary structure.  Rather than depending on averages, analysis at Verisk drills down to specifics and then highlights modeling problems by identifying the underlying CAS.  For the analysis to be useful it requires a hierarchy of supporting BI infrastructure:
  • Analytics utilization and integration delivered via SaaS and the Cloud to cope with the silos and data intensive nature. 
    
  • Analytics tools (BI) for PHM will be hard to develop.  
  • Complex data models must include clinical aspects of the patient specific data, including disease state population wide.  
  • A key aspect is providing clear signals about the nature of the data using data visualization. 
    
  • Data communication with the ability to exchange and transact.  HIEs and EMPI alliance approaches are all struggling to provide effective exchange. 
    
  • Data labeling and secure access and retreival.  While HIPAA was initially drafted as a secure MPI the index was removed from the legislation leaving the US without