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)
• 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). 
  , 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.  
  • Providing quantitative data on the imaged process or function enabling nanomedicine.  
  • 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, DNA 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.  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 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 a 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).  It is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes 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).  Commercial applications are focused on research and clinical tools for drug delivery, therapies, in vivo imaging, neuro-electronic interfaces, other nanosensors, and eventually cell repair machines!!  There are issues with determining toxicology etc. 
  will: Reduce the invasiveness of surgery and enhance 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 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 and prion infections such as Alzheimer's disease, 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 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 memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  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; It is initiated by an increasingly leaky blood-brain barrier and the innate immune response to subsequent infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form and set off the formation of tangled thread-like tau protein.
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • 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. 
    
  ), 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. 
  ); 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.  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 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. 
    
  , 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;
  
• Systemic understanding of antibiotics are compounds which kill bacteria, molds, etc.  The first 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. 
  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-patent setting. 
    
  • As of 2016 interfacing with the EHR is cumbersome and undermines face-to-face time between doctor and patient.  
  , Imaging and Molecular diagnostics (nano-materials in medicine May 2016) 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.  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, 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-patent setting. 
    
  • As of 2016 interfacing with the EHR is cumbersome and undermines face-to-face time between doctor and patient.  
  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.   
• 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.  Diagnostics are starting to leverage genomics and big databases (23 and me).  Treatments include:
  • Avastin
    
  • Tarceva 
  Jun 2016). 
  
• Watson supported genomics combines recombinant DNA, DNA 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.  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. 
    
  . 
• 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 to allow the value delivery system to optimize around low cost high quality long term health care.  This 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) 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 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)
• 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 to allow the value delivery system to optimize around low cost high quality long term health care.  This 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 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-patent setting. 
    
  • As of 2016 interfacing with the EHR is cumbersome and undermines face-to-face time between doctor and patient.  
  ) 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 observationsand 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 observationsand 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 observationsand 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 Kaiser like business models (Dec 2015, Sep 2016) focused on wellness, and rewarding doctors for preventing problems.  Advocate health illustrates the idea.  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 programs 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 low FFS leverage of the PCP compared to specialists. 
  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 healthcare-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.  
  • Providing quantitative data on the imaged process or function enabling nanomedicine.  
  • 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. 
  
  
• 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 and prion infections such as Alzheimer's disease, 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 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 memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  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; It is initiated by an increasingly leaky blood-brain barrier and the innate immune response to subsequent infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form and set off the formation of tangled thread-like tau protein.
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • 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. 
    
  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 and prion infections such as Alzheimer's disease, 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 appears to develop faster in women than men.   rates dropping as US is the United States of America.   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.  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)
• 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/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 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.  
    
  
  
• President Obama's precision medicine initiative 
• Finances million-person cohort is a precision medicine activity funded through the NIH with $130 million in December 2015 by Congress (Jul 2016). 
  (Jul 2016)
  
• 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.  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.  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 carinomas 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). 
  
  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). 
• Gilead to acquire Kite Pharma for $11.9 billion (Aug 2017)
  
• 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.  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)
• Cuban immunotherapy is indirect treatment of disease by stimulating the immune system.  Targeted diseases include cancers -- immuno-oncology.   vaccine are a core strategy of public health and have significantly extended global wellbeing over 200 years.  Recent successes include: HPV vaccine.  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).  
  • Where clinics have been driven into local neighborhoods health improves (Apr 2016).  
  • Retail clinics (Mar 2016): CVS Minute Clinics focus on vaccination.  
  • Key vaccines include: BCG, C. difficile (May 2015), Cholera (El Tor), Dengvaxia (Mexico Dec 2015), Gvax, Malaria vaccine, Provenge;
  • 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 a 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).  It is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes 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 a 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).  It is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes 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 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 stimulating the immune system.  Targeted diseases include cancers -- immuno-oncology.   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.  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, DNA 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, DNA 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).  
• 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.  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 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, nivolumab, pembrolizumab, atezolizumab;  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.  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)
• 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.  Biologics 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, 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). 
• 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.   (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 memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  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; It is initiated by an increasingly leaky blood-brain barrier and the innate immune response to subsequent infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form and set off the formation of tangled thread-like tau protein.
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • 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. 
    
  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 memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  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; It is initiated by an increasingly leaky blood-brain barrier and the innate immune response to subsequent infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form and set off the formation of tangled thread-like tau protein.
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • 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. 
    
  markers (Apr 2017)
• 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 memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  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; It is initiated by an increasingly leaky blood-brain barrier and the innate immune response to subsequent infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form and set off the formation of tangled thread-like tau protein.
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • 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. 
    
  (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.  But poisoning from MPTP has also been shown to destroy dopamine system neurons.  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. 
  .  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 (episodic and semantic), Implicit, Procedural, Spatial, Temporal, Verbal; Hebb noted that glutamate receptive neurons learn by (NMDA channel based) synaptic strengthening.  This strengthening is sustained by subsequent LTP.  The non-realtime 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. 
  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 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). 
  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.  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
  
• Vanderbilt University Medical Center's Titze reports on salt's effects on the body (May 2017)
• 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)
• 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 memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  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; It is initiated by an increasingly leaky blood-brain barrier and the innate immune response to subsequent infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form and set off the formation of tangled thread-like tau protein.
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • 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. 
    
  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 memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  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; It is initiated by an increasingly leaky blood-brain barrier and the innate immune response to subsequent infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form and set off the formation of tangled thread-like tau protein.
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • 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. 
    
  markers (Apr 2017)
• Poor application of statistics in prior trials results in misdiagnosis of Blacks / minorities (Aug 2016). 
• Robert Califf nominated by President Obama for FDA Food and Drug Administration. 
  commissioner's research praised: Cleveland Clinic (Sep 2015)
  
• 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.  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.  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/MSK'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 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 stimulating the immune system.  Targeted diseases include cancers -- immuno-oncology.   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.  Targeted therapies: GSK, Pfizer, Loxo Oncology; have even less potential patients which is a concern at Fred Hutchinson (Aug 2017)
  
• 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.  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 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, nivolumab, pembrolizumab, atezolizumab;  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 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, nivolumab, pembrolizumab, atezolizumab;  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)
• 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)
• 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.  Biologics 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, 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 stimulating the immune system.  Targeted diseases include cancers -- immuno-oncology.   vaccine are a core strategy of public health and have significantly extended global wellbeing over 200 years.  Recent successes include: HPV vaccine.  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).  
  • Where clinics have been driven into local neighborhoods health improves (Apr 2016).  
  • Retail clinics (Mar 2016): CVS Minute Clinics focus on vaccination.  
  • Key vaccines include: BCG, C. difficile (May 2015), Cholera (El Tor), Dengvaxia (Mexico Dec 2015), Gvax, Malaria vaccine, Provenge;
  • 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.  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.  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.  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 carinomas 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). 
  
  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.  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)
  
• 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 memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  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; It is initiated by an increasingly leaky blood-brain barrier and the innate immune response to subsequent infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form and set off the formation of tangled thread-like tau protein.
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • 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. 
    
  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
• Nobel for 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):  
• 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. 
• Oct 2015 AAP recommends screening for childhood hunger.
  
• 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.  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.  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 state which is facilitated by genetic predisposition - for example genes coding for relatively low serotonin levels; and an accumulation of traumatic events.  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, irritability, sleep disturbances, loss of appetite, and inability to experience pleasure.  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.  There is an association between depression and particular brain regions: Hippocampal dendrite and spine number reductions, Dorsal raphe nucleus linked to loneliness, Abnormalities of the ACC.  Childhood adversity can increase depression risk by linking recollections of uncontrollable situations to overgeneralizations that life will always be terrible and uncontrollable.  Treatments include: CBT, UMHS depression management.  As of 2010 drug treatments take weeks to facilitate a response & many patients do not respond to the first drug applied, often prolonging the agony.   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 and prion infections such as Alzheimer's disease, 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 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 memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  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; It is initiated by an increasingly leaky blood-brain barrier and the innate immune response to subsequent infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form and set off the formation of tangled thread-like tau protein.
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • 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. 
    
  (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)
• 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.  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 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. 
    
  
  
• 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.  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 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. 
    
  (May 2017)
• Infections and antibiotics are compounds which kill bacteria, molds, etc.  The first 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' UN is the United Nations. 
  plan to curb drug resistance (Oct 2016). 
• Limiting antibiotics are compounds which kill bacteria, molds, etc.  The first 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 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: 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 dificile infections (Jan 2017)
• 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. 
  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, 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.  
  • Development, deployment and maintenance of infrastructure including: sewers, water plants and pipes.  
  • Development, deployment and maintenance of vaccination strategies. 
    
  • 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.  Recent successes include: HPV vaccine.  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).  
  • Where clinics have been driven into local neighborhoods health improves (Apr 2016).  
  • Retail clinics (Mar 2016): CVS Minute Clinics focus on vaccination.  
  • Key vaccines include: BCG, C. difficile (May 2015), Cholera (El Tor), Dengvaxia (Mexico Dec 2015), Gvax, Malaria vaccine, Provenge;
  • 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.  The first 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 a 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).  It is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes 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, 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.  
  • Development, deployment and maintenance of infrastructure including: sewers, water plants and pipes.  
  • Development, deployment and maintenance of vaccination strategies. 
    
  • 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 a 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).  It is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes 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)

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) 
• 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.  The first 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.  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.  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 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
  
• 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.  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.  But there are severe side effects.  s (Dec 2016)
• Gilead to acquire Kite Pharma for $11.9 billion (Aug 2017)
  
• Novartis's Tisagenlecleucel treatment 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.  , 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. 
  '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 stimulating the immune system.  Targeted diseases include cancers -- immuno-oncology.   (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), 
  
• Trials suggest dupilumab is first safe and effective treatement for eczma (Oct 2016)
• Checkpoint inhibitors release the immune system's checkpoints 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, nivolumab, pembrolizumab, atezolizumab;  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)
• Cuban immunotherapy vaccine are a core strategy of public health and have significantly extended global wellbeing over 200 years.  Recent successes include: HPV vaccine.  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).  
  • Where clinics have been driven into local neighborhoods health improves (Apr 2016).  
  • Retail clinics (Mar 2016): CVS Minute Clinics focus on vaccination.  
  • Key vaccines include: BCG, C. difficile (May 2015), Cholera (El Tor), Dengvaxia (Mexico Dec 2015), Gvax, Malaria vaccine, Provenge;
  • 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 stimulating the immune system.  Targeted diseases include cancers -- immuno-oncology.  , 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.  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.   (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.  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 carinomas 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). 
  
  , 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.  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.  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 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 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 stimulating the immune system.  Targeted diseases include cancers -- immuno-oncology.   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)
  
• 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.  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 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.  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)
  
• 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. 
  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 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)
  
• 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 memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  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; It is initiated by an increasingly leaky blood-brain barrier and the innate immune response to subsequent infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form and set off the formation of tangled thread-like tau protein.
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • 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. 
    
  (May 2015)
  
• Alzheimer's develops faster in women than in men (Jul 2015)
• Alzheimer's develops faster and more often with obesity is a 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).  It is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes 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)
  
• 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; 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.  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)
  
• 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.  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)
  
• 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)
  
• Salt's effects on the body (May 2017)
  
• Obesity is a 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).  It is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes 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) 
• 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)
  

• 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.   (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. 
  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)
  
• Database search identifies healthy adults with mutations that typically kill in childhood (Apr 2016). 
  
• 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 a 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).  It is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes 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 a 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).  It is associated with: metabolic syndrome including inflammation, cancer (Aug 2016), high cholesterol, hypertension, type-2-diabetes 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.  
• 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. 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 exomes (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
  

• 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.  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 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. 
    
  
  
• 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.  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 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. 
    
  (May 2017)
  

• 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
• 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 amygdala increases in volume and is hyperactive.  As a result it remains in a heightened state, resulting in fear of recall and further stress.  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.  , 
• 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 memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  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; It is initiated by an increasingly leaky blood-brain barrier and the innate immune response to subsequent infections (May 2016).  The Alzheimer's pathway follows:
  • Plaques form and set off the formation of tangled thread-like tau protein.
  • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
  • BACE inhibitors block an enzyme needed to form amyloid. 
    
  • 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. 
    
  as a behavioral disorder (Jul 2016)
  
• Obama Brain Initiative
  
• Co chair Cori Bargmann (Sep 2015)
• Brain maps
  
• Connectome based map published (Jul 2016)
  
• Temporal Interference
  
• 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)
  
• 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)
  
• Memory
• 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. 
  implicated in active removal of memories in the brain includes functionally different types: Declarative (episodic and semantic), Implicit, Procedural, Spatial, Temporal, Verbal; Hebb noted that glutamate receptive neurons learn by (NMDA channel based) synaptic strengthening.  This strengthening is sustained by subsequent LTP.  The non-realtime 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.   (Feb 2010)
• Northeastern 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)
• Sleep
• 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. 
  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).  
• 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). 
  is an 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.  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 based phenomena argues MIT is Massachusetts Institute of Technology.   neuroscientist Earl Miller (Spring 2017). 
  
• Recognition
• Caltech's Chang & Tsao identify how specific faces are recognized by the brain's face cell are neurons which respond when the features of a face are presented to the retina.  Faces are recognized by dedicated neural networks consisting of face cells grouped into 6 patches of 10,000 cells on each side of the brain in the cortex just behind the ear.  The face cells respond abstractly to the dimensions and features of faces.  Each face cell responds to a combination of facial dimensions, creating a holistic representation.  A single face cell represents a vector of about 6 dimensions.  Two hundred cells can together represent the 50 dimensions which are required to identify a face in a face space where an infinite number of faces can be represented.  Cal tech's Chang & Tsao argue there is an average face at the origin of the face space and each actual face is represented as differences from it in the face space (Jun 2017). 
  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
    
  • Highly variable DNA schema using transposons. 
    
  (Jun 2017)
• Emory School of Medicine's pediatrician is a doctor who specializes in the treatment of infants, children and adolescents.  They are represented by the American Academy of Pediatrics. 
  Dr. Warren Jones, Washington School of Medicine's child psychiatrist Dr. John Constantino, & Children's Healthcare of Atlanta's psychologist Ami Klin; study links Autism is a major hereditary mental disorder that starts before age three.  Autistics do not attribute minds to other people.  They almost never pretend.  They can't explain the difference between an instance of an object and a memory of it.  Autism occurs in every country and social class.  It lasts a lifetime.  It has genetic and neurological causes.  The genes: SHANK3, CDH10; are involved but account for a very small percentage of the risk.  Facial gaze studies indicate a high genetic influence and an opportunity to identify more genes associated with autism (Jul 2017).  ASD is associated with a reduced fusiform face area response.  Tests [in development] for autism include: SynapDx's blood test. 
  , genes & where children look at faces (Jul 2017)
  
• Reference frames
• Cohen & Andersen's review on movement plan 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).  
  (Jul 2002)
  
• Development
  
• Mothers' sounds needed for babies' brains to grow (Feb 2015)
• For evolving brains need cooked carbs (Aug 2015)
• Early reading supports success (Aug 2015)
• Anorexia nervosa is an eating disorder.  As of 2015, 50 percent of hospitalized anorexic patients who are discharged at a normal rate relapse within a year.  It has the highest mortality of any mental illness.  It involves brain circuits involved in habitual behavior.  The initial weightloss acts as a reward with compliments relieving anxiety and increasing self-esteem.  Diet gets paired with weight loss (the reward) in the ventral striatum and eventually dieting becomes the reward as the dorsal striatum gets involved in the patient's decision making making it a habit. 
  may be a habit (Oct 2015)
• Neuroscience and diet (May 2016)
• Zika (May 2016)
  

• Business process management
  

• Report cards
• Rare diseases:
• 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). 
  (Feb 2017)
  
• for cardiac surgeons (Jul 2015)
• CPR is cardiopulmonary resuscitation aims to restore a flow of oxygenated blood to the brain and heart to delay tissue death.  For adults the procedure involves 100 to 120 chest compressions a minute of 5 to 6 cm depth.  The procedure should be administered for about one hour.  Pushing oxygen into the patient's lungs can be added where the rescuer has been trained.  If the pulse is checked it should be done only for 10 seconds at a time. 
  (Dec 2015)
  
• For medicine's digital makeover (May 2015)
• Continuous quality improvement metric issues (Sep 2015)
  
• Medical errors (Treatments: Sep 2015, Diagnostics: Oct 2015)

• Google and J. & J. to Work on Robot Surgery (Mar 2015)
  

• Problems with methodology of reporting science (Aug 2015, Sep 2015, Mar 2016)
• Scholarly Journals' paywalls: 
• Nobel prize for economics (Oct 2016)
  
• Cost of science and lack or reported results drives policy change (Oct 2015)
  

• Hypertension Guidelines Eased (Dec 2013)
• Racial gap in 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.  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 carinomas 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). 
  
  (Dec 2013)
• 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 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).   being removed too often (Aug 2016) 
• Overdiagnosis 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)
  

• Web search 
• IBM's Watson base of Watson business group (Jan 2014, Oct 2016, 2)
• Microsoft finds early 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).   identifiers in web search activities (Jun 2016)
• 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). 
  scan overuse exposes patients to deadly levels of radiation (Jan 2014)
• Blood pressure 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.   sensor upgrade (Dec 2015)
• Nano sensors 
• Nano is the application of nanotechnology to medicine (May 2016).  Commercial applications are focused on research and clinical tools for drug delivery, therapies, in vivo imaging, neuro-electronic interfaces, other nanosensors, and eventually cell repair machines!!  There are issues with determining toxicology etc. 
  particles in theranostic is a combination of diagnostics and therapy that are seen as key in personalized medicine.  Theranostic nanoparticles can be designed to have multiple capabilities: both imaging and carrier; to support diagnosis, drug delivery and monitoring of therapeutic response.   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).   (May 2016)
  
• State of nano sensors in medicine (May 2016)
• Neural dust (May 2016)
• Neuronal sensing with FND is fluorescent nano-diamond.  These are nano-scale particles with long-lived electron spin properties and indefinite photo-stability.  With negatively charged NV centers they are superior imaging probes.  They can detect both magnetic and electric fields.  They are non-cytotoxic.   (May 2016)
  
• Zigbee,
  

Neuroscience

• Syngenta's Eric Fyrwald responds to the NYT December & January articles (Jan 2017)

Jul 2016 NYT A new Harbinger of Alzheimers

Sep 2015 NYT Putting Her Mind to How the Brain Works

1. Create new and improved technologies to study the brain.  With better tools, all the neuroscience will move forward. 
   
2. Apply these technologies to make discoveries about how the brain functions. 
   

Jun 2017 NYT New Electrical Brain Stimulation Technique Shows Promise in Mice

Jul 2016 NYT In Brain Map, Mind's Gears Get Rare Look

Feb 2017 NYT When Mismatched Voices and Lips Make Your Brain Play Tricks

• Chooses a likely voice and mouth match based on experience with particular combinations in the past. 
  
• Integrates the sensory streams in the superior temporal sulcus separates the superior temporal gyrus from the middle temporal gyrus within the temporal lobe.  It is implicated in multi-sensory processing.  It helps mediate theory of mind.  It has been found to participate in the McGurk effect (Feb 2017). 
  . 

Feb 2010 NYT Forgetting, With a Purpose

1. Foul smelling odor
2. A different Foul smelling odor associated with an electric shock.  Under normal Rac levels the flies usually pick situation 1. 
   

Jan 2017 NYT How to Become a 'Superager'

Spring 2017 Kent State Magazine Attention, Please

• What happens in the inferior temporal cortex after a unified picture emerges?
  
• How do our brains tell us what it means?

1. Neurons firing when animals saw a second matching object
2. When an animal spotted a picture it was actively holding in working memory different neurons fired and much more intensely. 
   

• How attention is the focusing of our mental resources onto a specific piece of information.  Attention uses valuations assigned to each potential object of thought by the basal ganglia. 
  works.  
• How an animal can focus on a picture while suppressing a noise. 
  
• Why Phineas Gage had trouble blocking out distractions and focusing on the task at hand. 
  

Memory and sleep

Feb 2017 NYT The purpose of sleep? To Forget, Scientists Say

• University of Wisconsin-Maddison's Dr. de Vivo measured 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. 
  in mice that were awake or asleep and found an 18% reduction in size of 6,920 synapses for sleeping mice. 
  
• Johns Hopkins University's Dr. Diering showed:
  
• Surface proteins on synapses dropped during sleep.  
  
• 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.   protein being formed in sleepy brain 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
    
  • Highly variable DNA schema using transposons. 
    
  and shipped to the synapses.  Later during sleep the Homer1A supported the shrinking of synapses by turning on pruning machinery.  After sleeping mice without the ability to generate Homer1A did not differentiate between different environments while control mice did.  

Jun 2017 NYT You Look Familiar.  Now Scientists Know Why.

• Just 200 face cells are required to identify a face. 
  
• The pattern of face cell firing allowed the researchers to reconstruct the face the monkey was looking at from the set of features.  
• Faces could be presented that did not have the features a particular face cell was monitoring in face space and the face cell would not fire.  That ruled out a potential model of facial representation where face cells were comparing incoming images with a set of standard reference faces and looking for differences.  
• The face recognizers use specific sets of face cells with an obvious operational model.  Le Chang and Tsao contrast this finding with artificial 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.   which they view as operating more like a black box since it is hard to see how the recognition process is achieved and hence reconstruct it. 
  

Jul 2017 NYT Study of How We Look at Faces May Offer Insight Into Autism

• Which features they focus on
• When they move their eyes are major sensors in primates, based on opsins deployed in the retina & especially fovea, signalling the visual system: Superior colliculi, Thalamus (LGN), Primary visual cortex; and indirectly the amygdala.  They also signal [social] emotional state to other people.  And they have implicit censorious power with pictures of eyes encouraging people within their view to act more honorably.  Eyes are poor scanners and use a saccade to present detail slowly to the fovea.  The eye's optical structures and retina are supported by RPE.  Eyes do not connect to the brain through the brain stem and so still operate in locked-in syndrome.  Evo-devo shows eyes have deep homology.  High pressure within the eye can result in glaucoma.  Genetic inheritance can result in retinoblastoma.  Age is associated with AMD. 
  from place to place. 
  

• 250 toddlers who were developing normally including 41 pairs of identical twins, 42 pairs of non-identical twins and 84 unrelated children. 
• 88 children with autism. 
  

• Identical twins matched how much the other twin looked at the eyes [or mouths] of people on screen 91%.  The identical twins actually had matching movements of their eyes in terms of time and direction.  
  
• Fraternal twins the match dropped to 35%
• Unrelated children randomly paired had no matching.  
• Children with autism spent significantly less time looking at faces and more time looking at objects.  Children with autism could be identified from their eye tracking data. 
  

Jul 2002 Nature Neuroscience Review Yale Cohen & Richard Andersen describe a common movement planning reference frame

• Change the locus of attention
• Response selection
• Coordinate transformations
• Decision to act on sensory stimuli

• Head-centered representations of auditory targets to eye-centered representations. 
• Modelled body-centered representations of auditory targets had hidden layer neurons with gain effects for both eye and head position. 
  

Feb 2015 NYT Mothers' Sounds required for Babies' Brains to Grow

Aug 2015 NYT For Evolving Brains, a Diet of Carbs

1. Addition of meat
2. Addition of cooking released carbohydrates.  Campfires have been dated back to 1.8 million years ago. 
   

• Our bodies convert starch into glucose using amylase.  But the reaction works better on pre-cooked starches.  That was a significant benefit to a hungry hunter gatherer. 
• Chimpanzees have two copies of the amylase gene.  Humans have as many as 18 copies. 
  
• Studies of pre-agricultural hunters from Europe reveal that people had extra copies long before they started farming.  
• The survival value of the extra gene copies allowed them to spread through the population. 
  
• Brain size increases started about 800,000 years ago. 
  

Aug 2015 NYT Turn the Page, Spur the Brain

Oct 2015 NYT Anorexia May Be Habit, Not Resolve, Study Finds

May 2016 NYT Opinion Never Diet Again - The problem isn't willpower.  It's neuroscience.  And you can't fight back. 

• Metabolic suppression has been studied in hibernation, where the process of hibernation includes rapid inhibition of mitochondrial respiration.  Otherwise it seems poorly defined.  Fast and slow weight loss appear equally effective at inducing metabolic suppression.  
  

• Dieting is stressful.  Stress hormones are generated which cause fat cells to generate more abdominal fat.  
• Weight anxiety is manifested in the amygdala mediating inhibition of dopamine rewards.  Major anxiety results in elevated glucocorticoids and reduces hippocampal dendrite & spine density.  Some estrogen receptor variants are associated with anxiety in women. 
  and dieting are correlated with binge eating.  Under stress mice eat more sweet and fatty foods.  They learn to binge eat when deprivation alternates with food.  Subsequently when stressed the 'binge eaters' are more likely to respond by binge eating. 
  
• Dieting reduces the influence of the brain's weight-regulation system allowing people to ignore internal hunger signals.  But she argues they are more susceptible to the marketing signals that encourage eating large portions etc. 
  

May 2016 NYT Zika's Secret Assault

Study of Genome Deltas

• Richard Begley 454 life sciences microfluidic is a next generation DNA sequencing method that uses sequencing by synthesis.  Unlike Sanger sequencing it relies on the detection of pyrophosphate release on nucleotide incorporation.  Using light emission as a detection signal for incorporation of the next complementary nucleotide with only one of the four bases added to the reaction mixture identifies the complementary base in the single stranded DNA template being sequenced.  gene sequencing
  
• Daniel Branton Harvard 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. 
  sequencing using Nanopores is Daniel Branton's DNA sequencing method.  It uses a tunneling electron microscope to view the nucleotides.  The DNA is forced to flow through a nanopore, using a nanotube to orient the bases and encourage the DNA to flow, making it unwind and orient as the microscope requires.  Branton assumes it will eventually replace sequencing by synthesis.  
  
• Eugene Chan U.S. Genomics Low-cost fast optical DNA sequencing
  
• George Church Harvard DNA sequencing using polymerase-colony was developed at Harvard by George Church's lab.  It uses an invitro paired-tag libarary with emulsion PCR, an automated microscope, and ligation-based sequencing. 
  technology
  
• David Cox Perlegen
  

Perlegen

Perlegen scientists find genetic basis for difference between humans and non-human primates

Jan 2014 NYT Aiming to push genomics forward in new study

May 2016 NYT Private Talks Are Conducted About a Synthetic Genome

Big Data

Nov 2016 NYT Simons Foundation Looks to Enhance Computation Tools for Science

• Poor development techniques
• Lack of maintenance
• University departments not being able to hire professional programmers
  

Jan 2017 NYT Data Could Be the Next Tech Hot Button

• The European Commission and House of Lords have issued reports critical of the power of digital platform companies: Google, Facebook, Apple, Amazon, Microsoft; who can collect, analyse and distribute data and so create and shape markets. 
• An OECD is the Organisation for Economic Co-operation and Development. 
  meeting in November 2016 looked at competition policy for big data encompasses the IT systems and processes necessary to do population based data collection, management and analysis.  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. 
    
  . The discussion noted:
• Power is in the hands of a few companies
• Consumers could be afforded less privacy on platforms controlled by an oligarchy
  
• Antitrust arguments don't directly apply.  Users benefit from platforms:
  
• Using more data to improve a service 
• Free services which don't generate higher prices. 
  

• Artificial intelligence in mainstream business software makes certain data sets very valuable. 
  
• Microsoft paid 26.2 billion for LinkedIn because of:
• 467 million users
• Profiles and maps of connections of its users;  It is betting LinkedIn can be combined with Office 365 online data and Bing search data to obtain insights of unprecidented power.  CEO Nadella argues it allows the company to
  
• "Reinvent productivity and business processes."  
• Define "how people find jobs, build skills, sell, market and get work done." 
  
• IBM has bet heavily on private data for its future:
• $2.6 billion acquisition of Truven Health (Feb 2016) for its data on the cost and treatment of more than 200 million patients.  
• $2 billion acquisition of the digital assets of the Weather Company; which it aims to integrate with customer data and use the composite to train Watson to persue tasks:
• Helping medical researchers discover novel disease therapies
• Flagging suspect financial transactions for independent auditors.   
• Google has leveraged its search data and investments in image identification, speech recognition and language translation.  It:
• Has software for supporting job finding and recruiting.  It is based on data with:
• More than 17 million online job postings and public profiles and
  
• Resumes of 200 million people.  
• Machine-learning algorithms to collapse that detail to 4 million unique ranked job titles with skills. 
  
• Career builder, Dice and Fedex are working with the alpha software. 
  
• Baidu's chief scientist Andrew Ng notes "Data is the defensible barrier, not algorithms." 
  

Email

Oct 2016 NYT The age of Email is Nearing an End

1. There is a lot of discussion of Hillary Clinton's private Email server. 
   
2. Email as a discussion infrastructure fails
   

• Tempting
• Inescapable
• Asynchronous
  
• Easily forged
• Time consuming
• People feel efficient but often participate in pointless rumination. 
  
• Centralizes distributed group activities like planning
  
• Conveys news
• Set out tactics and strategy
• Broadcasts:
  
• Models for framing discussions
• Legal/Expert advice and warnings
• Summaries of meetings and proposed plans
  
• Theorize
• Push back
• Gossip
• Used in place of phone calls and face-to-face meetings
• Used as an instant messenger
• Daily calendar
• Collaborative whiteboard
• Email threads get long, and often do not result in resolution.  Real-time phone meetings are then used to clarify the meaning of the discussions, and to gain coherence and agree on the plan.  
• Flexible - which can be potentially confusing and chaotic
  
• Formal letters
• Joke
  

Moore's law

Oct 2016 NYT Looking Beyond Silicon to Squeeze More Out of Chips

• AI cost - it uses a 32 of the memory and runs 58 times faster than rival approaches. 
  
• Privacy - since the data is not distributed through a network. 
  

Nano Sensors

May 2016 Stanford radiology professor Zhen Cheng describes ONPs in cancer theranostics

• Melanin is a natural dark pigment that can be found in human skin and eyes.  It serves as a useful biomarker for melanoma. 
  nano-particles used in the radiology of 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).  .  Melanoma is a characteristic very dark color.  With targeting can get very high uptake of melanine nano-particles in melanomas. 
  
• Perylene-3, 4, 9, 10-tetracarboxylic diimide is a compound of the form (NH)2.  -based NIR is near-infrared.   absorptive ONPs.  These are multimodal nano-platforms for photoacoustic imaging 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. 
  . 
  
• Nano-particles encapsulated with novel dyes.  The dyes have a second NIR window at 650 - 950 nm fluorescence.  It can provide deep tissue penetration and high spatial and temporal resolution.  They show excellent imaging capability for cancer detection in small animal models. 
  

May 2016 San Jose State University scientist Dr. Folarin Erogbogbo outlines nano-medicine in the 21st century

• Tumor vasculature. 
  
• Similarly AMI is acute myocardial infarction which means that some of the heart muscle has died from a blocked blood supply.  AMI is hard to measure.  Nanosensors offer a possibility (May 2016).  
  has been hard to study effectively since few people want 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. 
    
  induced.  While there is evidence from animal studies that induced limited heart attacks may prophylactically help prevent major heart attacks researchers need an alternative way to gather data on AMI.  Nano sensors offer the possibility.  Lots of people could be monitored and then those that have heart attacks would provide a database for study.  One approach leverages CD44 is a cell-surface glycoprotein involved in cell-cell interactions and migration.   signalling which fine tunes the 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 to AMI by controlling the release of cytokines control the development of hematopoietic cell lines.  They regulate the immune response and are involved in the development of immune-competent cells.   and chemokines from cardiac fibroblasts which are necessary for the recruitment of neutrophils are a type of leukocyte.  They are the most abundant type.  They defend against bacterial and fungal attack.  They phagocytose pathogens but are short lived unlike Monocytes.   and macrophages are differentiated monocytes.  They are found in all tissue types.  They have specialized to perform phagocytosis ingesting pathogens into phagosomes which  then fuse with a lysosome whence the pathogen is digested.  They can digest more than 100 bacteria before they die due to the build up of their own metabolytes.  They play a critical role in innate immunity and help initiate adaptive immunity by recruiting other immune cells such as lymphocytes by presenting antigens from the digested pathogen.  M1 macrophages encourage inflammation.  M2 macrophages decrease inflammation and support tissue repair.  .
  
• HIV is human immunodeficiency virus, an RNA retrovirus which causes AIDS.  It infects T-lymphocytes destroying the host's immune system. 
  infected patients are critically at risk from TB, consumption or otherwise TB, is mostly an airborn bacterial lung infection, but it can also infect the brain, kidneys and other parts of the body.  The only vaccine is still the BCG.  The deployment of antibiotics during the 1940s allowed effective treatment: Streptomycin.  Diagnostic tools for TB are insufficient.  And because TB grows slowly in walled off pockets in the lungs it takes many months of treatment for antibiotics to eradicate the infection.  TB benefits from compromised hosts and has benefited from HIV/AIDS.  TB is also leveraging the plasmids that now carry immunity to all current antibiotics.  In 2016 it is estimated to latently infect two billion people.  9.6 million worldwide became infected in 2014.  1.5 million people will die from TB in 2016.  Deaths from the disease have fallen drastically since 2000.  TB has been halted or reversed in 16 of the 22 countries: India (Sep 2016, Infection base estimate increased Oct 2016), Vietnam, Indonesia; that have the majority of cases.  But it is still the infectious disease causing the most deaths world-wide.  Nano scale drug delivery has the potential to push back on TB and is being actively researched (May 2016).   .  South Africa has such a patient base.  They agreed to leverage 3D printed devices which generate nano particles that deliver Anti-TB drugs. 
  
• Chitosan/tripolyphosphate nanoparticles have been used in rats to treat cancer with a computer controlled modifications of regulatory pathways. 
  

May 2016 Cal Berkeley electrical engineering and computer science professor Michel M. Maharbiz, and Neural dust. 

• A mm-size unanchored free-floating sensor that detects and reports extracellular electrophysiological data by back-scattering received ultrasound.  
• High-fidelity transmission of EMG is electromyography, a diagnostic procedure to assess the health of muscles and the motor neurons that control them.  EMG translates the motor neurons electrical signals into graphs, sounds or numerical values for interpretation. 
  and ENG is electroneurogram a method to visualize directly recorded electrical activity of neurons of the CNS or peripheral nervous system.  It is typically recorded by placing an electrode in the neural tissue.   signals from anesthetized rats. 
  

1. Thousands of 10-100 micro scale free-floating independent sensor nodes (dust) to detect and report local extracellular electrophysiological data. 
   
2. Sub-cranial interrogator that establishes power and communication links with the dust. 
   

• Motion artifacts can be disambiguated
• Platform falls within FDA Food and Drug Administration. 
  constraints
  
• When put in muscle can get sigmoidal reports
• Beam steering is in development.  Deploy as a back pack.  Recalibrates to the dust as the mouse/rat moves around ensuring consistent signal tracking from specific dust generator. 
  

• The approach does not place an electrode inside a neuron.  So single neuron recording is not possible.  
• The electrodes in the dust must be kept apart limiting how small the dust can be -- not Nano scale. 
  

May 2016 SJSU Phys Chem prof Abraham Wolcott and FND

• He looked at the surface with various techniques including crystalographically.  He leveraged the insights by modifying the surface using wet chemistry to allow for enhanced stability in biological media and direct staining of membranes in live neurons. 
• Using an electrochemical cell as an artificial neuron to determine the mechanisms of fluorescence modulation of the NVC and
  
• Observing modulation with applied potentials as low as 100 meV and potential response times of about 5 milli-seconds.  
• Looked at issues with diamond staining of neurons.  It had been assumed that inhibition was due to the carboxylic acid rich surface.  But Wolcott argues this is wrong.  He used various probes to look at the situation: Crystalography, Optical, ODMR is optically detected magnetic resonance uses double resonance combining optical techniques such as (fluorescence, phosphorescence) with electron spin resonance spectroscopy. 
  , XRD is x-ray powder diffraction used for phase identification of crystalline materials.  , Raman is an inelastic scattering of a photon on interaction with matter first discovered by C.V. Raman and K. S. Krishnan and used in Raman spectroscopy to fingerprint molecules based on the observed vibrational, rotational and other low-frequency modes observed. 
  , High resolution TDM is time-division multiplexing. 
  ;
  

Applied AI

Sep 2014 NYT Can a Computer Replace Your Doctor

• One device attached to the iphone to create an ontoscope to check children for ear infections. 
  
• Another allows the iphone to check blood alcohol. 
  
• There were home cholesterol kits
• A wearable device to track the quality of breathing. 
  

Mar 2016 KQED Forum Tech Companies Race to Bring Artificial Intelligence to Market with Coursera & Baidu's Andrew Ng, Washington University's Pedro Domingos and Wired's Cade Metz

Spring 2017 UOM I.T. Minnesota Professor He develops mind-controlled robotic arm

Dec 2016 NYT magazine Alphabet going neural

1. An institutional story about a small group of artificial intelligence workers at Alphabet who persisted for five years with an old, unproven artificial neural network strategy to become "Google Brain".  
• Bootstrapped as Project Marvin in X lab by Andrew Ng (Mar 2016), it was adopted by Jeff Dean who brought in Greg Corrado along with Ng's graduate student Quoc Le.  The name morphed to Google Brain. 
• It was attractive because it could adapt by gradually altering its weights without preprogramming and fixed rules.  Starting with basic capabilities like sensory perception and motor control they hoped that advanced skill would emerge. 
  
• When Andrew Ng left Alphabet they hired Geoffrey Hinton, a specialist in deep neural networks, from the University of Toronto.  
• Deep neural networks trial-and-error strategies get very complicated.  Hinton enhanced an old solution to this layered error problem.  Once there was enough compute power this strategy began to pay off. 
  
• Google invested in Tensor Processing Units (T. P. U.) mass-produced and deployed within their operational network to ensure the Hinton architecture deep neural networks had the compute power they required. 
  
2. A seventy year long story about the evolution of ideas.  This relates the work of cognitive scientists, psychologists and engineers who worked in obscurity until a paradigm shift about the theory of consciousness occurred. 
   
3. A technical story where Google Translate was transformed, tested and introduced in nine months -- a quarter of the time anyone predicted. 
   
• Quoc Le proposed leveraging word embeddings are distributional vector representations of words allowing the higher layers of a deep neural network to convolve the lower layers' word vectors to support text classification. 
  to allow neural networks to handle the structure of language. 
  
• He realized that 1000 dimensional vector of word associations would allow most real world language mappings.  
• He needed to allow the input data to flow into the network over time.  
• His model initially worked well only with sentences of less than eight words. 
  
• Mike Schuster took Lee's insights and scaled them for real-world text structures.  
• He transcribed Lee's research code to run on the TensorFlow open source machine-learning platform Google was developing.  
• Jeff Dean and Greg Corrado requested Translate director Macduff Hughes consider leveraging the deep learning network.  
• Dean committed to integrating the network by the end of 2016.  
• Within a month the neural network was integrated with Google Translate allowing the team to compare the two.  They found:
• BLEU scores for English-French translation were seven points better for the neural network approach. 
  
• Human contractors' side-by-side comparisons agreed with the BLEU assessments. 
  
• The team was expanded from three to include many translation experts. 
  
• They began turning the project into a product
• They had to be able to process real world data.  People often wanted to translate small parts of sentences.  
• The ability to build a training data set that reflects all these use cases is a key aspect of the building a product.  And doing so is, Google agrees, an art. 
  
• They had to integrate with the T.P.U. chips.  That required two months of debugging.  
• They aimed to set expectations that Translate would be much improved but not as good as a human translation.  Reporters preferred to claim they were better than human translaters. 
  

• It will demonstrate a facility with the implicit, the interpretive. 
  
• It will be a general tool, designed for general purposes in a general context. 
  

Antibiotics

Mar 2014 NYT The Fat Drug

Raising mice on high calorie food and antibiotics

Interactions with the microbiome

Alan Meyers fructose consumption

Nov 2016 NYT Infections Tied to Obesity

• Antibiotic use
• Diagnosis
• Height and Weight from birth through age 18. 
  

• One untreated infection had a 15% increased risk for childhood obesity. 
• Three untreated infections resulted in 40% increased risk
• Antibiotic treated infections and others with similar infections left untreated had no difference in risk. 
  

Oct 2015 NYT Should We Bank Our Own Stool?

Sep 2015 NYT Antibiotics and Diabetes

May 2015 NYT Drug Overuse Begins an Epidemic

• Nontoxic C. diff. strains can be introduced to compete for the niche. 
  
• Monoclonal antibodies is a y-shaped blood transported protein generated by the adaptive immune system's plasma cells, B lymphocytes, to accurately identify and neutralize pathogens such as bacteria and viruses that exhibit a matching antigen. 
  have been developed to attack C. diff. toxins. 
  
• Vaccine are a core strategy of public health and have significantly extended global wellbeing over 200 years.  Recent successes include: HPV vaccine.  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).  
  • Where clinics have been driven into local neighborhoods health improves (Apr 2016).  
  • Retail clinics (Mar 2016): CVS Minute Clinics focus on vaccination.  
  • Key vaccines include: BCG, C. difficile (May 2015), Cholera (El Tor), Dengvaxia (Mexico Dec 2015), Gvax, Malaria vaccine, Provenge;
  • 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). 
    
  given by injection. 
  
• Fecal transplants to rebuild a competitive microbiome (Oct 2015).
  

May 2016 NYT An Infection Raises the Specter of Superbugs Resistant to All Antibiotics

Oct 2016 NYT Copper May Stem Infections

• Highest bacterial concentrations were on the toilet flush handles. 
  
• Fixtures in copper-equipped rooms had bacterial infection rates 92% lower than the controls. 
  

Personalized Medicines

Acute Myelogenous Leukemia (AML) inhibitor

Sep 2014 NewYorker The Transformation (of AML by AG-221)

Aug 2017 NYT A Cancer Conundrum: Too Many Drug Trials, Too Few Patients

• There are too many very similar experimental cancer drugs in too many clinical trials
• Over 1000 immunotherapy trials are underway and more are planned.  
• Genentech VP's Dr. Daniel Chen & Dr. Ira Mellman argued in Nature, that the proliferation of trials, "have outstripped our progress in understanding the basic underlying science." 
  
• Targeted therapies focus on extremly rare mutations so patients are hard to find.  And its prohibitively costly to identify them since their tumor 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. 
  must be sequenced 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.  
  which most insurance will not fund.  
• GlaxoSmithKline searched for patients from the US, Japan, South Korea, Europe for over a year and found 59 with target mutations.  
• Pfizer searched for 3 years to find 50 lung cancer patients with ROS1 mutation. 
  
• Loxo Oncology has benefited from Memorial Sloan-Kettering expanding its patient search to Lehigh Valley. 
  
• The F.D.A. Food and Drug Administration. 
  has helped by allowing small trial sizes. 
  
• There are not enough of America's cancer patients being treated at the academic medical centers where they can become participants in the trial network.  
• Memorial Sloan-Kettering Cancer Center's Dr. Peter Bach commented "I think there is a lot of exuberant rush to market.  And we are squandering our most precious resource -- patients."  MSKCC is searching for patients at other hospitals: Lehigh Valley, Hartford, Miami; and is funding the DNA testing.  There is real risk in this type of approach to trials.  Bach explained "Trials involving limited numbers of patients can be perilous.  The smaller the study and the shorter its duration, the more likely that what looks like an effect in a trial might simply be a result of chance.  That leaves some of use evidence geeks wondering if it works."
  
• 85,000 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).   occur each year in the US.  The majority are treated with surgery.  Some 10,000 of those patients will relapse and would be candidates for experimental treatments except most of them will not be being treated by doctors in the clinical trial network. 
  
• Yale Cancer Center declines to participate in 90% of immunotherapy trials it is asked to join.  Yale's chief of medical oncology Dr. Roy Herbst asserts that most of the trials are not testing any new science.  
• These two aspects interact resulting in companies competing for the few patients that can be treated by their drug who are in the clinical trial network.  This causes problems:
• The drugs are often very similar: 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. 
  immunotherapy drugs are being developed by many biotech companies; and targeting the same subset of patients with the same cancers.  
• Merck who already has an F.D.A. approved PD-1 immunotherapy drug: Ketruda; will benefit from any moratorium. 
  
• Too few patients enter company trials to gain access to a statistically valid sample 
• Fred Hutchinson's Dr. Scott Ramsey worries:
1. Serious side effects could be missed with a small sample base
2. These drugs have such high out-of-pocket costs that they may not be helping the regular patients overall. 
   

Aug 2016 NYT Animals Grow Human Parts? Labs Hope So

1. Addition of human stem cells to the embryos of animals prior to organ formation. 
   
2. Addition of human stem cells in differentiated embryos. 
   

• New types of stem cell have been isolated that can turn into any organ, and the placenta. 
  
• Rat stem cells put into mice with pancreas genes knocked out, resulted in mice with rat pancreases. 

1. To decide if there is a fundamental difference between adding 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. 
   from one species to another -- and adding human cells into an animal. 
   
2. Where to draw the human boundary is not agreed. 
   

Oct 2016 NYT 2 Trials Show New Treatment for Severe Eczema Can Provide Swift Relief

Dec 2016 NYT A patient, 7 Tumors, 100 Billion Cells and a Striking Recovery

• Analyze tumors for mutations that are not present in normal cells. The tumors must be large enough to yield TILs. 
  
• Study TILs for cells that recognize cells with the mutations but leave normal cells alone. 
  

Jul 2016 NYT Juno Halts Cancer Treatment Trial Using Gene-Altered Cells After 3 Deaths

Aug 2016 NYT Immunotherapy Drug Fails Lung Cancer Trial

Nov 2016 NYT Lifesaving Cancer Drugs May in Rare Cases Cause Heart Damage, Doctors Report

Jul 2016 NYT A sickened Body as Cancer Weapon

• Other checkpoints that are not being blocked. 

Aug 2016 NYT As Death Lurked, Tumors Melted

Dec 2016 NYT Taxpayers Finance Cancer Drug, but the Profits Will Be Private

• Bayh-Dole is the Patent and Trademark Law Amendments Act which allowed universities, small businesses and non-profits working with federal researchers to elect to pursue ownership of an invention in preference to the government taking ownership. 
  ,
  
• Stevenson-Wydler of 1980 required federal laboratories to actively participate in and budget for technology transfer activities. 
  ,
  
• Federal Technology Transfer Act is the Federal Technology Transfer Act of 1986.  It amended the Stevenson-Wydler Technology Innovation Act to allow Government-operated laboratories to enter into cooperative research agreements and by establishing the NSF's Federal Laboratory Consortium for Technology Transfer. 
  . 
  

Aug 2016 NYT Setting Body's 'Serial Killers' Loose on Cancer

• Identify more cancer specific antigens that can allow CAR-T to be used in a broad range of cancers.  And TCR is T cell receptor. 
  work should also allow a wider range of cancer targets, such as solid tumors.  Combined with personalized 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. 
  sequencing 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.  
  to identify the target mutated protein it may be possible to use cell therapy captures cells from a particular patient, modifies them, clones them and then deploys them back into the patient.  Platforms include CAR and TCR.  In 2016: The pricing schemes for cell therapies have not been announced but are expected to be expensive, The therapies are successful between 25 and 90% of the time for lymphoma and leukemia but patients may relapse after months or years of remission;  There are a number of challenges to the approach, some of which may require treatment in an ICU, including:
  • Lack of scale being specific to each patient. 
    
  • Immune system over reaction
    
  • Neurological toxicity including cerebral edema (Jul 2016). 
    
  in most people. 
• Dr. Sadelain and Juno are working on CARs that bind to the target and produce immune-stimulating chemicals
• Cellectis has treated two babies with an off the shelf CAR. 
  
• Bellicum is working on gene switches that can turn off the CAR if treatment is endangering the patient. 
  

• Novartis licensed the rights to Dr. June's labs therapies.  
• Kite Pharma licensed the NCI therapies.  
• Juno Therapeutics licensed Sloan-Ketterings therapies.  

But then problems occured with the CAR research

JUl 2017 NYT F.D.A. Panel Recommends Approval for Gene-Altering Leukemia Treatment

• Novartis is working on a treatment for another type of leukemia, for multiple myeloma is a cancer of B lymphocytes.  The cause is unknown, but alcohol and obesity are risk factors.  Abnormal antibodies are generated which cause kidney problems and overly thick blood.  If the abnormal lymphocytes form a single mass the diagnosis is plasmacytoma.  If there are multiple masses the diagnosis is multple myeloma.  Treatments include: Revlimid, Velcade;
  & an aggressive brain tumor. 
  

• Removing cells from a patient at an approved medical center
• Freezing them
• Shipping the cells to a Novartis plant for thawing & processing
• T-lymphocytes 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; 
    
  are genetically engineered to kill cancer cells using disabled HIV is human immunodeficiency virus, an RNA retrovirus which causes AIDS.  It infects T-lymphocytes destroying the host's immune system. 
  to carry new genetic material into the T-cells so they will target the CD-19 surface protein, a relatively long chain (polymer) of peptides.  Shorter chains of peptides are termed polypeptides.   of malignant B-cells.  Dr. Carl June notes each engineered T-cell can destroy up to 100,000 cancer cells. 
  
• Re-freezing them
• Shipping them back to the treatment center for infusion into the patient.  
• Supporting the patient to avoid infection while all their B-cells are destroyed by providing infusions of immune globulins. 
  

• Agrees on the lifesaving potential of the treatment
• Raised concerns about the life-threatening side effects:
• Short term like Emily's which oncologists have been able to treat. 
  
• Long-term potential for the infused cells to cause secondary cancers and other problems.  These patients will be tracked for 15 years. 
  
• Concerns about ability to produce consistent treatments and maintain quality control as the operations are scaled up.   
  

Jul 2017 NYT Companies Rush to Develop 'Utterly Tranformative' Gene Therapies

• Make them target CD19 cell surface signals, 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. 
  ,
• Generate a signal that activates NK Cells and helps sustain them
• Adds an off operon allowing researchers to shut-down the NK Cells if side-effects become problematic. 
  

Aug 2017 NYT Drug Aimed at Inflammation May Lower Risk of Heart Disease and Cancer

• 4.5 of every 100 in the placebo group had a heart attack in that year. 
  
• 3.86 of every 100 in the optimal dose treatment group had a heart attack in that year.  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. 
  reduction was 15%.  
• The drug reduced the risk of lung cancer.  MSKCC's Dr Rudin said "We know inflammation is a driver of lung cancer progression." 
  

Nov 2016 NYT Bringing Home Hope

• No adequate alternative is available in the US. 
  
• If treatment began in another country and the amount imported is less than three months' supply. 
  

Aug 2016 NYT Study Finds Misdiagnosis For Blacks in a Gene Test

• Emotional stress are low level agents distributed across the brain and body which associate, via the amygdala and rich club hubs, important environmental signals with encoded high speed sensors, and distributed programs of action to model: predict, prioritize guidance signals, select and respond effectively, coherently and rapidly to the initial signal.  The majority of emotion centered brain regions interface to the midbrain through the hypothalamus.  The most accessible signs of emotions are the hard to control and universal facial expressions.  Emotions provide prioritization for conscious access given that an animal has only one body, but possibly many cells, with which to achieve its highest level goals.  Because of this emotions clash with group goals and are disparaged by the powerful.  Evolutionary psychology argues evolution shaped human emotions during the long period of hunter-gatherer existence in the African savanna.  Human emotions are universal and include: Anger, Appreciation of natural beauty, Disgust, Fear, Gratitude, Grief, Guilt, Happiness, Honor, Jealousy, Liking, Love, Rage, Romantic love, Lust for revenge, Passion, Sadness, Self-control, Shame, Sympathy, Surprise; and the sham emotions and distrust induced by reciprocal altruism.  
  
• Costly medical followup (time and money).  
• Surgery to implant unnecessary devices. 
  
• Athletes giving up their sports. 
  

Jun 2015 NYT Pursuit of Cash Taints Promise of Gene Tests

Dec 2015 NYT Degrees of Danger

Sep 2016 NYT Prostate Study Details Validity of Treatments

• There was no difference in death rates between men treated with surgery, radiation or active monitoring. 
  
• Death rates from the cancer were low overall.  1% of patients 10 years after diagnosis. 
  
• Disease was more likely to progress and spread in the men who opted for monitoring.  Half the patients who started out being monitored eventually had surgery or radiation, although 80 percent of them had not shown signs of progression.  
• Men who had surgery to remove the prostate is a male only gland positioned between the bladder and rectum.  It generates part of the seminal fluid.  It enlarges during puberty to the size of a walnut stimulated by androgens and the remains stable or grows slowly with age.  The prostate includes several types of cells including the gland cells that make the prostate fluid.  The Urethra passes through the middle of the prostate. 
  were the most likely to have lingering impotence and urinary incontinence. 
  
• Men given radiation reported bowel problems after six months of treatment (usually with gradual improvement) but not urinary incontinence.  Sexual function also diminished after radiation, but recovered somewhat. 
  
• There was no difference among the three groups in anxiety is manifested in the amygdala mediating inhibition of dopamine rewards.  Major anxiety results in elevated glucocorticoids and reduces hippocampal dendrite & spine density.  Some estrogen receptor variants are associated with anxiety in women. 
  , depression is a debilitating state which is facilitated by genetic predisposition - for example genes coding for relatively low serotonin levels; and an accumulation of traumatic events.  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, irritability, sleep disturbances, loss of appetite, and inability to experience pleasure.  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.  There is an association between depression and particular brain regions: Hippocampal dendrite and spine number reductions, Dorsal raphe nucleus linked to loneliness, Abnormalities of the ACC.  Childhood adversity can increase depression risk by linking recollections of uncontrollable situations to overgeneralizations that life will always be terrible and uncontrollable.  Treatments include: CBT, UMHS depression management.  As of 2010 drug treatments take weeks to facilitate a response & many patients do not respond to the first drug applied, often prolonging the agony.   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; or other feelings on quality of life. 
  

Nov 2016 NYT Dried Blood Can Be Tested for Type of Leukemia

Jun 2016 NYT 'Liquid' Test Offers Hope for Alternative to Biopsies

Jun 2016 NYT Direct-to-You Lab Tests

Aug 2016 NYT Gene Tests Identify Breast Cancer Patients Who Can Skip Chemo, Study Says

Pregnancy

Sep 2015 NYT The Cords That Aren't Cut

Molecular diagnostics (research)

Oct 2004 GenoME Sciences Technology Review startup 

Oct 2004 Oxamer Technology Review startup

May 2016 NYT No More Room to Shrink

• A global alliance of chip makers (Semiconductor industry Associations of US, EU, Japan, South Korea, Taiwan) has decided to back away from reliance on Moore's Law, Gordon Moore characterized the two yearly doubling of the number of transistors in each new generation of integrated circuit. 
  used in the International Technology Roadmap for Semiconductors. 
  
• Chip scientists are nearly at the point where they are manipulating material as small as atoms  -- within the next 5 to 10 years they will do so.  
• IEEE is the institute of electrical and electronic engineers. 
  announced a replacement forecasting system -- the International Roadmap for Devices and Systems.  This would represent additional technologies:
• Quantum computing
  
• Graphene
  
• Processor heat was solved architecturally by splitting tasks among many processors. 
  

• Per transistor cost of computer chips has stopped falling. 
  

Mar 2016 Science Friday Mauro Ferrari talks about success in killing metastatic cancers in mice

• Metastatic cells build multiple barriers to attack
• It is thus necessary to design agents to attack the walls one after another in the right order. 
• Series of vectors and drugs must be built. 
• Nano particles can't penetrate the walls. 

Sep 2017 NYT Silicon Valley Courts Brand-Name Teachers, Raising Ethics Issues

• TenMarks offered teachers who acted as company advisers Amazon gift cards and an additional $80 gift card for writing a post on TenMarks blog. 
• Established start-ups provide travel expenses for teacher advocates to attend industry-sponsored conferences attended by teachers.  
• School administrators are keen to leverage free technology and product training.  
• Typically underappreciated teachers are pleased to get some attention from product & service companies that are interested in their needs. 
  
• Sophisticated yearlong teacher development programs select teachers to attend conferences and work with Apple, Google or Microsoft to help develop education innovations is the economic realization of invention and combinatorial exaptation. 
  :
  
• Apple's Apple Distinguished educators program.  Microsoft and Apple work with school districts to ensure compliance of any travel expenses they reimburse. 
  
• Google for Education's Certified Innovator Program.  Google provides meals but not travel expenses. 
  
• Microsoft's Microsoft Innovative Educator Expert
• Non-tech companies leverage the power of the star advocates; donating equipment in the hope of an endorsement. 
  

• The corporate relationships can result in schools hiring the advocates to train their teachers.  Training engagements are typically paid. 
  
• Influential teachers are selected to be speakers at conferences
• Ms. Delzer gets outfits from designers she endorses to wear to speaking engagements.  They select the items for her. 
  

• Drug makers cultivated 'Key Opinion Leader' doctors to promote brand-name medicines to other doctors.  
• Harvard Medical School's Aaron Kesselheim notes that the technique encourages selection of the medicine based on promotion rather than EBM is evidence based medicine where explicit and judicious use of current best practice evidence is used in making decisions about the care of patients.  There are differences in the application to individuals and populations.  Still the goal was to replace subjective use of basic and clinical research with:
  
  • Prioritization of clinical trial results to build conclusions. 
    
  • Adoption of processes that translated epidemiological methods to physician decision making. 
    
  • Widely used but innapropriate procedures were abandoned.  
  • There is now explicit evaluation of evidence of effectiveness before issuing practice guidelines.  A rational for adoption is required.  
  • HHS appointed USPSTF to develop evidence based recommendations.  
  .  And the incentive can be as small as a meal. 
  

Dec 2015 NYT Changing Up What's Passed Down

• University of Copenhagen's Dr. Romain Barres fed male rats a high-fat diet and then mated them with females.  Compared to control rats' offspring the experimental offspring tended to gain more weight, develop more fat and have more trouble regulating insulin regulates the metabolism of carbohydrates, fats and protein by signalling the absorption of glucose by fat, liver and skeletal muscle cells.  It is a peptide hormone generated in the islets of Langerhans beta cells of the pancreas.  Peter Medawar explains it was an early drug therapy success.  As manufacturers have shifted from products developed by extraction to biologics: Humulin, Lantus, Levemir; safety has improved.  But the US list price has risen steeply (Feb 2016, Jan 2017)
  levels. 
  
• Male rats exposed to stressful 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.  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. 
    
  • During depression, stress inhibits dopamine signalling. 
    
  • Strategies for stress reduction include: Mindfulness. 
    
  experiences -- smelling the odor of a fox -- offspring have a dampened response to stress. 
  

• MicroRNA is a small RNA molecule that supports schematic regulation of protein synthesis by inhibition of messenger RNA activity.  They are encoded in DNA and bind with support of a protein complex to complementary sequences within messenger RNA molecules.  They differ from RNAi's small interfering RNAs as microRNAs are large enough to fold back on themselves to produce hairpin structures.  There is considerable processing performed in the nucleus & later in the cytoplasm after nuclear export.  Key aspects include:
  • Transcription - Most microRNAs are transcribed by RNA polymerase II, and then capped at the 5 prime end and some are modified by RNA editing. The result after splicing is a long RNA molecule called the primary-microRNA. 
    
  • Nuclear processing - The primary-microRNA may contain up to six microRNA precursors.  DGCR8 cuts the RNA to form precursor microRNAs. 
    
  • Nuclear export - Exportin-5 exports the precursor microRNAs out of the nucleus. 
    
  • Cytoplasmic processing - Dicer cuts away the extra nucleotides allowing the microRNAs to bind into the silencing complex with messenger RNA. 
    
  • Silencing of messenger RNAs - by RNA-induced silencing complex supporting the interaction of the microRNA and its target messenger RNA.  
    
  s were elevated in the sperm.  Experimentally introducing microRNAs also changed the offspring's stress responses. 
  

Dec 2015 NYT Scientists Discover Reason Brain Tumors Grow Fast