Posts Tagged ‘Medical research’

US Responses to Coronavirus Outbreak Expose Many Flaws in Our Medical System

Curator: Stephen J. Williams, Ph.D.

The  coronavirus pandemic has affected almost every country in every continent however, after months of the novel advent of novel COVID-19 cases, it has become apparent that the varied clinical responses in this epidemic (and outcomes) have laid bare some of the strong and weak aspects in, both our worldwide capabilities to respond to infectious outbreaks in a global coordinated response and in individual countries’ response to their localized epidemics.


Some nations, like Israel, have initiated a coordinated government-private-health system wide action plan and have shown success in limiting both new cases and COVID-19 related deaths.  After the initial Wuhan China outbreak, China closed borders and the government initiated health related procedures including the building of new hospitals. As of writing today, Wuhan has experienced no new cases of COVID-19 for two straight days.


However, the response in the US has been perplexing and has highlighted some glaring problems that have been augmented in this crisis, in the view of this writer.    In my view, which has been formulated after social discussion with members in the field ,these issues can be centered on three major areas of deficiencies in the United States that have hindered a rapid and successful response to this current crisis and potential future crises of this nature.



  1. The mistrust or misunderstanding of science in the United States
  2. Lack of communication and connection between patients and those involved in the healthcare industry
  3. Socio-geographical inequalities within the US healthcare system


1. The mistrust or misunderstanding of science in the United States


For the past decade, anyone involved in science, whether directly as active bench scientists, regulatory scientists, scientists involved in science and health policy, or environmental scientists can attest to the constant pressure to not only defend their profession but also to defend the entire scientific process and community from an onslaught of misinformation, mistrust and anxiety toward the field of science.  This can be seen in many of the editorials in scientific publications including the journal Science and Scientific American (as shown below)


Stepping Away from Microscopes, Thousands Protest War on Science

Boston rally coincides with annual American Association for the Advancement of Science (AAAS) conference and is a precursor to the March for Science in Washington, D.C.

byLauren McCauley, staff writer

Responding to the troubling suppression of science under the Trump administration, thousands of scientists, allies, and frontline communities are holding a rally in Boston’s Copley Square on Sunday.

#standupforscience Tweets


“Science serves the common good,” reads the call to action. “It protects the health of our communities, the safety of our families, the education of our children, the foundation of our economy and jobs, and the future we all want to live in and preserve for coming generations.”

It continues: 

But it’s under attack—both science itself, and the unalienable rights that scientists help uphold and protect. 

From the muzzling of scientists and government agencies, to the immigration ban, the deletion of scientific data, and the de-funding of public science, the erosion of our institutions of science is a dangerous direction for our country. Real people and communities bear the brunt of these actions.

The rally was planned to coincide with the annual American Association for the Advancement of Science (AAAS) conference, which draws thousands of science professionals, and is a precursor to the March for Science in Washington, D.C. and in cities around the world on April 22.


Source: https://www.commondreams.org/news/2017/02/19/stepping-away-microscopes-thousands-protest-war-science






The American Association for Cancer Research (AACR) also had marches for public awareness of science and meaningful science policy at their annual conference in Washington, D.C. in 2017 (see here for free recordings of some talks including Joe Biden’s announcement of the Cancer Moonshot program) and also sponsored events such as the Rally for Medical Research.  This patient advocacy effort is led by the cancer clinicians and scientific researchers to rally public support for cancer research for the benefit of those affected by the disease.

Source: https://leadingdiscoveries.aacr.org/cancer-patients-front-and-center/



     However, some feel that scientists are being too sensitive and that science policy and science-based decision making may not be under that much of a threat in this country. Yet even as some people think that there is no actual war on science and on scientists they realize that the public is not engaged in science and may not be sympathetic to the scientific process or trust scientists’ opinions. 



From Scientific American: Is There Really a War on Science? People who oppose vaccines, GMOs and climate change evidence may be more anxious than antagonistic


Certainly, opponents of genetically modified crops, vaccinations that are required for children and climate science have become louder and more organized in recent times. But opponents typically live in separate camps and protest single issues, not science as a whole, said science historian and philosopher Roberta Millstein of the University of California, Davis. She spoke at a standing-room only panel session at the American Association for the Advancement of Science’s annual meeting, held in Washington, D.C. All the speakers advocated for a scientifically informed citizenry and public policy, and most discouraged broadly applied battle-themed rhetoric.


Source: https://www.scientificamerican.com/article/is-there-really-a-war-on-science/


      In general, it appears to be a major misunderstanding by the public of the scientific process, and principles of scientific discovery, which may be the fault of miscommunication by scientists or agendas which have the goals of subverting or misdirecting public policy decisions from scientific discourse and investigation.


This can lead to an information vacuum, which, in this age of rapid social media communication,

can quickly perpetuate misinformation.


This perpetuation of misinformation was very evident in a Twitter feed discussion with Dr. Eric Topol, M.D. (cardiologist and Founder and Director of the Scripps Research Translational  Institute) on the US President’s tweet on the use of the antimalarial drug hydroxychloroquine based on President Trump referencing a single study in the International Journal of Antimicrobial Agents.  The Twitter thread became a sort of “scientific journal club” with input from international scientists discussing and critiquing the results in the paper.  


Please note that when we scientists CRITIQUE a paper it does not mean CRITICIZE it.  A critique is merely an in depth analysis of the results and conclusions with an open discussion on the paper.  This is part of the normal peer review process.


Below is the original Tweet by Dr. Eric Topol as well as the ensuing tweet thread




Within the tweet thread it was discussed some of the limitations or study design flaws of the referenced paper leading the scientists in this impromptu discussion that the study could not reasonably conclude that hydroxychloroquine was not a reliable therapeutic for this coronavirus strain.


The lesson: The public has to realize CRITIQUE does not mean CRITICISM.


Scientific discourse has to occur to allow for the proper critique of results.  When this is allowed science becomes better, more robust, and we protect ourselves from maybe heading down an incorrect path, which may have major impacts on a clinical outcome, in this case.



2.  Lack of communication and connection between patients and those involved in the healthcare industry


In normal times, it is imperative for the patient-physician relationship to be intact in order for the physician to be able to communicate proper information to their patient during and after therapy/care.  In these critical times, this relationship and good communication skills becomes even more important.


Recently, I have had multiple communications, either through Twitter, Facebook, and other social media outlets with cancer patients, cancer advocacy groups, and cancer survivorship forums concerning their risks of getting infected with the coronavirus and how they should handle various aspects of their therapy, whether they were currently undergoing therapy or just about to start chemotherapy.  This made me realize that there were a huge subset of patients who were not receiving all the information and support they needed; namely patients who are immunocompromised.


These are patients represent

  1. cancer patient undergoing/or about to start chemotherapy
  2. Patients taking immunosuppressive drugs: organ transplant recipients, patients with autoimmune diseases, multiple sclerosis patients
  3. Patients with immunodeficiency disorders


These concerns prompted me to write a posting curating the guidance from National Cancer Institute (NCI) designated cancer centers to cancer patients concerning their risk to COVID19 (which can be found here).


Surprisingly, there were only 14 of the 51 US NCI Cancer Centers which had posted guidance (either there own or from organizations like NCI or the National Cancer Coalition Network (NCCN).  Most of the guidance to patients had stemmed from a paper written by Dr. Markham of the Fred Hutchinson Cancer Center in Seattle Washington, the first major US city which was impacted by COVID19.


Also I was surprised at the reactions to this posting, with patients and oncologists enthusiastic to discuss concerns around the coronavirus problem.  This led to having additional contact with patients and oncologists who, as I was surprised, are not having these conversations with each other or are totally confused on courses of action during this pandemic.  There was a true need for each party, both patients/caregivers and physicians/oncologists to be able to communicate with each other and disseminate good information.


Last night there was a Tweet conversation on Twitter #OTChat sponsored by @OncologyTimes.  A few tweets are included below





The Lesson:  Rapid Communication of Vital Information in times of stress is crucial in maintaining a good patient/physician relationship and preventing Misinformation.


3.  Socio-geographical Inequalities in the US Healthcare System

It has become very clear that the US healthcare system is fractioned and multiple inequalities (based on race, sex, geography, socio-economic status, age) exist across the whole healthcare system.  These inequalities are exacerbated in times of stress, especially when access to care is limited.


An example:


On May 12, 2015, an Amtrak Northeast Regional train from Washington, D.C. bound for New York City derailed and wrecked on the Northeast Corridor in the Port Richmond neighborhood of Philadelphia, Pennsylvania. Of 238 passengers and 5 crew on board, 8 were killed and over 200 injured, 11 critically. The train was traveling at 102 mph (164 km/h) in a 50 mph (80 km/h) zone of curved tracks when it derailed.[3]

Some of the passengers had to be extricated from the wrecked cars. Many of the passengers and local residents helped first responders during the rescue operation. Five local hospitals treated the injured. The derailment disrupted train service for several days. 

(Source Wikipedia https://en.wikipedia.org/wiki/2015_Philadelphia_train_derailment)

What was not reported was the difficulties that first responders, namely paramedics had in finding an emergency room capable of taking on the massive load of patients.  In the years prior to this accident, several hospitals, due to monetary reasons, had to close their emergency rooms or reduce them in size. In addition only two in Philadelphia were capable of accepting gun shot victims (Temple University Hospital was the closest to the derailment but one of the emergency rooms which would accept gun shot victims. This was important as Temple University ER, being in North Philadelphia, is usually very busy on any given night.  The stress to the local health system revealed how one disaster could easily overburden many hospitals.


Over the past decade many hospitals, especially rural hospitals, have been shuttered or consolidated into bigger health systems.  The graphic below shows this

From Bloomberg: US Hospital Closings Leave Patients with Nowhere to go





Note the huge swath of hospital closures in the midwest, especially in rural areas.  This has become an ongoing problem as the health care system deals with rising costs.


Lesson:  Epidemic Stresses an already stressed out US healthcare system


Please see our Coronavirus Portal at



for more up-to-date scientific, clinical information as well as persona stories, videos, interviews and economic impact analyses

and @pharma_BI

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 A Revolution in Medicine: Medical 3D BioPrinting

Curated by : Irina Robu, PhD

Imagine a scenario, where years from now, one of your organs stop working properly. What would you do?  The current option is to wait in line for a transplant, hoping that the donor is a match. But what if you can get an organ ready for you with no chance of rejection? Even though it may sound like science fiction at the current moment, organ 3D bioprinting can revolutionize medicine and health care.

I have always found the field of tissue engineering and 3D bioprinting fascinating. What interests me about 3D bioprinting is that it has the capacity to be a game changer, because it would make organs widely available to those who need them and it would eliminate the need for a living or deceased donor.  Moreover, it would be beneficial for pediatric patients who suffer specific problems that the current bio-prosthetic options might not address. It would minimize the risk of rejection as well as the components would be customized to size.

There have been advancements in the field of 3D bioprinting and one such advancement is using a 3D printed cranium by neurosurgeons at the University Medical Centre Utrecht. The patient was a young woman who suffered from a chronic bone disorder. The 3D reconstruction of her skull would minimize the brain damage that might have occurred if doctors used a durable plastic cranium.

So, what exactly is bioprinting? 3D bioprinting is an additive manufacturing procedure where biomaterials, such as cells and growth factors, are combined to generate tissue-like structures that duplicate natural tissues. At its core, bioprinting works in a similar way to conventional 3D printing. A digital model becomes a physical 3D object layer-by-layer.  However, in the case of bioprinting, a living cell suspension is used instead of a thermoplastic.

The procedure mostly involves preparation, printing, maturation and application and can be summarized in three steps:

  1. Pre-bioprinting step which includes creating a digital model obtained by using computed tomography (CT) and magnetic resonance imaging (MRI) scans which are then fed to the printer.
  2. Bioprinting step where the actual printing process takes place, where the bioink is placed in a printer cartridge and deposition occurs based on the digital model.
  3. Post-bioprinting step is the mechanical and chemical stimulation of printed parts in order to create stable biostructures which can ultimately be implanted.

3D bioprinting allows suitable microarchitectures that provide mechanical stability and promote cell ingrowth to be produced while preventing any homogeneity issues that occur after conventional cell seeding, such as cell placement. Immediate vascularization of implanted scaffolds is critical, because it provides an influx of nutrients and outflow of by-products preventing necrosis. The benefits of homogeneous seeded scaffolds are that it allows them to integrate faster into the host tissue, uniform cell growth in vivo and lower risk of rejection.

However, in order to address the limitations of the commercially available technology for producing tissue implants, researchers are working to develop a 3D bioprinter that can fit into a laminar flow hood, ultra-low cost and customizable for different organs. Bioprinting can be applied in a clinical setting where the ultimate goal is to implant 3D bioprinted structures into the patients, it is necessary to maintain sterile printing solutions and ensure accuracy in complex tissues, needed for cell-to-cell distances and correct output.

The final aim of bioprinting is to promote an alternative to autologous and allogeneic tissue implants, which will replace animal testing for the study of disease and development of treatments.  We know that for now a short-term goal for 3D bioprinting is to create alternatives to animal testing and to increase the speed of drug testing. The long-term goal is to change the status quo, to develop a personalized organ made from patient’s own cells. However, some ethical challenges still exist regarding the ownership of the organ.

A powerful starting point is the creation of tissue components for heart, liver, pancreas, and other vital organs.  Moreover, each small progress in 3D bioprinting will allow 3D bioprinting to make organs widely available to those who need them, instead of waiting years for a transplant to become available.

I invite you to read a biomedical e-book that I had the pleasure to author along with several other scientists, called Medical 3D BioPrinting – The Revolution in Medicine Technologies for Patient-centered Medicine: From R&D in Biologics to New Medical Devices (Series E: Patient-Centered Medicine Book 4).




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3D-printed body parts could replace cadavers for medical training

Reporter: Irina Robu, PhD

Even though, the 3-D printing based tissue modeling is still in early phases it is considered a promising approach for anatomy training. Models that are produced on a computer screen can be reproduced as tangible objects that students can examine and even dissect. According to a recent report in Medical Science Educator, the latest advancement in 3D printing can revolutionize how anatomy students learn.

For now, human cadavers have been the norm for studying human anatomy but they come with financial and logistical concerns both on storage and disposal. However, with the advancement of custom designed 3D organs, made possible by using 3D printing the need to keep large collection of physical models are reduced. With just a 3D printer, a digital model of the organ needed to study can be reproduced either with resin, thermoplastics, photopolymers and other material. Different materials can be used to allow construction of complex models with hard, soft, opaque and transparent conditions. The printed body parts will look exactly the same as the real thing because they are falsely colored to help students distinguish between the different parts of the anatomy including ligaments, muscles and blood vessels. Medical schools and hospitals around the world would be able to buy just an arm or a foot or the entire body depending on their training need.

Furthermore, to customizing anatomy lessons, 3D printed models can be used for teaching pathology/radiology by comparing CT images of the organs to their 3D-printed counterparts which students can examine and understand. Yet, the methods of 3D printing vary by materials used, resolution accuracy, long term stability, cost, speed and more. The printer cost is still a concern at this point partly because 3D bioprinters cost thousands of dollars nonetheless the cost is dropping due to the introduction of innovative printing materials.

Therefore, in order for 3-D printing to become more widely used, costs must be reduced while resolution must continue to improve. Instructors can potentially print one model per student in a material of their choosing that can be dissected. And no matter how much medical science moves with the times, there would always be the requisite skeleton model in the corner of most anatomy rooms.




Additional Resources

Medical Science Educator, June 2015, Volume 25, Issue 2, pp 183–194| Cite as

Anatomical Models: a Digital Revolution



Goodbye to Cadavers?



3-D Printing: Innovation Allows Customized Airway Stents



Exploring 3-D Printing’s Potential in Renal Surgery



How 3-D Printing Is Revolutionizing Medicine at Cleveland Clinic


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State of Cardiology on Wall Stress, Ventricular Workload and Myocardial Contractile Reserve: Aspects of Translational Medicine (TM)

Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC


Article Curator, Aviva Lev-Ari, PhD, RN

This article is based on and all citations are from the following two articles that have appeared in Journal of Translational Medicine in 2013


Identifying translational science within the triangle of biomedicine


Griffin M Weber

Journal of Translational Medicine 2013, 11:126 (24 May 2013)


Integrated wall stress: a new methodological approach to assess ventricular

workload and myocardial contractile reserve


Dong H, Mosca H, Gao E, Akins RE, Gidding SS and Tsuda T

Journal of Translational Medicine 2013, 11:183 (7 August 2013)

In this article we expose the e-Reader to

A. The State of Cardiology on

  • wall stress
  • ventricular workload and
  • myocardial contractile reserve

B. Innovations in a Case Study in Cardiology Physiological Research on above subjects

C. Prevailing Models in Translational Medicine

D. Mapping of One Case Study in Cardiology Physiological Research onto Weber’s Triangle of Biomedicine.

The mapping facilitate e-Reader’s effort to capture the complexity of aspects of Translational Medicine and visualization of the distance on this Triangle between where the results of this case study are and the Human Corner — the Roadmap of the “bench-to-bedside” research, or the “translation” of physiological and basic science research into practical clinical applications.

This article has the following sections:


Author:  Justin Pearlman, MD, PhD, FACC

Translational medicine aims to fast track the pathway from scientific discovery to clinical applications and assessment of benefits. Cardiovascular examples include novel biomarkers of disease, new heart assist devices, new technologies for catheter intervention, and new medications. The Institute of Medicine’s Clinical Research Roundtable describes translation medicine in two fundamental blocks:  “…the transfer of new understandings of disease mechanisms gained in the laboratory into the development of new methods for diagnosis, therapy, and prevention [with] first testing in humans…”, and  “…the translation of results from clinical studies into everyday clinical practice and health decision making…” [2].

Identifying where contributions are achieving translation has been addressed by the biometric tool called the triangle of biomedine [3].


  1. Jiang F, Zhang J, Wang X, Shen X: Important steps to improve translation from medical research to health policy.J Trans Med 2013, 11:33. BioMed Central Full Text OpenURL
  2. Sung NS, Crowley WF Jr, Genel M, Salber P, Sandy L, Sherwood LM, Johnson SB, Catanese V, Tilson H, Getz K, Larson EL, Scheinberg D, Reece EA, Slavkin H, Dobs A, Grebb J, Martinez RA, Korn A, Rimoin D: Central challenges facing the national clinical research enterprise.JAMA 2003, 289:1278-1287. PubMed Abstract | Publisher Full Text
  3. Identifying translational science within the triangle of biomedicineGriffin M WeberJournal of Translational Medicine 2013, 11:126 (24 May 2013)
  4. Woolf SH: The meaning of translational research and why it matters.JAMA 2008, 299(2):211-213. PubMed Abstract | Publisher Full Text OpenURL
  5. Chiappelli F: From translational research to translational effectiveness: the “patient-centered dental home” model.Dental Hypotheses 2011, 2:105-112. Publisher Full Text OpenURL
  6. Maida C: Building communities of practice in comparative effectiveness research.In Comparative effectiveness and efficacy research and analysis for practice (CEERAP): applications for treatment options in health care. Edited by Chiappelli F, Brant X, Cajulis C. Heidelberg: Springer–Verlag; 2012.
  7. Agency for Healthcare Research and QualityBudget estimates for appropriations committees, fiscal year (FY) 2008: performance budget submission for congressional justification. 
    http://www.ahrq.gov/about/cj2008/cjweb08a.htm#Statement webcite. Accessed 11 May 2013OpenURL
  8. Westfall JM, Mold J, Fagnan L: Practice-based research—“blue highways” on the NIH roadmap.JAMA 2007, 297:403-406. PubMed Abstract | Publisher Full Text OpenURL
  9. Chiappelli F, Brant X, Cajulis C: Comparative effectiveness and efficacy research and analysis for practice (CEERAP) applications for treatment options in health care. Heidelberg: Springer–Verlag; 2012. OpenURL
  10. Dousti M, Ramchandani MH, Chiappelli F: Evidence-based clinical significance in health care: toward an inferential analysis of clinical relevance.Dental Hypotheses 2011, 2:165-177. Publisher Full Text
  11. CRD: Systematic Reviews: CRD’s guidance for undertaking reviews in health care. National Institute for Health Research (NIHR). University of York, UK: Center for reviews and dissemination; 2009. PubMed Abstract | Publisher Full Text OpenURL
  12. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA, Cochrane Bias Methods Group; Cochrane Statistical Methods Group:The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials.British Med J 2011, 343:d5928. Publisher Full Text OpenURL
  13. Bartolucci AA, Hillegas WB: Overview, strengths, and limitations of systematic reviews and meta-analyses. In Understanding evidence-based practice: toward optimizing clinical outcomes. Edited by Chiappelli F, Brant XMC, Oluwadara OO, Neagos N, Ramchandani MH. Heidelberg: Springer–Verlag; 2010.
  14. Jüni P, Altman DG, Egger M: Systematic reviews in health care: assessing the quality of controlled clinical trials.British Med J 2001, 323(7303):42-46. Publisher Full Text OpenURL
  15. Chiappelli F, Arora R, Barkhordarian B, Ramchandani M: Evidence-based clinical research: toward a New conceptualization of the level and the quality of the evidence.Annals Ayurvedic Med 2012, 1:60-64. OpenURL
  16. Chiappelli F, Barkhordarian A, Arora R, Phi L, Giroux A, Uyeda M, Kung K, Ramchandani M:Reliability of quality assessments in research synthesis: securing the highest quality bioinformation for HIT.Bioinformation 2012, 8:691-694. PubMed Abstract | Publisher Full Text |PubMed Central Full Text OpenURL
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 This article has the following EIGHT Sections:

I. Key Explanation Models for the Translational Process in BioMedicine, aka Translational Medicine (TM)

II. TM Model selection in this article, for mapping the fit of a Case Study in Cardiology Physiological Research, within the TM Model selected

III. Limitations of the TM Model to explain the Translational Process in BioMedicine

IV. Mapping the fit of a Case Study in Cardiology Physiological Research, within the TM Model selected

V. Clinical Implications of the Case Study in Cardiology Physiological Research

VI. Limitations of the Case Study in Cardiology Physiological Research

VII. The State of Cardiology on

  • wall stress
  • ventricular workload and
  • myocardial contractile reserve

VIII. What are the Innovations of the Case Study in Cardiology Physiological Research

I. Key Explanation Models for the Translational Process in BioMedicine, aka Translational Medicine (TM)

The National Institutes of Health (NIH) Roadmap places special emphasis on “bench-to-bedside” research, or the “translation” of basic science research into practical clinical applications. The Clinical and Translational Science Awards (CTSA) Consortium is one example of the large investments being made to develop a national infrastructure to support translational science, which involves reducing regulatory burdens, launching new educational initiatives, and forming partnerships between academia and industry. However, while numerous definitions have been suggested for translational science, including the qualitative T1-T4 classification, a consensus has not yet been reached. This makes it challenging to measure the impact of these major policy changes.


Model A: QUALTITATIVE T1-T4 CLASSIFICATION [(7) & (8-10) in Weber’s list of Reference, below]

In biomedicine, translational science is research that has gone from “bench” to “bedside”, resulting in applications such as drug discovery that can benefit human health  [16]. However, this is an imprecise description. Numerous definitions have been suggested, including the qualitative T1-T4 classification [7].

Several bibliometric techniques have been developed to quantitatively place publications in the translational spectrum. Narin assigned journals to fields, and then grouped these fields into either “Basic Research” or “Clinical Medicine” [8-10]. Narin also developed another classification called research levels, in which journals are assigned to “Clinical Observation” (Level 1), “Clinical Mix” (Level 2), “Clinical Investigation” (Level 3), or “Basic Research” (Level 4) [8]. He combines Levels 1 and 2 into “Clinical Medicine” and Levels 3 and 4 to “Biomedical Research”.

Model B: Average research level of a collection of articles as the mean of the research levels of those articles

Lewison developed methods to score the translational research level of individual articles from keywords within the articles’ titles and addresses. He defines the average research level of a collection of articles as the mean of the research levels of those articles [1113] .  For validity, one must assume that the keywords reflect content fairly and without bias. If the government adapts such a scoring system to influence funding in order to promote translational research, that will create a bias.

Model C:  “Translatability” of drug development projects 

A multidimensional scoring system has been developed to assess the “translatability” of drug development projects [29,30]. This requires manual review of the literature which poses difficulties for scalability and consistency across reviewers and over time.

Model D: Fontelo’s  59 words and phrases suggesting that the article is Translational 

Fontelo identified 59 words and phrases, which when present in the titles or abstracts of articles, suggest that the article is translational [31]. It is an interesting sampling method, but it may present a bias to particular styles of presentation.

Model E:  The triangle of biomedicine by Griffin M Weber – This Model is the main focus of this article



The Triangle of Biomedicine uses a bibliometric approach to map PubMed articles onto a graph. The corners of the triangle represent research related to animals, to cells and molecules. The position of a publication on the graph is based on its topics, as determined by its Medical Subject Headings (MeSH). Translation is defined as movement of a collection of articles, or the articles that cite those articles, towards the human corner.


The Triangle of Biomedicine provides a quantitative way of determining if an individual scientist, research organization, funding agency, or scientific field is producing results that are relevant to clinical medicine. Validation of the method examined examples that have been previously described in the literature, comparing it to other methods of measuring translational science.


The Triangle of Biomedicine is a novel way to identify translational science and track changes over time. This is important to policy makers in evaluating the impact of the large investments being made to accelerate translation. The Triangle of Biomedicine also provides a simple visual way of depicting this impact, which can be far more powerful than numbers alone. As with any metric, its limitations and potential biases should always be kept in mind. As a result, it should be used to supplement rather than replace alternative methods of measuring or defining translational science. What is unique, though, to the Triangle of Biomedicine, is its simple visual way of depicting translation, which can be far more powerful to policy makers than numbers alone.


Translational science; Bibliometric analysis; Medical subject headings; Data visualization; Citation analysis

II. TM Model selection in this article, for mapping the fit of a Case Study in Cardiology Physiological Research, within the TM Model selected

Model E:  The triangle of biomedicine by Griffin M Weber

In this study, we analyze the 20 million publications in the National Library of Medicine’s PubMed database by extending these bibliometric approaches in three ways: (1) We divide basic science into two subcategories, research done on animals or other complex organisms and research done on the cellular or molecular level. We believe it is important to make this distinction due to the rapid increase in “-omics” research and related fields in recent years. (2) We classify articles using their Medical Subject Headings (MeSH), which are assigned based on the content of the articles. Journal fields, title keywords, and addresses only approximate an article’s content. (3) We map the classification scheme onto a graphical diagram, which we call the Triangle of Biomedicine, which makes it possible to visualize patterns and identify trends over time.

Article classification technique

Using a simple algorithm based on an article’s MeSH descriptors, we determined whether each article in PubMed contained research related to three broad topic areas—animals and other complex organisms (A), cells and molecules (C), or humans (H). An article can have more than one topic area. Articles about both animals and cells are classified as AC, articles about both animals and humans are AH, articles about cells and humans are CH, and articles about all three are ACH. Articles that have none of these topic areas are unclassified by this method.

In order to identify translational research, we constructed a trilinear graph [21], where the three topic areas are placed at the corners of an equilateral triangle, with A on the lower-left, C on the top, and H on the lower-right. The midpoints of the edges correspond to AC, AH, and CH articles, and the center of the triangle corresponds to ACH articles.

An article can be plotted on the Triangle of Biomedicine according to the MeSH descriptors that have been assigned to it. For example, if only human descriptors, and no animal or cell descriptors have been assigned to an article, then it is classified as an H article and placed at the H corner. An article with both animal and cell descriptors, and no human descriptors, is classified as an AC article and placed at the AC point. A collection of articles is represented by the average position of its articles. Although an individual article can only be mapped to one of seven points, a collection of articles can be plotted anywhere in the triangle.

An imaginary line, the Translational Axis, can be drawn from the AC point to the H corner. The position of one or more articles when projected onto this axis is the Translational Index (TI). By distorting the Triangle of Biomedicine by bringing the A and C corners together at the AC point, the entire triangle can be collapsed down along the Translational Axis to the more traditional depiction of translational science being a linear path from basic to clinical research. In other words, the Triangle of Biomedicine does not replace the traditional linear view, but rather provides additional clarity into the path research takes towards translation.

Summary of categories

Mapping A-C-H categories to Narin’s basic-clinical classification scheme

The National Library of Medicine (NLM) classifies journals into different disciplines, such as microbiology, pharmacology, or neurology, with the use of Broad Journal Headings. We used Narin’s mappings to group these disciplines into basic research or clinical medicine. Individual articles were given a “basic research” score of 1 if they were in a basic research journal and 0 if they were in a “clinical medicine” journal. For each A-C-H category, a weighted average of its articles’ scores was calculated, with the weights being the inverse of the total number of basic research (4,316,495) and clinical medicine (11,689,341) articles in PubMed. That gives a numeric value for the fraction of articles within a category that are basic research, which is corrected for the fact that PubMed as a whole has a greater number of clinical medicine articles.

Mapping A-C-H categories to Narin’s four-level classification scheme

For each of his four research levels, Narin selected a prototype journal to conduct his analyses:The Journal of the American Medical Association (JAMA, Level 1), The New England Journal of Medicine (NEJM, Level 2), The Journal of Clinical Investigation (JCI, Level 3), and The Journal of Biological Chemistry (JBC, Level 4). Each is widely considered a leading journal and has over 25,000 articles spanning more than 50 years. For each A-C-H category, we determined the number of articles from each of these four journals and calculated a weighted average of their research levels, with the weights being the inverse of the total number of articles each journal has in PubMed.

III. Limitations of the TM Model to explain the Translational Process in BioMedicine:  The triangle of biomedicine by Griffin M Weber

This work is limited in several ways. It takes at least a year for most articles to be assigned MeSH descriptors. During that time the articles cannot be classified using the method described in this paper. Also, our classification method is based on a somewhat arbitrary set of MeSH descriptors—different descriptors could have been used to map articles to A-C-H categories. However, the ones we used seemed intuitive and they produced results that were consistent with Narin’s classification schemes. Finally, any metric based on citation analysis is dependent on the particular citation database used, and there are significant differences among the leading databases [22]. In this study, we used citations in PubMed that are derived from PubMed Central because they are freely available in their entirety, and therefore our method can be used without subscriptions to commercial citation databases, such as Scopus and Web of Science, which are cost-prohibitive to most people. However, because these commercial databases have a greater number of citations and index different journals than PubMed, they might show shorter or alternative paths towards translation (i.e., fewer citation generations or less time). Though, as described in our Methods, there is evidence that suggests these differences might be relatively small. Selecting the best citation database for identifying translational research is a topic for future research.

Another area of future research could attempt to identify a subset of H articles that truly reflect changes in health practice and create a separate category P for these articles. This might be possible, for example, by using Khoury’s approach of using PubMed’s “publication type” categorization of each article to select for those that are clinical trials or practice guidelines [7]. This could be visualized in the Triangle of Biomedicine by moving H articles to the center of the triangle and placing P articles in the lower-right corner, thereby highlighting research that has translated beyond H into health practice.

IV. Mapping the fit of a Case Study in Cardiology Physiological Research, within the TM Model selected

The triangle of biomedicine by Griffin M Weber


Figure 1. Disciplines mapped onto the Triangle of Biomedicine.The corners of the triangle correspond to animal (A), cellular or molecular (C), and human (H) research. The dashed blue line indicates the Translational Axis from basic research to clinical medicine. The position of each circle represents the average location of the articles in a discipline. The size of the circle is proportional to the number of articles in that discipline. The color of the circle indicates the Translational Distance (TD)—the average number of citation generations needed to reach an H article. The position of the light blue box connected to each discipline represents the average location of articles citing publications in that discipline. To provide clarity, not all disciplines are shown. Note however, that if authors knew this measurement would be applied and could affect their funding, then they might increase human study citation of basic research to game the “translational distance.”

For this article we selected A Case Study in Cardiology Physiological Research

Integrated wall stress: a new methodological approach to assess ventricular workload and myocardial contractile reserve  

Hailong Dong124Heather Mosca1Erhe Gao3Robert E Akins1Samuel S Gidding2and Takeshi Tsuda12*

This study appeared in 2013 in the Journal of Translational Medicine. It studied mice, creating heart attacks in order to evaluate the physiologic significance of “integrated wall stress” (IWS) as a marker of total ventricular workload. The measure IWS was obtained by integrating continuous wall stress curve by accumulating wall stress values at millisecond sampling intervals over one minute, in order to include in  wall stress effects of heart rate and contractility (inotropic status of the myocardium). As an example of translational medicine, it raises numerous issues. As a mouse study, it qualifies as basic science. It examines the impact of heart attack on changes inducible by the inotropic agent dobutamine. If the concept were to influence clinical care and outcomes, it would qualify as translational. All of the tools applied to the mice are applicable to patients: heart attacks (albeit not purposefully induced), the echocardiography measurements, and the dobutamine impact. That enables citation of human studies in the references, and ready application to human studies in the future. Mice however have much faster heart rates, so the choice of one minute for the integral may have different significance for humans. Gene expression was also measured. The authors conclude IWS represents  a balance between external ventricular workload and intrinsic myocardial contractile reserve. The fact that the Journal has the word “translational” may represent a bias. Many of the links between animal and human focused references occur electively in the discussion section. The authors propose the measurement might help identify pre-clinical borderline failing of contractility. If so, the full axis of translational value will require that IWS can improve outcomes. Currently, blood levels of brain naturetic peptide are used as a marker of myocardial strain that may help identify early failing contractility. Presumably, early recognition could identify a population that might benefit from early intervention to forestall progression. Evidence based medicine will have difficulties. First, it is biased by the “Will Roger’s Effect” whereby early recognition of a disease subdivides the lowest class, inherently shifting the apparent status of each half of the subdivision (Will Roger’s made a joke that when Oklahoma residents moved to California for the gold rush, they improved the average intelligence of both groups, an observation adapted to explain a redefinition bias). Second, the actual basis for a change in clinical application will be complex, with political as well as scientific influences. Third, it will be even more difficult to discern its impact on outcomes, even if targeted therapy for patients with distinctive IWS is associated with an apparent improvement in outcomes. Convincing documentation would require extensive comparisons and controlled studies, but once a method is clinically adapted, it is commonly considered unethical to perform a controlled study in which the “preferred method” is not applied to a group.

V. Clinical Implications of the Case Study in Cardiology Physiological Research


Wall stress is a useful concept to understand the progression of ventricular remodeling. We measured cumulative LV wall stress throughout the cardiac cycle over unit time and tested whether this “integrated wall stress (IWS)” would provide a reliable marker of total ventricular workload.

Methods and results

We applied IWS to mice after experimental myocardial infarction (MI) and sham-operated mice, both at rest and under dobutamine stimulation. Small infarcts were created so as not to cause subsequent overt hemodynamic decompensation. IWS was calculated over one minute through simultaneous measurement of LV internal diameter and wall thickness by echocardiography and LV pressure by LV catheterization. At rest, the MI group showed concentric LV hypertrophy pattern with preserved LV cavity size, LV systolic function, and IWS comparable with the sham group. Dobutamine stimulation induced a dose-dependent increase in IWS in MI mice, but not in sham mice; MI mice mainly increased heart rate, whereas sham mice increased LV systolic and diastolic function. IWS showed good correlation with a product of peak-systolic wall stress and heart rate. We postulate that this increase in IWS in postMI mice represents limited myocardial contractile reserve.


We hereby propose that IWS provides a useful estimate of total ventricular workload in the mouse model and that increased IWS indicates limited LV myocardial contractile reserve.


Wall stress; Ventricular workload; Myocardial contractile reserve; Ventricular remodeling

Clinical implications

IWS can be estimated by obtaining IWS index, which is calculated non-invasively by simultaneous M-mode echocardiogram and cuff blood pressure measurement, i.e., PS-WS instead of ES-WS and heart rate. This will provide a sensitive way to detect subclinical borderline failing myocardium in which the decline in LV myocardial contractile reserve precedes apparent LV dysfunction. This method may be clinically useful to address LV myocardial reserve in those patients who are not amenable to perform on exercise stress test, such as immediate post-operative patients under mechanical ventilation, critically ill patients with questionable LV dysfunction, and patients with primary muscular disorders and general muscular weakness (i.e., Duchenne muscular dystrophy).

VI. Limitations of the Case Study in Cardiology Physiological Research

There are certain limitations in this study.

  • First, wall stress measurement is reliable when there is an equal wall thickness with symmetrical structure. Obviously, with the creation of small MI, there is an asymmetry of LV myocardium in both structure and consistency (myocardium vs. scar tissue). However, the scar tissue is small and restricted to the LV apex (approximately 14% of entire LV myocardium [5]). In fact, most of LV wall was thickened after induction of this small experimental MI. Nevertheless, we acknowledge that this is our major limitation.
  • Secondly, there is an individual variability in response to dobutamine stimulation even in sham mice. Although the average sham mice (n = 5) showed only a modest increase in HR, PS-WS, and IWS during dobutamine stimulation, one mouse presented in Figure 1 showed a notable increase in HR and PS-WS in response to dobutamine. Nevertheless, even with increased HR and PS-WS, the calculated IWS remained relatively unchanged in the sham-operated mice.
  • Lastly, the reliability of IWS index is based upon the stipulation that ED-WS is significantly low compared with the systolic wall stress. Thus, IWS index may not be accurate in obvious volume overload cases and/or dilated hearts with LV dysfunction where ED-WS is significantly higher than that in normal condition. Of note, ED-WS in human is higher than that in mice in relation to PS-WS, probably around 15 to 20% of PS-WS [12].

VII. State of Cardiology on

  • wall stress
  • ventricular workload and
  • myocardial contractile reserve

Ventricular remodeling is a chronic progressive pathological process that results in heart failure after myocardial infarction (MI) or persistent unrelieved biomechanical overload [1,2]. Persistent and unrelieved biomechanical overload in combination with activation of inflammatory mediators and neurohormones is thought to be responsible for progressive ventricular remodeling after MI [3,4], but studies to investigate specific mechanisms in animals are hampered by the difficulty involved in quantifying biomechanical workload in vivo. The magnitude of ventricular remodeling advances in line with progressive ventricular geometric changes including myocardial hypertrophy and chamber dilatation with accompanying functional deterioration [1,2]. Previously, we proposed that post-ischemic ventricular remodeling is a pathological spectrum ranging from benign myocardial hypertrophy to progressive heart failure in the mouse model in which the prognosis is primarily determined by the magnitude of residual hemodynamic effects [5]. However, there has been no optimum quantitative measurement of ventricular workload as a contributory indicator of ventricular remodeling other than wall stress theory to explain how ventricular dilatation and hypertrophy develop after loss of viable working myocardium [6,7].

The concept of ventricular wall stress was introduced by Strauer et al. as a primary determinant of myocardial oxygen demand [8]. They indicated that overall myocardial energy demand depends upon intramyocardial wall tension, inotropic state of the myocardium, and heart rate. Wall stress theory is commonly introduced to explain development of concentric hypertrophy in chronic pressure overload and progressive ventricular dilatation in the failing heart. One study argued that peak-systolic wall stress increased as LV function worsened in a chronic volume overloaded status [9], and another suggested that peak-systolic wall stress closely reflected LV functional reserve during exercise [10]. However, the effect of heart rate or myocardial contractility was not considered in either study. Heart rate has been shown to be one of several important factors contributing to myocardial oxygen consumption [11].

Herein, we introduce a novel concept of “integrated wall stress (IWS)” to assess its significance as a marker of total ventricular workload and to validate its physiological relevance in the mouse model. The concept of continuous LV wall stress measurement was reported previously, but authors did not address the overall effects of changing wall stress during the cardiac cycle on the working myocardium [12]. We have defined IWS as cumulative wall stress over unit time: IWS was obtained by integrating continuous wall stress curve by accumulating wall stress values at millisecond sampling intervals over 1 min. By calculating IWS, we were able to incorporate the effects of not only systolic wall stress, but also of heart rate and inotropic status of the myocardium. These data were analyzed against conventional hemodynamic parameters in animals with and without MI in conjunction with incremental dobutamine stress. We hypothesize that unchanged IWS represents stable ventricular myocardial contractile reserve and that increase in IWS implies an early sign of mismatch between myocardial reserve and workload imposed on ventricular myocardium.

VIII. What are the Innovations of the Case Study in Cardiology Physiological Research

IWS measures total wall stress throughout the cardiac cycle over a unit time (= 1 min) including the effect of heart rate and inotropic state of the ventricular myocardium, whereas one-spot measurement of PS-WS and ED-WS only reflects maximum and minimum wall stress during a cardiac cycle, respectively. We hypothesized that increase in IWS indicates failure of myocardium to counteract increased ventricular workload. We have measured IWS in the mouse model in various physiological and pathological conditions to validate this hypothesis. Unchanged IWS observed in sham operated mice may imply that the contractile reserve of ventricular myocardium can absorb the increased cardiac output, whereas increased IWS after MI suggests that ventricular workloads exceeds intrinsic myocardial contractile reserve. Thus, we postulate that IWS is a reliable physiological marker in indicating a balance between external ventricular workload and intrinsic myocardial contractile reserve.


IWS and myocardial reserve

“Wall stress theory” is an important concept in understanding the process of cardiac hypertrophy in response to increased hemodynamic loading [16]. When the LV myocardium encounters biomechanical overload, either pressure overload or volume overload, cardiac hypertrophy is naturally induced to normalize the wall stress so that myocardium can minimize the increase in myocardial oxygen demand; myocardial oxygen consumption depends mainly on systolic wall stress, heart rate, and contractility [8,17]. A question arises whether this hypertrophic response is a compensatory physiological adaptation to stabilize the wall stress or a pathological process leading to ventricular remodeling and heart failure. Physiological hypertrophy as seen in trained athletes reveals increased contractile reserve, whereas pathological hypertrophy shows a decrease in contractile reserve in addition to molecular expression of ventricular remodeling [1820]. However, what regulates the transition from compensatory adaptation to maladaptive process is not well understood.

Systolic wall stress has been studied extensively as a clinical marker for myocardial reserve. Systolic wall stress reflects the major determinants of the degree of LV hypertrophy and plays a predominant role in LV function and myocardial energy balance [17]. It has been shown that increased systolic wall stress inversely correlates with systolic function and myocardial reserve in patients with chronic volume overload [9,10,21], chronic pressure overload [22,23], and dilated cardiomyopathy [24]. However, one-point measurement of systolic wall stress does not encompass the effect of heart rate and contractile status, the other critical factors that affect myocardial oxygen demand [11]. The idea of IWS has been proposed to incorporate wall stress throughout the cardiac cycle and reflects the effects of heart rate and contractile status.

Myocardial oxygen consumption is determined mainly by ventricular wall stress, heart rate and contractility [17], which are all incorporated in IWS measurement. Continuous measurement of LV wall stress was previously reported in humans [12,15] and dogs [11] with a similar method, but not in mice. By integrating the continuous WS over one minute, we estimated the balance between myocardial contractile reserve and total external ventricular workload and examined its trend in relation to inotropic stimulation in the mouse heart in vivo. In this study, we have proposed unchanged IWS as a marker of sufficient myocardial contractile reserve, since increased wall stress demands higher myocardial oxygen consumption. Indeed, systolic wall stress does not increase with strenuous isometric exercise in healthy young athletes [25]. Thus, we propose that increase in IWS indicates diminished myocardial contractile reserve.


Small MI model as a unique model to study early phase of progressive ventricular remodeling

A complex series of protective and damaging events takes place after MI, resulting in increased ventricular workload [26]. Initial ventricular geometric change is considered as a primary compensatory response to counteract an abrupt loss of contractile tissue. In classical theories of wall stress, which rely on the law of Laplace, the mechanisms of progressive ventricular dilatation and functional deterioration of the LV are attributed to the increased wall stress that is not compensated by the intrinsic compensatory mechanisms [2,16]. Although this theory is obvious in advanced stage of heart failure, the subclinical ventricular remodeling following borderline cases such as following small MI with initial full compensatory response is not well explained.

Study shown that our small MI model induced concentric hypertrophy without LV dilatation as if initial myocardial damage was completely compensated (Figure 2[5]. Although LV hypertrophy is induced initially to normalize the wall stress and to prevent ventricular dilatation, this hypertrophy is not altogether a physiological one because of decreased inotrophic and lusitropic reserve when stimulated with dobutamine (Figure 4) and because of simultaneous molecular and histological evidence of remodeling in the remote nonischemic LV myocardium (Figure 3). IWS and PS-WS become normalized in small MI at rest under anesthesia as a result of reactive hypertrophy accompanied by increased ANP and BNP mRNA level. Borderline maladaptive LVH is characterized by maintained LV performance at the expense of limited myocardial contractile reserve, and this abnormality can be unmasked by inotropic stimulation [18]. The trend of IWS at rest and with dobutamine stimulation suggests that MI mice were likely exposed to higher IWS during usual awake and active condition than sham-operated mice. In contrast, systolic wall stress in the pressure overload-induced LV hypertrophy showed a level comparable to that of sham both at rest and under stimulation by β1 adrenergic agonist, prenalterol, with comparable heart rate changes [27]. For this reason, IWS assessment by measuring cumulative WS in a unit time with and without inotropic stimuation should serve as a sensitive marker to assess whether induced LV hypertrophy is a compensatory physiological adaptation process or a pathological maladaptation process. Increased IWS that indicates imposed workload surpassing myocardial contractile reserve is likely to become a major driving factor in inducing progressive ventricular remodeling or initiating deleterious maladaptive processes after MI.


IWS represents myocardial oxygen demand that can be estimated non-invasively

Study demonstrated a very good correlation between IWS and the product of PS-WS and HR (“IWS index”) in both MI and sham-operated hearts (Figure 6). This formula appears physiologically acceptable provided that ED-WS is sufficiently low compared with the PS-WS (approximately 10%, as is shown in Figures 4B and C). ES-WS was previously introduced as a useful tool for assessing myocardial loading status and myocardial oxygen consumption, but its measurement requires complicated preparation [28,29]. Because there is an excellent correlation between PS-WS and ES-WS, it has been demonstrated that ES-WS can be substituted by PS-WS [28], which can be easily obtained non-invasively [30]. ES-WS was previously determined as a useful marker to quantify LV afterload and contractility that can be simply and accurately measured non-invasively [15]. As myocardial oxygen consumption is mainly dependent upon systolic wall stress, contractility, and heart rate, it seems reasonable to propose that IWS and IWS index represent the status of myocardial contractile reserve.

Conclusions & Next Phases in Translational Medicine and Cardiology Physiological Research

Author: Justin Pearlman, MD, PhD, FACC 

Visual and numeric scores that assess the commitment to translation of basic discoveries to measured impact on human outcomes followed by increased prevalence of the benefits is of course desirable, but fraught with challenges.  Metrics of translational medicine may lead to rewards that can “game” the system by promoting choices of MeSH codes that augment the score for individual articles and/or clusters of work from a center of research without correlation to the actual impact of the body of work. The fairness of a metric also must account for division of labor whereby one group of researchers achieves major basic discoveries that ferment useful applications to improved outcomes in patient care, while others focus on applications or application assessments that may have widely disparate degrees of impact on the reduction to practice, validation and dissemination of improved care.

Thus in order to promote useful metrics of translational medicine progress, we propose a set of metrics on the metrics:

1. impact of reviewer skill/bias

2. impact of author coding/bias

3. ability to assess an impact factor independent of author word choices

4. ability to credit basic research for its downstream impact on other researchers culminating in clinical applications, validation, and dissemination of human benefits

5. ability to discern pioneering advances from “me too” duplications of effort and minor variations on work of the same group or others

6. ability to assess cost effectiveness, including the occurrences of subsequent re-investigations to clarify issues that could have been addressed in the instance study

7. ability to compute contribution to quality life year gain per dollar of added care


Identifying translational science within the triangle of biomedicine


Griffin M Weber

Journal of Translational Medicine 2013, 11:126 (24 May 2013)

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Integrated wall stress: a new methodological approach to assess ventricular

workload and myocardial contractile reserve


Dong H, Mosca H, Gao E, Akins RE, Gidding SS and Tsuda T

Journal of Translational Medicine 2013, 11:183 (7 August 2013)

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  19. Force T, Michael A, Kilter H, Haq S: Stretch-activated pathways and left ventricular remodeling.J Card Fail 2002, 8:S351-S358. PubMed Abstract | Publisher Full Text OpenURL
  20. Weber KT, Clark WA, Janicki JS, Shroff SG: Physiologic versus pathologic hypertrophy and the pressure-overloaded myocardium.J Cardiovasc Pharmacol 1987, 10(Suppl 6):S37-S50. PubMed Abstract OpenURL
  21. Borow KM, Green LH, Mann T, Sloss LJ, Braunwald E, Collins JJ, Cohn L, Grossman W:End-systolic volume as a predictor of postoperative left ventricular performance in volume overload from valvular regurgitation.Am J Med 1980, 68:655-663. PubMed Abstract | Publisher Full Text OpenURL
  22. Krayenbuehl HP, Hess OM, Ritter M, Monrad ES, Hoppeler H: Left ventricular systolic function in aortic stenosis.Eur Heart J 1988, 9(Suppl E):19-23. PubMed Abstract | Publisher Full Text OpenURL
  23. Yuda S, Khoury V, Marwick TH: Influence of wall stress and left ventricular geometry on the accuracy of dobutamine stress echocardiography.J Am Coll Cardiol 2002, 40:1311-1319. PubMed Abstract | Publisher Full Text OpenURL
  24. Paraskevaidis IA, Tsiapras DP, Adamopoulos S, Kremastinos DT: Assessment of the functional status of heart failure in non ischemic dilated cardiomyopathy: an echo-dobutamine study.Cardiovasc Res 1999, 43:58-66. PubMed Abstract | Publisher Full Text OpenURL
  25. Haykowsky M, Taylor D, Teo K, Quinney A, Humen D: Left ventricular wall stress during leg-press exercise performed with a brief valsalva maneuver.Chest 2001, 119:150-154. PubMed Abstract | Publisher Full Text OpenURL
  26. Opie LHCP, Gersh B, Pfeffer MA: Controversies in ventricular remodeling.Lancet 2006, 367:356-367. PubMed Abstract | Publisher Full Text OpenURL
  27. Fujii AM, Vatner SF, Serur J, Als A, Mirsky I: Mechanical and inotropic reserve in conscious dogs with left ventricular hypertrophy.Am J Physiol 1986, 251:H815-H823. PubMed Abstract | Publisher Full Text OpenURL
  28. Colan SD, Borow KM, MacPherson D, Sanders SP: Use of the indirect axillary pulse tracing for noninvasive determination of ejection time, upstroke time, and left ventricular wall stress throughout ejection in infants and young children.Am J Cardiol 1984, 53:1154-1158. PubMed Abstract | Publisher Full Text OpenURL
  29. Colan SD, Borow KM, Neumann A: Effects of loading conditions and contractile state (methoxamine and dobutamine) on left ventricular early diastolic function in normal subjects.Am J Cardiol 1985, 55:790-796. PubMed Abstract | Publisher Full Text OpenURL
  30. Borow KM, Green LH, Grossman W, Braunwald E: Left ventricular end-systolic stress-shortening and stress-length relations in human. Normal values and sensitivity to inotropic state.Am J Cardiol 1982, 50:1301-1308. PubMed Abstract | Publisher Full Text OpenURL

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The Affordable Care Act: A Considered Evaluation. The Implementation of the ACA, Impact on Physicians and Patients, and the Dis-Ease of the Accountable Care Organizations.

The Affordable Care Act: A Considered Evaluation. Part II: The Implementation of the ACA, Impact on Physicians and Patients, and the Dis-Ease of the Accountable Care Organizations.

Writer and Curator: Larry H. Bernstein, MD, FCAP


Curator and Editor: Aviva Lev-Ari, PhD, RN 


This discussion is the second of two distinct chapters. The first is a clarification of what is contained in the Accountable Care Act (ACA), the model of care it is crafted from, the insurance mandate, the inclusion of groups considered high risk and uninsured, the inclusion of groups low risk and uninsured, and the economics involved in going from a fractured for profit health care industry to a more stable coverage for patients with problems in creating a new workable model from an actuarial standpoint, with the built in complexity of not just age, but education, achievement in the workforce, and a consolidating hospital and eldercare industry, the unpredictability of disease evolution, and add on the multicultural and social structures, as well as rapidly evolving communications and computational platforms needed to transform the U.S. Healthcare system.. The second is taken from selected articles on the care process in the New England Journal of Medicine about the cost and consequences for improving quality at lower cost. Dr. Justin Pearlman has chosen this topic to become as the Second Chapter in the Cardiovascular Disease Volume and Dr. Aviva Lev Ari has selected the sub-universe of sources been elaborated on in this Chapter

There are inherent problems at looking at this from a systems point of view, mainly impacted by the relationship of providers to hospitals and clinics, and by the relationships of insurers to the patients and providers in an Accountable Care Organization (ACO) model. These relationships have been evolving for many decades, first with the increased availability of highly skilled medical specialists trained in numerous university-based programs funded by Training Grants from the National Institutes of Health, then a high concentration of these skilled physicians in metropolitan locations, where there was an adequate patient-base for developing groups of refering physicians. Prior to WWII, there were many Asian physicians receiving their postgraduate training in the U.K. The number of foreign graduates coming to the U.S. Increased enormously with the opportunities that opened up in U.S. The first change in medical education that created a science-based professional came after the Flexner Report in 1910, sponsored by the Carnegie Endowment. Many aspects of the present-day American medical profession stem from the Flexner Report and its aftermath.The Report (also called Carnegie Foundation Bulletin Number Four) called on American medical schools to enact higher admission and graduation standards, and to adhere strictly to the protocols of mainstream science in their teaching and research. Joseph Goldberger discovered the cause of pellagra in 1916.  When the 1918 influenza pandemic struck Washington, physicians from the then PHS laboratory were pressed into service treating patients in the District of Columbia because so many local doctors fell ill.

goldberger  1916  Pellagra


In 1930, the Ransdell Act changed the name of the Hygienic Laboratory to National Institute (singular) of Health (NIH) and authorized the establishment of fellowships for research into basic biological and medical problems. The roots of this act extended to 1918, when chemists who had worked with the Chemical Warfare Service in World War I sought to establish an institute in the private sector to apply fundamental knowledge in chemistry to problems of medicine. In 1926, after no philanthropic patron could be found to endow such an institute, the proponents joined with Louisiana Senator Joseph E. Ransdell to seek federal sponsorship. The truncated form in which the bill was finally enacted in 1930 reflected the harsh economic realities imposed by the Great Depression. Nonetheless, this legislation marked a change in the attitude of the U.S. scientific community toward public funding of medical research.

bengston_lg nurse in bacteriology lab of NIH


cholera_sm  cholera epidemic of 19th century  (Koch bacillus)


Vaccines and therapies to deal with tropical diseases were also critically important to the WWII war effort by the PHS. At the NIH’s Rocky Mountain Laboratory in Hamilton, Montana, yellow fever and typhus vaccines were prepared for military forces. In Bethesda as well as through grants to investigators at universities a synthetic substitute for quinine was sought to treat malaria.  Research in the Division of Chemotherapy revealed that sodium deficiency was the critical element leading to death after burns or traumatic shock. This led to the widespread use of oral saline therapy as a first-aid measure on the battlefield. NIH and military physiologists collaborated on research into problems related to high altitude flying. As the war drew to a close, PHS officials guided through Congress the 1944 Public Health Service Act, which defined the shape of medical research in the post-war world. Two provisions in particular had an impact on the NIH. First, in 1946 the successful grants program of the NCI was expanded to the entire NIH. From just over $4 million in 1947, the program grew to more than $100 million in 1957 and to $1 billion in 1974. The entire NIH budget expanded from $8 million in 1947 to more than $1 billion in 1966. Between 1955 and 1968. In this period, there was expansion of the NIH extramural budget, as well, and the grants dispursed were in support of developing the medical faculty of the future. It has nothing to do with then organization of the practice of medicine, but it has contributed much to the widespread quality of american medical education.

flowchart_sm  NIH 1949


 As the cost of healthcare was increasing, mainly after the Korean and Vietnam War periods, there was a medically initiated concept of a National not-for-profit health maintenance organization (HMO), which would be modeled after the likes of Mayo Clinic, Cleveland Clinic, the Kaiser Permanente Plan, and Geisinger. But the insurance industry was already mature, and the hospitals were closely tied to Aetna, CIGNA, and Blue Cross Blue Shields, which had the actuarial pieces needed. Then an HMO industry emerged with a for-profit motive. As the U.S. Became enmesshed in two military engagements in Iraq and Afganistan for a full decade, there was a fierce competition between the need to support military requirements and the need to support the welfare of the community, with brilliant accelerated achievements that brought the Human Genome Project to a successful conclusion in 2003, and from that emerged advances in both clinical laboratory diagnostics and imaging, and which portends to continuing significant advances in treatments in cardiology, surgery, endocrinology, and cancer. In order to succeed, there has been a redesign or rearrangement of how these services are delivered, with a business model intended to – in time – bring down costs, and to also improve quality. Ironically, there is an insufficiency of primary care physicians, even considering internal medicine, pediatrics, obstetrics, and general surgery, as well as osteopathic physicians.

Part I. The Establishment, Structure, and Nature of the Accountable Care Act (ACA)

Part II. The Implementation of the ACA, Impact on Physicians and Patients, and the Dis-Ease of the Accountable Care

Failure to Launch? The Independent Payment Advisory Board’s Uncertain Prospects

Jonathan Oberlander, Ph.D., and Marisa Morrison, B.A.
N Engl J Med 2013; 369:105-107July 11, 2013 http://dx.doi.org/10.1056/NEJMp1306051

The Affordable Care Act (ACA) established the IPAB as a 15-member, nonelected board. Among other duties, the IPAB is empowered to recommend changes to Medicare if projected per-beneficiary spending growth exceeds specified targets. If Congress does not enact legislation containing those proposals or alternative policies that achieve the same savings, the IPAB’s recommendations are to be implemented by the secretary of health and human services. President Obama has proposed strengthening the board’s role by lowering the Medicare spending targets that would trigger IPAB action.

Because the board is prohibited by law from making recommendations that raise revenues, increase cost sharing of Medicare beneficiaries, or restrict benefits and eligibility, it is expected to focus on savings from medical providers. In January 2013, the GOP adopted a House rule declaring that the IPAB “shall not apply” in the current Congress, thereby rejecting the special procedures that the ACA had established for congressional consideration of IPAB recommendations.

On April 30, the chief actuary of the Centers for Medicare and Medicaid Services released a report projecting Medicare spending growth during 2011–2015. According to the report, per-person Medicare spending will grow at an average rate of 1.15% during that period, far below the target growth rate set by the ACA — the average of the Consumer Price Index (CPI) and the Medical CPI (see graph).

8443-exhibit-2-3  increase in medicaid_CHIP all states expanding medicaid50-Graph-4-33_2012  Hospitalization Rates for Heart Failure, Ages 45–64 and 65 and Older, U.S., 1971–2010

8443-exhibit-2-7  nonelderly population uninsured52-Graph-4-35_2012  Total Economic Costs of the Leading Diagnostic Groups, U.S., 2009


Projected Growth in Medicare Per Capita Spending, the Consumer Price Index (CPI), and the Medical CPI, 2011–2015.

       healthprices  time price of HC over 50 yearsjournal.pmed.0020133.g001  Global Mortality and Burden of Disease Attributable to Cardiovascular Diseases and Their Major Risk Factors for People 30 y of Age and Older

NHEbyDCforHS1  NHE annual growth rate of 4%      percentageincreasekff  % increase in HI premiums

journal.pmed.0020133.t001   Risk and Socioeconomic Variables Used in the Analysis     T1.large  uninsured by health and disability by region 2000-2005

T3.large  uninsured by medicaid eligibility        T5  Characteristics Of Insurance, By Insurance Adequacy, Among Insured Adults Ages 19–64, 2007

The rate of increase in Medicare expenditures per enrollee has slowed since 2006, and because Medicare spending growth has moderated, the IPAB will be irrelevant to cost containment. 3 years after the ACA’s enactment, the IPAB still has no members. If no members are appointed, the power to recommend changes to Medicare when spending targets are exceeded does not disappear: it reverts to the secretary of health and human services.

The board’s appeal lies largely in its aspiration to remove politics from Medicare — to create a policymaking process that is informed by experts and insulated from pressures outside their professional overview. If Medicare spending growth accelerates, the IPAB’s role could expand. But that future is uncertain.


The Road Ahead for the Affordable Care Act

John E. McDonough, Dr.P.H.
N Engl J Med 2012; 367:199-201 http://dx.doi.org/10.1056/NEJMp1206845

The Affordable Care Act (ACA), the U.S. health care reform law enacted in 2010, was upheld as constitutional by the U.S. Supreme Court on June 28, 2012. As a result of the Court’s ruling –

  • the individual responsibility requirement (the individual mandate to obtain insurance coverage),
  • insurance reforms such as the elimination of coverage exclusions for preexisting conditions,
  • the establishment of state health insurance exchanges, and
  • the provision of private health insurance subsidies

stand unaltered despite the Court-ordered switch in the basis for constitutional legitimacy from the Commerce Clause to Congress’s taxing authority.

One consequential outcome of the ruling is the continuing benefit, and harm averted, for millions of Americans from ACA provisions that have already been implemented. Those benefiting include more than 6 million young adults enrolled in their parents’ insurance plans, 5.2 million Medicare enrollees who have saved on prescription-drug costs because of the shrinking Part D “doughnut hole,” 600,000 new adult Medicaid enrollees in seven states that have already expanded Medicaid eligibility, 12.8 million consumers who will receive more than $1 billion in insurance-premium rebates, and many others.

Also undisturbed are the ACA’s numerous system reforms, such as accountable care organizations, patient-centered medical homes, the Prevention and Public Health Fund, and the Patient-Centered Outcomes Research Institute. Since the ACA’s passage, health system innovation has surged — a dynamic that would have been undermined by a negative Court ruling.

The biggest change involves Medicaid. The ACA required that Medicaid serve nearly all legal residents with incomes below 138% of the federal poverty level. As a result, there is a new inequity in the health system: by 2014, all Americans will have guaranteed access to affordable health insurance except adults with incomes below the poverty level who were previously ineligible for Medicaid (those with incomes between 100 and 138% of the poverty level will be allowed to obtain coverage through insurance exchanges). States have strong economic incentives to expand Medicaid, since the federal government will pay 100% of expansion costs between 2014 and 2016. By 2020, the federal share will drop to no less than 90% — much more generous than the 50 to 83% that the federal government contributes for traditional Medicaid and the Children’s Health Insurance Plan.

The current implementation queue includes writing definitions and rules for private health insurance markets, clarifying rules for determining required “essential health benefits,” explaining how employer-responsibility provisions will be devised, and much more. The ACA is the first U.S. law to attempt comprehensive reform touching nearly every aspect of our health system. The law addresses far more than coverage, including health system quality and efficiency, prevention and wellness, the health care workforce, fraud and abuse, long-term care, biopharmaceuticals, elder abuse and neglect, the Indian Health Service, and other matters.

Encouraging competition among health plans, even if one of them is “public,” will also fail to solve the cost problem. With the exception of highly integrated organizations, such as Kaiser Permanente, health plans have only two tools to control costs: financial disincentives for patients and fee reductions for providers. Acceptable out-of-pocket maximums, however, vitiate economic incentives to restrain use, particularly for expensive care such as inpatient care. Unable to alter provider behavior, health plans primarily try to avoid enrolling people who are likely to need costly care.

Budget Sequestration and the U.S. Health Sector

McDonough J.E.N Engl J Med 2013; 368:1269-1271 http://dx.doi.org/10.1056/NEJMp1303266

In August 2011, in an agreement to raise the nation’s debt ceiling, bipartisan majorities in the House and Senate approved the Budget Control Act of 2011 (BCA) to reduce the deficit by $1.2 trillion between 2013 and 2021. The BCA established a threat of across-the-board cuts, or “sequestration,” if the Joint Select Committee on Deficit Reduction failed to approve, and Congress to enact, alternative reductions. Sequestration became operational on March 1. Of the $1.2 trillion in cuts, $216 billion will be reductions in debt-service payments, and the remaining $984 billion will be split evenly over 9 years at $109 billion per year, and further adjusted and split evenly between cuts to national defense and nondefense functions at $42.667 billion each.

T2.large  Adults Ages 19–64 Who Were Uninsured And Underinsured, By Various Characteristics, 2003 And 2007   T3.large  uninsured by medicaid eligibility

The $42.667 billion per year in nondefense cuts will not fall equally on all health-related government programs. Nonexempt and nondefense discretionary funding faces reductions of 7.6 to 8.2% in this fiscal year; certain programs such as Medicare and community health centers will have 2% reductions; and certain programs such as Medicaid and the Veterans Health Administration are exempt.

nejmp1303266_t1  Impact of Budget Sequestration on Key Federal Health and Safety Programs,

Impact of Budget Sequestration on Key Federal Health and Safety Programs, Fiscal Year 2013.


Medicare funding will be cut by 2% ($11.08 billion) through reductions in payments to hospitals, physicians, and other health care providers, as well as insurers participating in Medicare Advantage (Part C). The BCA prohibits cuts affecting premiums for Medicare Parts B and D, cost sharing, Part D subsidies, and Part A trust-fund revenues. The sequestration cuts arrive just as Medicare is beginning to fully implement the savings and cuts required by the Affordable Care Act (ACA), which the Congressional Budget Office estimates will slow Medicare’s rate of growth by $716 billion between 2013 and 2022. The National Institutes of Health (NIH) faces an 8.2% across-the-board reduction for the 7 months remaining in fiscal 2013, equaling cuts of $1.55 billion.

The Centers for Disease Control and Prevention (CDC), which is still recovering from major budget reductions in 2011, anticipates effective reductions of 8 to 10% for the remainder of the year. The American Public Health Association has projected that the reductions could result in 424,000 fewer HIV tests (the CDC funded 3.26 million in 2010) and 50,000 fewer immunizations for adults and children (from a baseline of about 300 million), elimination of tuberculosis programs in 11 states, and shutting down of the National Healthcare Safety Network.

Unaffected for all 9 years of the sequester are most expenses associated with the ACA. Medicaid is exempt, as is funding for its expansion, beginning next January, to all lower-income Americans in states that choose to participate. Also exempt are private insurance subsidies that will be available next January through new health insurance exchanges, because they were designed as refundable tax credits, another BCA-exempt category. Finally, the Children’s Health Insurance Plan, the Supplemental Nutrition Assistance Program, Temporary Assistance to Needy Families, and Supplemental Security Income are all exempt.

Threading the Needle ‹ Medicaid and the 113th Congress

fs310_graph3  leading causes of death by income class worldwideFUSA_INFOGRAPHIC_50-state-medicaid-expansion_rev_06-27-13_FACEBOOKCOVER

Rosenbaum S.N Engl J Med 2012; 367:2368-2369 http://dx.doi.org/10.1056/NEJMp1213901

Medicaid is a veteran of decades of warfare over its size and cost. Nevertheless, the program now plays a vital role in the U.S. health care system and a foundational role in health care reform. The central question, as we approach a major debate over U.S. spending and federal deficits, is how to preserve this role and shield Medicaid from crippling spending reductions. The Budget Control Act, which provides the initial framework for this debate, insulates Medicaid from sequestration. Budgetary protections for Medicaid date to the 1980s, but today’s politics are less tolerant of programs for poor and vulnerable populations. Medicaid is also at a deep political disadvantage. Medicaid is unequaled among federal grant programs: more than 60 million children and adults rely on the program, and it’s projected to grow to 80 million beneficiaries by 2020 if all states adopt the eligibility expansion in the Affordable Care Act (ACA). Medicaid’s cost is driven by high enrollment, not excessive per capita spending.2 As a result, there’s very little money to wring out of Medicaid without shaking its structure in ways that reduce basic coverage. Medicaid is part of the base on which health care reform rests; if it is not expanded per the ACA, the nation will lose its chance at near-universal health insurance coverage, which is essential to achieving systemwide savings and halting a $50 billion annual cost shift to insurers and patients. Deep federal spending reductions could lead states to abandon Medicaid expansion as a result of a confluence of factors —

  • the still-fragile nature of many state economies,
  • the continuing ideological opposition to Medicaid expansion, and
  • the Supreme Court decision to permit states to opt out of such expansion altogether.

Considerable evidence shows its effectiveness: most recently, a study by Sommers et al. documented its positive effects on health and health care. Experts in Medicaid spending also acknowledge the program’s operational efficiencies, achieved by states through the aggressive use of managed care and strict controls on spending for long-term care. Much of the health care that Medicaid beneficiaries receive is furnished through safety-net providers such as community health centers, which are highly efficient and accustomed to operating on tight budgets with only limited access to costly specialty care. Furthermore, Medicaid’s physician payments are substantially lower than those from commercial insurers and Medicare — a disparity that unfortunately limits provider participation even as it helps to keep per capita spending low. Indeed, the CBO has found that insuring the poor through Medicaid will cost 50% less per capita than doing so through tax-subsidized private insurance plans offered through state health insurance exchanges.

nejmp1306051_f1  Projected Growth in Medicare Per Capita Spending, the Consumer Price Index (CPI), and the Medical CPI, 2011–2015

The essential task is to thread the needle by accelerating efficiency reforms in health care payment and organization that, in turn, can generate savings over time while not damaging Medicaid’s role as a pillar of health care reform. Of particular importance is a heightened focus, begun under the ACA, on reforms that emphasize community care for millions of severely disabled children and adults, including patients who are dually enrolled in Medicare and Medicaid and who rely heavily on long-term institutional care.

The Shortfalls of ‘Obamacare’

Wilensky G.R. N Engl J Med 2012; 367:1479-1481 http://dx.doi.org/10.1056/NEJMp1210763

U.S. health care suffers from three major problems: millions of people go without insurance, health care costs are rising at unaffordable rates, and the quality of care is not what it should be. The Affordable Care Act (ACA) primarily addresses the first — and easiest — of these problems by expanding coverage to a substantial number of the uninsured. Solutions to the other two remain aspirations. The ACA’s primary accomplishment is that approximately 30 million previously uninsured people may end up with coverage — about half with subsidized private coverage purchased in the mostly yet-to-be-formed state insurance exchanges and the other half through Medicaid expansions. The law’s most controversial provision remains the individual mandate, which requires people either to have insurance coverage or to pay a penalty. The penalty for not having insurance is very small, particularly for younger people with modest incomes. It would have been smarter to mimic Medicare’s policies: seniors who don’t purchase the voluntary parts of Medicare covering physician services and outpatient prescription drugs during the first year in which they lack comparable coverage must pay a penalty for every month they have gone without coverage whenever they finally do purchase it.

Despite widespread recognition that fee-for-service reimbursement rewards providers for the quantity and complexity of services and encourages fragmentation in care delivery, the ACA retains all the predominantly fee-for-service reimbursement strategies currently used in Medicare. Much of the coverage expansion is financed through Medicare budget savings, which are produced by reducing the fees paid by Medicare to institutional providers such as hospitals, home care agencies, and nursing homes — but using the same perverse reimbursement system currently in place. Reducing payments to institutional providers should not be confused with lowering the cost of providing care.

The ACA also provides Medicare “productivity adjustments,” which assume that inflation adjustments can be reduced over time because institutions will become more productive, whether or not hospitals and other providers actually find ways to increase their productivity. Unless these institutions find ways to reduce costs, lower Medicare reimbursements will force providers to bargain for higher payments from private insurers. And eventually, seniors’ access to services will be threatened. The Medicare actuary expects that 15% of institutional providers will lose money on their Medicare business by 2019, and the proportion will increase to 25% by 2030 — a situation that he calls unsustainable

Most troubling, the ACA contains no reform of the way physicians are paid, which is the most dysfunctional part of the Medicare program. Through the Resource-Based Relative Value Scale, physicians are reimbursed on the basis of service codes, and payment for each physician service is reduced whenever aggregate spending on physician services exceeds a prespecified limit. This system disregards whether clinicians are providing low-cost, high-value care for patients. Given physicians’ key role in providing patient care, it’s impossible to imagine a reformed delivery system without one that rewards them for providing clinically appropriate care efficiently.

What is needed are reforms that create clear financial incentives that promote value over volume, with active engagement by both consumers and the health care sector. Market-friendly reforms require empowering individuals, armed with good information and nondistorting subsidies, to choose the type of Medicare delivery system they want. Being market-friendly means allowing seniors to buy more expensive plans if they wish, by paying the extra cost out of pocket, or to buy coverage in health plans with more tightly structured delivery systems at lower prices if that’s what suits them. 

Financing Graduate Medical Education — Mounting Pressure for Reform

John K. Iglehart N Engl J Med 2012; 366:1562-1563 http:dx.doi.org/10.1056/NEJMp1114236

Disparate voices from the White House, a national fiscal commission, Congress, a Medicare advisory body, private foundations, and academic medical leaders are advocating changes to Medicare’s investment in graduate medical education (GME), which currently totals $9.5 billion annually. They offer various prescriptions, including reducing federal support, developing new achievement measures for which GME programs should be held accountable, and seeking independent assessment of the governance and financing of training programs.

The influential GME community has withstood most past efforts to change Medicare’s GME policies. But recognizing today’s more challenging political environment, the Association of American Medical Colleges (AAMC) has begun discussing alternative methods of financing GME that could better align training with the future health care delivery system and address U.S. workforce needs. The association is also examining the influence of student debt on the enrollment of a diverse student body.

When Congress enacted Medicare in 1965, it assigned to the program functions that reached well beyond its mission of financing health care for the elderly. One function was supporting GME, at least until the society at large undertook “to bear such education costs in some other way.” Almost 50 years later, Medicare remains the largest supporter of GME, providing both direct payments to hospitals that cover medical education expenses related to the care of Medicare patients (about $3 billion per year) and an indirect medical education (IME) adjustment to teaching hospitals for the added patient-care costs associated with training (about $6.5 billion).

In its 2013 budget, unveiled on February 13, 2012, the Obama administration proposed reducing Medicare’s IME adjustment by $9.7 billion over 10 years, beginning in 2014, citing a report from the Medicare Payment Advisory Commission (MedPAC) indicating that Medicare’s IME adjustments “significantly exceed the actual added patient care costs these hospitals incur.” The administration also proposed that the secretary of health and human services be granted the authority to assess GME programs’ performance in instilling in residents the necessary skills to promote high-quality health care. Similarly, MedPAC had recommended redirecting about half the IME adjustments ($3.5 billion) into “incentive payments” that GME programs could earn by meeting performance standards. The Obama budget would also eliminate coverage of the IME expenses of free-standing children’s hospitals with pediatric residency programs — which do not treat Medicare patients — reducing their federal support by 66% (to $88 million). Moreover, Congress has revealed its uncertainty over how to change federal workforce policy. In the Affordable Care Act (ACA), Congress emphasized the importance of expanding the primary care workforce. But legislators rejected the AAMC’s call to expand the number of Medicare-funded GME positions by 15% in response to reported physician shortages in some specialties.

On December 21, seven senators — Democrats Michael Bennet (CO), Jeff Bingaman (NM), Mark Udall (CO), and Tom Udall (NM) and Republicans Mike Crapo (ID), Chuck Grassley (IA), and Jon Kyl (AZ) — sent a letter to the Institute of Medicine (IOM) encouraging it to “conduct an independent review of the governance and financing of our system of [GME].” They urged the IOM to explore subjects including accreditation; reimbursement policy; the use of GME to better predict and ensure adequate workforce supply in terms of type of provider, specialty, and demographic mix; GME’s role in care of the underserved; and use of GME to ensure the creation of a workforce with the skills necessary for addressing future health care needs. The senators emphasized their interest “in IOM’s observations about the uneven distribution of GME funding across states based on need and capacity, and how to address this inequity.” In an interview, Bingaman said he initiated the letter for the same reasons he had championed creation of a National Health Care Workforce Commission as part of the ACA: to strengthen the government’s resolve to do “a more credible job of assessing workforce shortages” and because he believes Medicare’s GME policies are “outmoded.”

The priorities cited in the IOM letter parallel some of the recommendations of a group of academic medical leaders who gathered at two conferences underwritten by the Josiah Macy Jr. Foundation. At the first conference, in October 2010, the top recommendation was that “an independent external review of the goals, governance, and financing of the GME system should be undertaken by the Institute of Medicine, or a similar body.”3 George Thibault, president of the Macy Foundation, says the group concluded that “because GME is a public good and is significantly financed with public dollars, the GME system must be accountable to the needs of the public.” Acknowledging that some people in academic medicine “favor a behind-the-scenes discussion of GME reform alternatives,” Thibault noted, “I believe we should be upfront, providing examples of change that could influence the thinking of policymakers.” The foundation awarded the IOM $750,000 — about half the support it needs for the GME study.

Among subjects under discussion are the collection of more data highlighting the importance of the safety-net functions and unique services of academic medical centers and the creation of a long-term vision for GME financing that is more closely aligned with emerging care delivery models, such as accountable care organizations. The association is also revisiting a potential financial model under which all health care payers would explicitly cover GME expenses. Private insurers maintain that they accomplish this implicitly by paying teaching hospitals more for clinical services than they pay most other hospitals. GME leaders think one possibility would be to include the costs of residency training when calculating premium amounts for products sold through health insurance exchanges. Similarly, a recent Carnegie Foundation report asserted that “GME redesign demands . . . a more broad-based, less politicized flow of funds.”

Dr. Darrell Kirch noted, CEO of AAMC, “A significant step forward is the announcement by the ACGME [Accreditation Council for Graduate Medical Education] describing major changes in how the nation’s residency programs will be accredited in the future, putting in place an outcomes-based evaluation system by which new physicians will be measured for their competency in performing the essential tasks necessary for clinical practice in the 21st century.”

Achieving Health Care Reform — How Physicians Can Help

Elliott S. Fisher, M.D., M.P.H., Donald M. Berwick, M.D., M.P.P., and Karen Davis, Ph.D.
N Engl J Med 2009; 360:2495-2497 http://dx.doi.org/10.1056/NEJMp0903923

The recent commitment by several major stakeholders — including the American Medical Association — to slowing the growth of health care spending is a promising development. But the controversy about whether the organizations actually agreed to a 1.5-percentage-point reduction in annual spending growth is just one indication that success is still far from assured.

Two threats in particular put reform at risk: conflicting doctrines (regarding the creation of a new public insurance option and government support for comparative-effectiveness studies) and opposition to change among some current stakeholders. In the face of this uncertainty, physicians have a choice: to wait and see what happens or to lead the change our country needs. We’d prefer the latter.

The first level is aims. For health care reform, we propose that physicians, through their advocacy, help lead the country to embrace the so-called triple aim: better experience of care (safe, effective, patient-centered, timely, efficient, and equitable), better health for the population, and lower total per capita costs.

The second level is the design of the care processes that affect the patient — clinical “microsystems.” Health care microsystems are famously unreliable, variable in costs, and often unsafe. Physicians, through their participation in quality-improvement initiatives in their practices and hospitals, can and should lead the needed changes in the systems of care in which they work, to make them safer, more reliable, more patient-centered, and more affordable.

However, neither physicians nor anyone else on the front lines can improve care much on their own. Their most important source of support for improvement is the third level described by the IOM — the health care organizations that house almost all clinical microsystems and can ensure coordination among them. We need organizations large enough to be accountable for the full continuum of patients’ care as well as for achieving the triple aim. We will create a high-performing health care system only if integrated delivery systems become the mainstay of organizational design. Organizations could be virtually integrated, such as networks of independent physicians sharing electronic health records and administrative and clinical support for care management and quality improvement, or structurally integrated, such as multispecialty group practices or staff-model health maintenance organizations. Fostering the development of such accountable care organizations need not be disruptive to patients or providers: almost all physicians already work within natural referral networks that provide the vast majority of care to patients seen by the primary care physicians within the network.


The IOM’s fourth level is the environment, which includes the payment, regulatory, legal, and educational systems. On this front, too, we need physician advocacy. The United States cannot achieve the triple aim without health insurance for everyone. Integrated delivery systems that are accountable for populations won’t thrive unless payment systems encourage their development and unless we change the laws and regulations — including proscriptions of gainsharing and anti-kickback rules — that prevent cooperation among health care professionals and organizations.

If stakeholders can agree on such a vision of health care reform, perhaps we could shift our focus from the conflict over whether a new public plan should be created to a more constructive insistence that all health plans, whether public or private, focus on the development of professionally led, integrated systems.

If health care providers and suppliers could actually achieve this reduction in growth rates, the federal government would harvest about $1.1 trillion in savings over the 11-year period — enough, perhaps, to close the deal on affordable health insurance for all. Others would also see savings: $497 billion for employers, $529 billion for state and local governments, and $671 billion for households. One simple way for physicians to start contributing to this goal is by reassessing and scaling back, where appropriate, their use of clinical practices now listed as “overused” by the National Quality Forum’s National Priorities Partnership.

Editor-in-Chief Eric J. Topol, MD, interviews Secretary of Health and Human Services (HHS) Kathleen Sebelius


Editor’s Note: On the eve of the first anniversary of the Supreme Court’s ruling to uphold most provisions of the Affordable Care Act (ACA), Medscape Editor-in-Chief Eric J. Topol, MD, questioned Secretary of Health and Human Services (HHS) Kathleen Sebelius about the act’s effect on medical technology, clinical trial participation, genetic testing, primary care, and patient safety.


Dr. Topol: We are experiencing a digital revolution in which technological advances are putting healthcare where it should be: in the hands of patients. How is the ACA helping to foster medical innovation?
Secretary Sebelius: A recent New York Times column, “Obamacare’s Other Surprise,”[1] by Thomas L. Friedman, echoes what we’ve been hearing from healthcare providers and innovators: Data that support medical decision-making and collaboration, dovetailing with new tools in the Affordable Care Act, are spurring the innovation necessary to deliver improved healthcare for more people at affordable prices.
Today we are focused on driving a smarter healthcare system with an emphasis on the quality — not quantity — of care. The healthcare law includes many tools to increase transparency, avoid costly mistakes and hospital readmissions, keep patients healthy, and test new payment and care delivery models, like Accountable Care Organizations (ACOs). Health information technology is a critical underpinning to this larger strategy.
In May we reached an important milestone in the adoption of health information technology. More than half of all doctors and other eligible providers, and nearly 80% of hospitals, are using electronic health records (EHRs) to improve care, an increase of at least 200% since 2008. Also in May, we announced a $1 billion challenge to help jump-start innovative projects that test creative ways to deliver high-quality medical care and lower costs to people enrolled in Medicare and Medicaid, following 81 Health Care Innovation Awards that HHS awarded last year.
Dr. Topol: Physicians have long lamented the lack of participation by patients in clinical trials, but the ACA is opening the door for greater participation by allowing patients to keep their health insurance while participating in clinical research. Are patients even aware that this provision now exists? How do you see it affecting clinical trial participation in the future?
Secretary Sebelius: In 2014, thanks to the ACA, insurance companies will no longer be able to deny patients from participating in an approved clinical trial for treatment of cancer or another life-threatening disease or condition, nor can they deny or limit the coverage of routine patient costs for items or services in connection with trial participation. For many patients, access to cutting-edge medicine available through clinical trials can increase their likelihood of survival. This is an important protection for patients that not only could have a life-altering impact, but it’s also one that serves to facilitate participation in research that is critical to expanding our knowledge base and finding cures and treatments for those illnesses that threaten the lives of Americans each day.
Dr. Topol: One of the intentions of the ACA is to increase the primary care workforce. This is critical as we approach 2014, when more Americans than ever will have either private insurance or Medicaid. Have you seen any movement in the primary care workforce? Are there concerns that there aren’t enough clinicians available to meet the forthcoming patient load?
Secretary Sebelius: Primary care providers are critical to ensuring better coordinated care and better health outcomes for all Americans. To meet the health needs of Americans, the Obama Administration has made the recruitment, training, and retention of primary care professionals a top priority.
Together, the ACA, the American Recovery and Reinvestment Act of 2009, and ongoing federal investments in the healthcare workforce have led to significant progress in training new primary care providers — such as physicians, nurse practitioners, and physician assistants — and encouraging primary care providers to practice in underserved areas, including:
Nearly tripling the National Health Service Corps;
Increasing the number of medical residents, nurse practitioners, and physician assistants trained in primary care, including placing over 1500 new primary care providers in underserved areas;
Creating primary care payment incentives for providers; and Redistributing unused residency positions and directing those slots for the training of primary care physicians.
Additionally, the ACA is modernizing the primary care training infrastructure, creating new primary care clinical training opportunities, supporting primary care practice, and improving payment and financial incentives for coordinated care.
Improving Hospital Safety
Dr. Topol: George Orwell once said that the hospital is the antechamber to the tomb. That was written decades ago, and unfortunately there’s still truth to that today. One in 4 hospital patients in America have a problem with medical mistakes, contract hospital-acquired infections, and experience medication errors. The ACA last year began linking Medicare payments to quality of patient care, offering financial incentives to hospitals that improve patient care. How is this working? Have there been any meaningful care improvements over the past year?
Secretary Sebelius: The ACA includes steps to improve the quality of healthcare and, in so doing, lowers costs for taxpayers and patients. This means avoiding costly mistakes and readmissions, keeping patients healthy, rewarding quality instead of quantity, and creating the health information technology infrastructure that enables new payment and delivery models to work. These reforms and investments will build a healthcare system that will ensure quality care for generations to come.
Already we have made significant progress:
Healthcare Spending Is Slowing
Secretary Sebelius: Medicare spending per beneficiary grew just 0.4% per capita in fiscal year 2012, continuing the pattern of very low growth in 2010 and 2011. Medicaid spending per beneficiary also decreased 0.9% in 2011, compared with 0.6% growth in 2010. Average annual increases in family premiums for employer-sponsored insurance were 6.2% from 2004 to 2008, 5.6% from 2009 to 2012, and 4.5% in 2012 alone.
Health Outcomes Are Improving and Adverse Events Are Decreasing
Secretary Sebelius: Several programs tie Medicare reimbursement for hospitals to their readmission rates, when patients have to come back into the hospital within 30 days of being discharged. Additionally, as part of a new ACA initiative, clinicians at some hospitals have reduced their early elective deliveries to close to zero, meaning fewer at-risk newborns and fewer admissions to the NICU.
Providers Are Engaged
Secretary Sebelius: In 2012, we debuted the Medicare Shared Savings Program and the Pioneer Accountable Care Organization Model. These programs encourage providers to invest in redesigning care for higher-quality and more efficient service delivery, without restricting patients’ freedom to go to the Medicare provider of their choice.
Over 250 organizations are participating in Medicare ACOs, serving approximately 4 million, or 8%, of Medicare beneficiaries. As existing ACOs choose to add providers and as more organizations join the program, participation in ACOs is expected to grow. ACOs are estimated to save up to $940 million in the first 4 years.
Bundle with Care ‹ Rethinking Medicare Incentives for Post­Acute Care Services

Feder J. N Engl J Med 2013; 369:400-401

A Medicare payment approach in which savings and risk are shared may achieve a better balance of cost, quality, and access than a system of single bundled payments, at least until our capacity to measure patients’ care needs and outcomes is sufficiently robust.

Healthcare Reform 2014: Mandated Coverage, Insurance Exchanges, and Employer Requirements

3 of 5 in Series: The Essentials of Healthcare Reform

The Affordable Care Act federal and state officials are working with leaders in the health and insurance industries to restructure our nation’s healthcare system. That restructuring means most Americans will be required to have health insurance and most businesses will be required to offer it to their employees. It also means the creation of another kind of insurance plan called a health insurance exchange.

The government will require most Americans to have health insurance by 2014. The government has enacted this provision as a way to get healthy people who don’t feel the need to pay for coverage to buy insurance. That way, the healthy people can help fund the cost of people who require more medical care.

Several states filed, and lost, a suit against the federal government saying that it is unconstitutional to make individual citizens to buy health insurance.

If you don’t have coverage and you’re not in one of the groups that is an exception to the rule, you’ll pay a penalty. You may not be required to purchase health insurance if you

  • Face financial hardships.
  • Have been uninsured for less than three months.
  • Have religious objections.
  • Are American Indian.
  • Are a prison inmate.
  • Are an undocumented immigrant.

If you’re penalized, the amount you’ll be fined will go up each year for the first three years. In 2014, you’ll pay $95 or 1 percent of your taxable income, whichever is greater. In 2015, the fine will be $325 or 2 percent of taxable income, and in 2016 the penalty will be $695 or 2.5 percent of income. Each year after 2016, the government will refigure the fine based on a cost-of-living adjustment.

To help you meet the cost of mandated insurance, the government will offer premium credits and cost sharing subsidies if you and your family meet certain income guidelines and if you enroll in one of the new state-run insurance exchanges.

If your income falls between 133 and 400 percent of the federal poverty level (FPL), you could receive premium credits that will lower the maximum amount of premium you have to pay for your coverage.

  • There will be a catastrophic plan for people under 30 and for those who are exempt from mandated coverage.

States don’t have to set up the exchanges. If a state chooses not to, the federal government can come in and create them. States that do opt for exchanges will decide whether they’ll be run by a government or not-for-profit entity.

Health Care Reform — Why So Much Talk and So Little Action?

Victor R. Fuchs, Ph.D
N Engl J Med 2009; 360:208-209 http://dx.doi.org/10.1056/NEJMp0809733

First, many organizations and individuals prefer the status quo. This category includes health insurance companies; manufacturers of drugs, medical devices, and medical equipment; companies that employ mostly young, healthy workers and therefore have lower health care costs than they would if required to help subsidize care for the poor and the sick; high-income employees, whose health insurance is heavily subsidized through a tax exemption for the portion of their compensation spent on health insurance; business leaders and others who are ideologically opposed to a larger role of government; highly paid physicians in some surgical and medical specialties; and workers who mistakenly believe that their employment-based insurance is a gift from their employer rather than an offset to their potential take-home pay.

Second, as Niccoló Machiavelli presciently wrote in 1513, “There is nothing more difficult to manage, more dubious to accomplish, nor more doubtful of success . . . than to initiate a new order of things. The reformer has enemies in all those who profit from the old order and only lukewarm defenders in all those who would profit from the new order.”

Third, our country’s political system renders Machiavelli’s Law of Reform particularly relevant in the United States, where many potential “choke points” offer opportunities to stifle change. The problem starts in the primary elections in so-called safe congressional districts, where special-interest money can exert a great deal of influence because of low voter turnout. The fact that Congress has two houses increases the difficulty of passing complex legislation, especially when several committees may claim jurisdiction over portions of a bill. Also, a supermajority of 60% may be needed to force a vote in the filibuster-prone Senate.

Fourth, reformers have failed to unite behind a single approach. Disagreement among reformers has been a major obstacle to substantial reform since early in the last century. According to historian Daniel Hirshfield, “Some saw health insurance primarily as an educational and public health measure, while others argued that it was an economic device to precipitate a needed reorganization of medical practice. . . . Some saw it as a device to save money for all concerned, while others felt sure that it would increase expenditures significantly.” These differences in objectives persist to this day.

Health insurers are opening stores alongside department stores, other typical mall tenants.

Jayne O’Donnell , USA TODAY

,The new health law known as the Affordable Care Act means most uninsured Americans are required to have insurance beginning March 31 or pay a penalty at tax time in 2015.

Insurers need to sign up as many healthy, younger people as they can to pay for all of the older, sick customers they will be taking on. The law prohibits insurers from denying people insurance because of pre-existing health problems and limits how much more they can charge older than younger people.

So, for the first time, insurers are fiercely competing to attract individual consumers and turning to traditional retail marketing techniques to do so, luring them into stores with special events and using splashy advertising. As any retailer knows, they have the greatest chance of converting shoppers to customers once they have them in their retail locations or on their sites.

The Medical Breakthrough Nobody’s Talking About

Toby CosgroveCEO and President at Cleveland Clinic


The latest medical breakthrough hasn’t gotten much press, but it’s changing medicine even as we speak. It’s the dawning realization that healthcare is not about how many patients you can see, how many tests and procedures you can order, or how much you can charge for these things. The breakthrough is the understanding that healthcare is a value proposition, which means getting patients the right care, at the right time, in the right place. It’s a matter of focusing on outcomes and cost, so that more Americans will start getting what they pay for in healthcare dollars.

Value-based care focuses on two targets: outcomes and cost. Until recently, providers pursued these goals separately, with doctors concentrating on outcomes and the administrators trying to control costs. Value-based care does something different. It works to bring these targets into alignment. The caregivers in a value-based provider work with cost-experts as a team to simultaneously improve outcomes and lower expenses.

Doctors, hospitals and payers are partners in the move to value-based care. The Affordable Care Act includes incentives for providers to improve outcomes and lower costs. But this is one breakthrough that will take time for implementation nationwide. Providers who make the transition early will be rewarded with more satisfied patients, lower expenses and pride in a job well done.

Six-Month Enforcement Delay After Guidance

According to AAMC, the language in the final rule requires that the order to admit a patient be written by a practitioner “who has admitting privileges at the hospital,” something that few residents have as they are not considered members of the hospital’s medical staff.

AAMC said it brought the issue to CMS’s attention during an Open Door Forum call Aug. 15. The agency acknowledged it did not intend to prohibit residents from admitting patients, and said it would be issuing a Q&A. However, AAMC said until the issue can be resolved “to the satisfaction of the teaching hospital community,” CMS should make clear to all contractors that no inpatient admission should be denied because it was ordered by a resident while under the supervision of an attending physician.

AAMC said CMS should delay enforcing the new requirements for at least six months following the release of the guidance so hospitals will have sufficient time to understand the rules, educate physicians and others, and ensure that they have put in place the mechanisms that are needed to comply with the new requirements.

“As short inpatient stays have been a focus of audits by [Recovery Audit Contractors], hospitals feel especially at risk for failure to properly implement CMS requirements,” AAMC said.

The letter is available at http://op.bna.com/hl.nsf/r?Open=nwel-9auqls.

Read Full Post »

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED 6/5/2013

GenomeWeb Feature: Researchers Weigh in on Grants in the Time of Sequester

June 05, 2013

NEW YORK (GenomeWeb News) – When Nicholas Navin’s R01 grant to use single-cell sequencing to study tumor evolution in breast cancer was first funded in 2012, it was funded at 83 percent of the requested budget.

Because of the sequester, Navin’s grant now will be cut a further 6 percent. In addition, he has only been given funding for the next three months.

“After those three months, I assume that it will continue to be funded for the rest of the year,” said Navin, an assistant professor at the University of Texas MD Anderson Cancer Center, “but they only give you enough funding to support you for three months.”

The sequester — the across-the-board cuts to the US budget that were implemented at the beginning of March — has led to budget decreases across the federal government, including at research funding agencies like the National Institutes of Health and the National Science Foundation. The cuts exacerbated what was seen by many as an already tight funding situation that was not keeping pace with inflation, making it increasingly difficult for researchers to fund their work.

Steven Salzberg, a professor at Johns Hopkins University School of Medicine, recently had a grant rejected that was ranked in the top 11th percent of applications. In the past, he’s had grants funded that were in the 16th percentile or 17th percentile.

“They are funding, one would hope, grants at the 11th percentile, but not this particular one,” he said. “So you have to resubmit it or you can give up. Those are your two choices.”

As budgets decline and competition for grants increase, researchers are submitting more proposals and are beginning to look elsewhere for funding. At the same time, they are wondering what the effect of sequestration will be on science and scientists, particularly early career investigators. Still, there are steps investigators can take to try to get their proposal to stand out.

Cuts and effect

Because of the sequester, both NIH and NSF have seen their budgets fall about 5 percent. For this fiscal year, NIH’s budget is about $29.15 billion, as compared to $30.86 billion for fiscal year 2012. At the same time, NSF has about $6.9 billion for 2013, compared to last year’s $7.0 billion.

To cope with these decreases, NIH has cut all noncompeting renewals by 4.5 percent, but other changes were mostly left up to the various institutes that comprise NIH. For example, NHGRI, like other parts of NIH, is cutting noncompeting renewals, but it is not touching small grants, which it defines as ones with commitments of $250,000 or less and that typically are funded through R03 or R21 mechanisms. In addition, NHGRI won’t be giving future inflationary increases to competing applications.

“NHGRI deals with such a relatively small number of grants that we can look at each one individually and make decisions on the basis of how that particular application addresses institute aims and what the application needs in order to be successful,” Mark Guyer, the deputy director of NHGRI, told GenomeWeb Daily News. “Almost everything we do is really on a case-by-case basis beyond the across-the-board cuts to non-competing.”

The sequester, though, comes on the heels of years of small increases to funding agencies’ budgets. While the NIH budget went through an unprecedented doubling between about 1998 and 2003, it has since languished, with increases that typically did not keep pace with inflation.

“The field generally was in dire straits [heading into the sequester], given the very low payline by NIH, for example, and even NSF,” said Sarah Tishkoff, a professor at the University of Pennsylvania.

Salzberg noted that the two NIH R01 grants that he already has — awarded prior to the sequester — were cut about 15 percent to 20 percent. This, he added, was done “administratively because of budget reasons, not because of the peer review.”

“Now [the sequester] comes along and makes it even worse,” Tishkoff added.

Overall, NIH has estimated that it will fund nearly 8,300 competing research grants for FY2013, a decrease of about 700 from last year.

NHGRI also said that, in the face of the sequester, it is aiming to keep the average size of the awards it makes for FY2013 similar to the sizes of those it gave out in FY2012 — meaning that it will be giving out fewer total awards. Competition for grants, then, will become increasingly competitive.

“The [scientific] opportunities over the last decade at least and certainly into the foreseeable future are increasing hand over fist … and available funding is not keeping up with that,” Guyer said. “So necessarily things have gotten more competitive, and the sequester approach to managing the federal budget has only exacerbated the competitive aspects of things.”

As fewer proposals get funded and there’s less money to go around, many investigators may find themselves submitting more proposals to a number of funders.

“I am looking at submitting [more] proposals because it looks like funding is tight, and it is going to remain tight,” Salzberg told GWDN. “Unfortunately this produces a vicious cycle where many of us feel like our chances of getting funded are lower, therefore we should submit more proposals, but that then in return reduces the percentage that gets funded.”

It also increases the amount of time researchers spend reviewing proposals.

Others are looking to supplement their funds by turning to alternative funding sources. Navin, for example, is looking at private foundations and other organizations that fund cancer research, such as the Susan G. Komen Foundation or the Damon Runyon Cancer Research Foundation.

There, he said, he may have a few options given that he studies breast cancer. Other researchers, he noted, may not have such options. “I know some of my colleagues that work on colon cancer or some of the more rare cancers like testicular cancer or bladder cancer, they really have a hard time finding funding now,” he said.

In addition, cuts and uncertainty about future reductions in funding could make a lab a precarious place. After such budget cuts or in anticipation of cuts, some labs have slowed down their growth or have even begun to let people go.

Salzberg said that, as a computational biologist, his main expenses are the salaries of the students, postdocs, and staff who power his lab.

“[The funding situation] also makes me much more reluctant to hire postdocs or any new staff because I don’t have any more money coming in. You need more money to hire new people,” he said. He added that he still gets a number of requests from people looking for positions, but “I don’t have the funding for a new postdoc. Until I get some new funding that’s what I’ll keep saying.”

“I’ve seen [colleagues’] grants just get slashed by huge amounts,” Tishkoff added, noting that she’s seen technicians beginning to lose their jobs.”[Investigators] either have to cut some of the staff or they have to cut one of the aims.”

And as grant budgets are cut, researchers have to accomplish their research aims with less, and this often means cutting back on some of the science they would like to have done.

“Because they cut the budget, you have to cut the scope,” Salzberg said. “You still do the work, but you don’t do all the things that you want to do.”

Navin, for example, is looking to use a smaller study size, even though that’ll affect the statistical power of his work.

And that’s for the grants that get funded.

“Some projects just aren’t getting done,” Salzberg added. “[My grant] that wasn’t funded was a different project and we’re not going to do it.”

This, he said, may lead to delays in improvements to healthcare. New treatments and drugs will come, he said, but it may be in 20 years rather than in 10 years or 15 years.

Concern for new investigators

One common fear is that the sequester will disproportionately affect new investigators as they try to start labs and fund them or even dissuade them from pursuing a career in academia.

“It looks like it is disturbing a lot of young people and influencing the way that they are thinking about a potential career,” Guyer said.

Tishkoff added that she is worried that junior scientists will see how the more senior people are struggling to find funding, and opt out. “[New investigators] have to get grants if they want to get tenure. They have to get grants to be successful and to continue to be a scientist in the future,” she said.

“That’s the question that I get over and over again” from students and postdocs, Navin added. “What’s it going to be like in … five to 10 years?”

“I try to stay optimistic and tell them that there will be funding, but it is hard to predict the future,” he said.

Still, junior scientists may look for careers in industry or outside of the research realm.

“I think that when they hear all of this gloom and doom talk going on, it is really discouraging them. And that makes me really worried that we are losing talented scientists,” Tishkoff said. She added that she’s noticed that people with computational biology or bioinformatic backgrounds seem to be heading to industry.

Salzberg added that the field may never even know what it is losing. “People will leave the field — they won’t announce it — they just go get a job doing something else,” he said. “Generally, you lose that [talent] forever because that person doesn’t come back.”

Funding agencies like NIH do have mechanisms in place to try to help new investigators get grants. For example, proposals from new investigators are reviewed separately from ones submitted by established PIs. That way, early-career researchers compete against each other, rather than against those with more experience.

Further, in its policy statement for this fiscal year, NIH said that it would continue to support new investigators applying for R01 grants with success rates similar to those of established PIs.

“I really think they are doing as much as they can, but there is a bottom line,” Tishkoff noted. “If you do not have the money to give out, then it is going to be more and more and more competitive. That’s just how it is.”

NHGRI, in its own policy statement, said that it is “very flexible” in supporting early-stage investigators by not reducing recommended budgets if possible, by giving special consideration when applying for renewals to avoid gaps in funding, and by its Pathway to Independence Awards, which are targeted to postdocs who are moving toward running their own lab.

Outside of federal support, there are also a number of grants that specifically fund new investigators, such as the David and Lucile Packard Foundation Fellowships for Science and Engineering, Burroughs Wellcome Fund Career Awards, or the Sloan Research Fellowship, among others.

Tips for getting a grant

With increased competition for a smaller pot of money, submitting a well-crafted grant proposal might help it stick out from the rest in the pile. While some researchers may be quickly churning out as many proposals as they can, Tishkoff said that approach may not be the best one.

“The fact is it’s now even more competitive, it is even more important that people are taking time to really work on the grants carefully and not try to rush through them,” she told GWDN.

Still, submit a proposal quickly. “Don’t wait to apply for your first grant,” Salzberg said. “Very few people get funded on their first time around. You learn a lot from the reviews you get back.”

For his first grant, Salzberg partnered with a senior colleague to be a co-PI on the grant. “You can learn a lot about grantsmanship that way,” he said. “And then if the senior colleague gets funded, then you get some money out of that.” In addition, “you also learn some of the administrative hoops.”

Once on a grant, investigators begin to be invited to review panels that evaluate such grant proposals. “That’s a very valuable experience,” Salzberg said. “The first couple of times you are on a review panel, you learn a tremendous amount because you see a lot of other people’s grant applications and you see what the reviewers are saying about them.”

Tishkoff said one common problem she’s seen, particularly among new investigators, is that the proposals can feel hurried and too full of jargon. “You’ve got to take your time, write clearly in a manner that a general scientist can understand,” she said, adding that investigators have to sell their idea to a “broad scientific audience [and] make the point of why it is cutting edge and important and advances the field.”

Having other, more senior people look over a proposal is often a key step, she added, saying that she’s seen applications in which there were simple errors like numbers not adding up that could have easily been avoided by having someone else take a look at it.

An oft-overlooked step, by new and established PIs alike, is getting in touch with their program officers. “Start out talking to NIH program people as soon as possible,” Guyer said.

Program officers can provide information on funding mechanisms, initiatives, and budgets, and offer feedback on how project ideas fit within institutes’ priorities. “And we think, at least we tell ourselves, that it can help save people a lot of wasted time,” he added.

Tishkoff said that she typically calls up her program officer when she’s thinking about and applying for a grant to see how her idea fits with what the institute is interested in funding and to discuss a potentially reasonable budget.

“You could say, ‘I am thinking about applying for this, this, and this. Is that something that you or this institute would be interested in funding?'” she said. “And so you can try to aim to make your proposal fit with what their goals are at the moment.”

“Secondly, I always tell them, ‘OK, here’s the budget I have in mind. Is that going to be realistic or not?'” she added.

And once, she said, she was told her budget for what she called an “all-in-one, big giant grant” was too high to be funded. Instead, Tishkoff broke that large, all-inclusive grant into smaller, more focused projects, and she stripped the budgets to the bare bones.

However, not all proposals will be funded, even well-written ones. “There’s no magic bullet here, though, it’s just times are tough,” Salzberg added. “If they are only funding 10 percent of proposals, then whatever happens, 90 percent of them are going to be rejected, so try to be in the top 10 percent, but we can’t all be in the top 10 percent all the time.”

Navin added that those who get rejected should not give up and should keep submitting. “I just think you have to be very optimistic, be an eternal optimist and just keep submitting your grants to as many different funding agencies as possible,” he said. “And eventually, if it is a good idea, it’ll get funded.”

The next fiscal cycle

While fiscal year 2013 is more than half over, the US federal budget for fiscal year 2014 isn’t yet set, so what is in store for research funding — and whether the sequester will continue —isn’t clear.

The Obama administration released its budget proposal for FY 2014 in April, which would replace the sequester. It called for $31.3 billion for the National Institutes of Health — an increase of 1.5 percent over the FY 2012 budget — and $7.6 billion for the National Science Foundation — an 8.4 percent increase over its FY 2012 appropriation.

The budget, though, needs to pass Congress.

“We’re making plans for FY ’14 on the basis of what the administration presented as a budget,” Guyer said. “We’re hoping the Congress can do better than that. On the other hand, we are realistic.”

Ciara Curtin is GenomeWeb’s science features editor as well as the editor of the Daily Scan and Careers blogs. E-mail Ciara Curtinand follow @DailyScan, and @CareersGW on Twitter.

Fact sheet: Impact of Sequestration on the National Institutes of Health

The National Institutes of Health is the nation’s medical research agency and the leading supporter of biomedical research in the world. NIH’smission is to seek fundamental knowledge about the nature and behavior of living systems and apply that knowledge to enhance health, lengthen life, and reduce the burdens of illness and disability. Due in large measure to NIH research, a person born in the United States today can expect to live nearly 30 years longer than someone born in 1900.

More than 80 percent of the NIH’s budget goes to over 300,000 research personnel at more than 2,500 universities and research institutions throughout the United States. In addition, about 6,000 scientists work in NIH’s own Intramural Research laboratories, most of which are on the NIH main campus in Bethesda, Md. The main campus is also home to theNIH Clinical Center, the largest hospital in the world totally dedicated to clinical research.


On March 1, 2013, as required by statute, President Obama signed an order initiating sequestration. The sequestration requires NIH to cut 5 percent or $1.55 billion of its fiscal year (FY) 2013 budget. NIH must apply the cut evenly across all programs, projects, and activities (PPAs), which are primarily NIH institutes and centers. This means every area of medical research will be affected.

NIH FY2013 operating plans:

NIH FY2013 Operating Plan

NIH FY2013 Operating Plan Mechanism Table

NIH Guide Notice: Fiscal Policy for Grant Awards FY2013

NIH Institutes and Centers FY2013 Funding Strategies

The estimated numbers:

(FY 2013 figures compared to FY 2012)

While much of these decreases are due to sequester, NIH funding is always a dynamic situation with multiple drivers:

  • Approximately 700 fewer competitive research project grants issued
  • Approximately 750 fewer new patients admitted to the NIH Clinical Center
  • No increase in stipends for National Research Service Award recipients in FY2013

The impact:

  • Delay in medical progress:
    • Medical breakthroughs do not happen overnight. In almost all instances, breakthrough discoveries result from years of incremental research to understand how disease starts and progresses.
    • Even after the cause and potential drug target of a disease is discovered, it takes on average 13 years and $1 billion to develop a treatment for that target.
    • Therefore, cuts to research are delaying progress in medical breakthroughs, including:
      • development of better cancer drugs that zero in on a tumor with fewer side effects
      • research on a universal flu vaccine that could fight every strain of influenza without needing a yearly shot.
      • prevention of debilitating chronic conditions that are costly to society and delay development of more effective treatments for common and rare diseases affecting millions of Americans.
  • Risk to scientific workforce:
    • NIH drives job creation and economic growth. NIH research funding directly supports hundreds of thousands of American jobs and serves as a foundation for the medical innovation sector, which employs 1 million U.S. citizens. Cuts to NIH funding will have an economic impact in communities throughout the U.S. For every six applications submitted to the NIH, only one will be funded. Sequestration is reducing the overall funding available for grants. See the history of NIH funding success rates.

Frequently asked questions:

How many fewer grants will be awarded?
Approximately 700 fewer research project grants compared to FY 2012.

Have the institutes and centers announced their adjusted paylines based on these cuts?
The adjusted NIH Institute and Center (IC) paylines and funding strategies can be found here:http://grants.nih.gov/grants/financial/index.htm#strategies

What percent cut will be made to existing grants?
Reductions to noncompeting research project grants (RPG) vary depending on the circumstances of the particular IC. The NIH-wide average is -4.7 percent.

Will the duration of existing grants be shortened to accommodate the cuts?
In general, no.

Will all grants receive the same percentage cut or will some grants be cut more than others?
Institutes and centers have flexibility to accommodate the new budget level in a fashion that allows them to meet their scientific and strategic goals. As noted above, there are different percentages for different ICs, and in some cases for different mechanisms within an IC (RPGs, Centers, etc.). In addition, there may be reductions to grants for reasons other than sequestration, as is the case every year.

Will certain areas of science that are at a critical juncture be affected by these cuts? 
All areas of science are expected to be affected.

Will some areas of science be affected more than others?
The sequester does not stipulate the precise reduction to each scientific area. However, it is likely that most scientific areas will be reduced by about 5 percent because the sequester is being applied broadly at the NIH institute and center level.

What will be the impact of these cuts to NIH’s intramural research at its Bethesda campus and off-campus facilities?
The impact on NIH’s intramural research is substantial, especially because it applies retroactively to spending since Oct. 1, 2012. That can double the effect — a full year’s cut has to be absorbed in less than half a year.

Will NIH be furloughing or cutting employees at its NIH campus and off-campus facilities?
There are no current plans to do so. At present, HHS is pursuing non-furlough administrative cost savings such as delayed/forgone hiring and reducing administrative services contracts so that furloughs and layoffs can be avoided. Additionally, employee salaries at NIH make up a very small percentage (only 7 percent) of the NIH budget.

How will current patients at the NIH Clinical Center be affected?
Services to patients will not be reduced.

Will the NIH Clinical Center see fewer patients because of the cuts?
Approximately 750 fewer new patients will be admitted to the NIH Clinical Center hospital in 2013 or a decrease from 10,695 new patients in 2012 to approximately 9,945 new patients in 2013. While much of this decrease is due to funding, clinical activity is always a dynamic situation with multiple drivers.

Will the sequester cut need to be applied to the FY 2014 budget?
The President’s FY 2014 Budget would replace sequestration and reduce the deficit in a balanced way. The President is ready to work with Congress to further reduce deficits while continuing to make critical investments.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

NIH…Turning Discovery Into Health®

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Reporter: Aviva lev-Ari, PhD, RN

Rock Talk

Helping connect you with the NIH perspective

Diversifying the Training Experiences of the Biomedical Research Workforce

Posted on March 8, 2013 by 

I’m eager to tell you about another important biomedical workforce-related initiative that NIH is launching based on the Advisory Committee to the Director (ACD) working group recommendations. This initiative seeks to expand existing research training and allow research institutions to best prepare their trainees for a variety of research-related career outcomes. The ACD working group report showed that while almost half of US-trained doctorates work in academia, an increasing proportion of newly trained doctorates finds employment opportunities in non-academic sectors and in other research-related occupations.

US-trained doctorates post-training employment as of 2008: 18% non science related, 18% science-related non-research, 6% government research, 18% industry research, 43% academia. NSF Survey of Earned Doctorates data based on 130,000 individuals which is an underestimate of total biomedical research workforce

Especially in challenging financial times, it is important to not only prepare trainees for a diverse set of career outcomes, but to leverage existing resources and enlist additional support from the potential beneficiaries of NIH-supported training – the employers of PhD scientists. TheBroadening Experiences in Scientific Training (BEST) program aims to do just that.

The BEST awards will be piloted through the NIH Common Fund, and support the development of new and innovative methods for preparing graduate students for the full breadth of research and research-related careers in the biomedical, behavioral, social, or clinical sciences. How applicant research institutions choose to approach this may vary. For example, scientific research institutions might initiate mutually beneficial collaborations with schools of business, public policy or economics, or might propose developing partnerships beyond academia and engaging the private sector or non-profit entities. But all programs should introduce students and postdoctoral scientists to the wide array of biomedical careers early in their training, and provide them with experiences in the career they plan to pursue, in addition to their PhD studies and traditional postdoctoral training.

BEST intends to change the culture of biomedical graduate education by seeding the development of diverse training experiences. Up to 15 BEST awards will be made in fiscal year 2013 to support research institutions’ program and administrative needs during the initial stages of development, and to create self-sustaining programs in collaboration with external support. Communication among awardees and rigorous monitoring of outcomes are essential aspects of this award program so that effective and proven models for training can be shared with universities across the United States.

We plan to review applications to the BEST funding opportunity this summer. An informational webinar to advise applicants will be held in March, letters of intent are due in April, and applications are due in May of this year; more details on the program are in the NIH GuideNotice and on the program website.

As the centerpiece of all the ACD biomedical workforce recommendations, this program is an important part of supporting the biomedical research enterprise as a whole, at all stages of the scientific process. This investment is just the beginning of how we prepare biomedical research trainees for a broader set of career options, and I look forward to following the work of BEST awardees as they pioneer these diverse training programs.



  1. It’s fantastic that the ACD is recognizing the need for training and experiential learning outside of pure academic career tracks! I am part of a group of graduate students and postdocs at Washington University School of Medicine who, while looking for an opportunity to gain training and experience, formed a nonprofit consulting company that forms collaborations between early and late stage life sciences companies and small groups of graduate students and postdocs. Through these team strategic consulting projects, all participants whether academic or non-academic focused, receive hands-on, real-world learning experiences. These opportunities train participants in becoming effective communicators, collaborators, leaders, and managers—skills that are often under-developed in many recent graduates and aspiring principal investigators. The group has had tremendous success over the past two years working with 32 companies and 140+ student consultants, many of whom have gone onto academic and non-academic careers and even started their own company. The group also earmarks a significant portion of their revenue for outreach initiatives to support science and career development throughout the community. Importantly, because these projects are inexpensive, the demand for the services is high throughout the country, opening up a huge opportunity for similar initiatives to develop at other universities. Indeed, several groups of graduate students around the U.S are currently taking steps to creating similar initiatives at their institution. We hope the BEST program can foster similar self-sustaining initiatives.

  2. Could anyone from the Rock Talk Blog team comment on why NSF survey data from 2008 is being shown here instead of data from 2011 which was released in December? It would seem to me that the 2011 data would be much more relevant given that 2008 was the start of the recession and that 2% unemployment number back then must have surely risen since then. I would also be curious to see how the percent of people in “Academia” and “Industry research” has changed from 2008 to 2011. My guess is that in the three years from 2008-2011 there have been some dramatic changes in these percentages with “Academia” and “Industry research” comprising now less than 40% combined.


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What is the Future for Genomics in Clinical Medicine?

What is the Future for Genomics in Clinical Medicine?

Author and Curator: Larry H Bernstein, MD, FCAP



This is the last in a series of articles looking at the past and future of the genome revolution.  It is a revolution indeed that has had a beginning with the first phase discovery leading to the Watson-Crick model, the second phase leading to the completion of the Human Genome Project, a third phase in elaboration of ENCODE.  But we are entering a fourth phase, not so designated, except that it leads to designing a path to the patient clinical experience.
What is most remarkable on this journey, which has little to show in treatment results at this time, is that the boundary between metabolism and genomics is breaking down.  The reality is that we are a magnificent “magical” experience in evolutionary time, functioning in a bioenvironment, put rogether like a truly complex machine, and with interacting parts.  What are those parts – organelles, a genetic message that may be constrained and it may be modified based on chemical structure, feedback, crosstalk, and signaling pathways.  This brings in diet as a source of essential nutrients, exercise as a method for delay of structural loss (not in excess), stress oxidation, repair mechanisms, and an entirely unexpected impact of this knowledge on pharmacotherapy.  I illustrate this with some very new observations.

Gutenberg Redone

The first is a recent talk on how genomic medicine has constructed a novel version of the “printing press”, that led us out of the dark ages.


In our series The Creative Destruction of Medicine, I’m trying to get into critical aspects of how we can Schumpeter or reboot the future of healthcare by leveraging the big innovations that are occurring in the digital world, including digital medicine.

We have this big thing about evidence-based medicine and, of course, the sanctimonious randomized, placebo-controlled clinical trial. Well, that’s great if one can do that, but often we’re talking about needing thousands, if not tens of thousands, of patients for these types of clinical trials. And things are changing so fast with respect to medicine and, for example, genomically guided interventions that it’s going to become increasingly difficult to justify these very large clinical trials.

For example, there was a drug trial for melanoma and the mutation of BRAF, which is the gene that is found in about 60% of people with malignant melanoma. When that trial was done, there was a placebo control, and there was a big ethical charge asking whether it is justifiable to have a body count. This was a matched drug for the biology underpinning metastatic melanoma, which is essentially a fatal condition within 1 year, and researchers were giving some individuals a placebo.

The next observation is a progression of what he have already learned. The genome has a role is cellular regulation that we could not have dreamed of 25 years ago, or less. The role is far more than just the translation of a message from DNA to RNA to construction of proteins, lipoproteins, cellular and organelle structures, and more than a regulation of glycosidic and glycolytic pathways, and under the influence of endocrine and apocrine interactions. Despite what we have learned, the strength of inter-molecular interactions, strong and weak chemical bonds, essential for 3-D folding, we know little about the importance of trace metals that have key roles in catalysis and because of their orbital structures, are essential for organic-inorganic interplay. This will not be coming soon because we know almost nothing about the intracellular, interstitial, and intrvesicular distributions and how they affect the metabolic – truly metabolic events.

I shall however, use some new information that gives real cause for joy.

Reprogramming Alters Cells’ Fate

Kathy Liszewski
Gordon Conference  Report: June 21, 2012;32(11)
New and emerging strategies were showcased at Gordon Conference’s recent “Reprogramming Cell Fate” meeting. For example, cutting-edge studies described how only a handful of key transcription factors were needed to entirely reprogram cells.
M. Azim Surani, Ph.D., Marshall-Walton professor at the Gurdon Institute, University of Cambridge, U.K., is examining cellular reprogramming in a mouse model. Epiblast stem cells are derived from the early-stage embryonic stage after implantation of blastocysts, about six days into development, and retain the potential to undergo reversion to embryonic stem cells (ESCs) or to PGCs.”  They report two critical steps both of which are needed for exploring epigenetic reprogramming.  “Although there are two X chromosomes in females, the inactivation of one is necessary for cell differentiation. Only after epigenetic reprogramming of the X chromosome can pluripotency be acquired. Pluripotent stem cells can generate any fetal or adult cell type but are not capable of developing into a complete organism.”
The second read-out is the activation of Oct4, a key transcription factor involved in ESC development. The expression of Oct4 in epiSCs requires its proximal enhancer.  Dr. Surani said that their cell-based system demonstrates how a systematic analysis can be performed to analyze how other key genes contribute to the many-faceted events involved in reprogramming the germline.
Reprogramming Expressway
A number of other recent studies have shown the importance of Oct4 for self-renewal of undifferentiated ESCs. It is sufficient to induce pluripotency in neural tissues and somatic cells, among others. The expression of Oct4 must be tightly regulated to control cellular differentiation. But, Oct4 is much more than a simple regulator of pluripotency, according to Hans R. Schöler, Ph.D., professor in the department of cell and developmental biology at the Max Planck Institute for Molecular Biomedicine.
Oct4 has a critical role in committing pluripotent cells into the somatic cellular pathway. When embryonic stem cells overexpress Oct4, they undergo rapid differentiation and then lose their ability for pluripotency. Other studies have shown that Oct4 expression in somatic cells reprograms them for transformation into a particular germ cell layer and also gives rise to induced pluripotent stem cells (iPSCs) under specific culture conditions.
Oct4 is the gatekeeper into and out of the reprogramming expressway. By modifying experimental conditions, Oct4 plus additional factors can induce formation of iPSCs, epiblast stem cells, neural cells, or cardiac cells. Dr. Schöler suggests that Oct4 a potentially key factor not only for inducing iPSCs but also for transdifferention.  “Therapeutic applications might eventually focus less on pluripotency and more on multipotency, especially if one can dedifferentiate cells within the same lineage. Although fibroblasts are from a different germ layer, we recently showed that adding a cocktail of transcription factors induces mouse fibroblasts to directly acquire a neural stem cell identity.
Stem cell diagram illustrates a human fetus st...

Stem cell diagram illustrates a human fetus stem cell and possible uses on the circulatory, nervous, and immune systems. (Photo credit: Wikipedia)

English: Embryonic Stem Cells. (A) shows hESCs...

English: Embryonic Stem Cells. (A) shows hESCs. (B) shows neurons derived from hESCs. (Photo credit: Wikipedia)

Transforming growth factor beta (TGF-β) is a s...

Transforming growth factor beta (TGF-β) is a secreted protein that controls proliferation, cellular differentiation, and other functions in most cells. http://en.wikipedia.org/wiki/TGFbeta (Photo credit: Wikipedia)

Pioneer Transcription Factors

Pioneer transcription factors take the lead in facilitating cellular reprogramming and responses to environmental cues. Multicellular organisms consist of functionally distinct cellular types produced by differential activation of gene expression. They seek out and bind specific regulatory sequences in DNA. Even though DNA is coated with and condensed into a thick fiber of chromatin. The pioneer factor, discovered by Prof. KS Zaret at UPenn SOM in 1996, he says, endows the competence for gene activity, being among the first transcription factors to engage and pry open the target sites in chromatin.
FoxA factors, expressed in the foregut endoderm of the mouse,are necessary for induction of the liver program. They found that nearly one-third of the DNA sites bound by FoxA in the adult liver occur near silent genes

A Nontranscriptional Role for HIF-1α as a Direct Inhibitor of DNA Replication

ME Hubbi, K Shitiz, DM Gilkes, S Rey,….GL Semenza. Johns Hopkins University SOM
Sci. Signal 2013; 6(262) 10pgs. [DOI: 10.1126/scisignal.2003417]   http:dx.doi.org/10.1126/scisignal.2003417

http://SciSignal.com/A Nontranscriptional Role for HIF-1α as a Direct Inhibitor of DNA Replication/

Many of the cellular responses to reduced O2 availability are mediated through the transcriptional activity of hypoxia-inducible factor 1 (HIF-1). We report a role for the isolated HIF-1α subunit as an inhibitor of DNA replication, and this role was independent of HIF-1β and transcriptional regulation. In response to hypoxia, HIF-1α bound to Cdc6, a protein that is essential for loading of the mini-chromosome maintenance (MCM) complex (which has DNA helicase activity) onto DNA, and promoted the interaction between Cdc6 and the MCM complex. The binding of HIF-1α to the complex decreased phosphorylation and activation of the MCM complex by the kinase Cdc7. As a result, HIF-1α inhibited firing of replication origins, decreased DNA replication, and induced cell cycle arrest in various cell types. To whom correspondence should be addressed. E-mail: gsemenza@jhmi.edu
Citation: M. E. Hubbi, Kshitiz, D. M. Gilkes, S. Rey, C. C. Wong, W. Luo, D.-H. Kim, C. V. Dang, A. Levchenko, G. L. Semenza, A Nontranscriptional Role for HIF-1α as a Direct Inhibitor of DNA Replication. Sci. Signal. 6, ra10 (2013).

Identification of a Candidate Therapeutic Autophagy-inducing Peptide

Nature 2013;494(7436).    http://nature.com/Identification_of_a_candidate_therapeutic_autophagy-inducing_peptide/   http://www.ncbi.nlm.nih.gov/pubmed/23364696

Beth Levine and colleagues have constructed a cell-permeable peptide derived from part of an autophagy protein called beclin 1. This peptide is a potent inducer of autophagy in mammalian cells and in vivo in mice and was effective in the clearance of several viruses including chikungunya virus, West Nile virus and HIV-1.

Could this small autophagy-inducing peptide may be effective in the prevention and treatment of human diseases?

PR-Set7 Is a Nucleosome-Specific Methyltransferase that Modifies Lysine 20 of

Histone H4 and Is Associated with Silent Chromatin

K Nishioka, JC Rice, K Sarma, H Erdjument-Bromage, …, D Reinberg.   Molecular Cell, Vol. 9, 1201–1213, June, 2002, Copyright 2002 by Cell Press   http://www.cell.com/molecular-cell/abstract/S1097-2765(02)00548-8

http://www.sciencedirect.com/science/article/pii/S1097276502005488           http://www.ncbi.nlm.nih.gov/pubmed/12086618

We have purified a human histone H4 lysine 20methyl-transferase and cloned the encoding gene, PR/SET07. A mutation in Drosophila pr-set7 is lethal: second in-star larval death coincides with the loss of H4 lysine 20 methylation, indicating a fundamental role for PR-Set7 in development. Transcriptionally competent regions lack H4 lysine 20 methylation, but the modification coincided with condensed chromosomal regions polytene chromosomes, including chromocenter euchromatic arms. The Drosophila male X chromosome, which is hyperacetylated at H4 lysine 16, has significantly decreased levels of lysine 20 methylation compared to that of females. In vitro, methylation of lysine 20 and acetylation of lysine 16 on the H4 tail are competitive. Taken together, these results support the hypothesis that methylation of H4 lysine 20 maintains silent chromatin, in part, by precluding neighboring acetylation on the H4 tail.

Next-Generation Sequencing vs. Microarrays

Shawn C. Baker, Ph.D., CSO of BlueSEQ
GEN Feb 2013
With recent advancements and a radical decline in sequencing costs, the popularity of next generation sequencing (NGS) has skyrocketed. As costs become less prohibitive and methods become simpler and more widespread, researchers are choosing NGS over microarrays for more of their genomic applications. The immense number of journal articles citing NGS technologies it looks like NGS is no longer just for the early adopters. Once thought of as cost prohibitive and technically out of reach, NGS has become a mainstream option for many laboratories, allowing researchers to generate more complete and scientifically accurate data than previously possible with microarrays.

Gene Expression

Researchers have been eager to use NGS for gene expression experiments for a detailed look at the transcriptome. Arrays suffer from fundamental ‘design bias’ —they only return results from those regions for which probes have been designed. The various RNA-Seq methods cover all aspects of the transcriptome without any a priori knowledge of it, allowing for the analysis of such things as novel transcripts, splice junctions and noncoding RNAs. Despite NGS advancements, expression arrays are still cheaper and easier when processing large numbers of samples (e.g., hundreds to thousands).
While NGS unquestionably provides a more complete picture of the methylome, whole genome methods are still quite expensive. To reduce costs and increase throughput, some researchers are using targeted methods, which only look at a portion of the methylome. Because details of exactly how methylation impacts the genome and transcriptome are still being investigated, many researchers find a combination of NGS for discovery and microarrays for rapid profiling.


They are interested in ease of use, consistent results, and regulatory approval, which microarrays offer. With NGS, there’s always the possibility of revealing something new and unexpected. Clinicians aren’t prepared for the extra information NGS offers. But the power and potential cost savings of NGS-based diagnostics is alluring, leading to their cautious adoption for certain tests such as non-invasive prenatal testing.
Perhaps the application that has made the least progress in transitioning to NGS is cytogenetics. Researchers and clinicians, who are used to using older technologies such as karyotyping, are just now starting to embrace microarrays. NGS has the potential to offer even higher resolution and a more comprehensive view of the genome, but it currently comes at a substantially higher price due to the greater sequencing depth. While dropping prices and maturing technology are causing NGS to make headway in becoming the technology of choice for a wide range of applications, the transition away from microarrays is a long and varied one. Different applications have different requirements, so researchers need to carefully weigh their options when making the choice to switch to a new technology or platform. Regardless of which technology they choose, genomic researchers have never had more options.

Sequencing Hones In on Targets

Greg Crowther, Ph.D.

GEN Feb 2013

Cliff Han, PhD, team leader at the Joint Genome Institute in the Los Alamo National Lab, was one of a number of scientists who made presentations regarding target enrichment at the “Sequencing, Finishing, and Analysis in the Future” (SFAF) conference in Santa Fe, which was co-sponsored by the Los Alamos National Laboratory and DOE Joint Genome Institute. One of the main challenges is that of target enrichment: the selective sequencing of genomic or transcriptomic regions. The polymerase chain reaction (PCR) can be considered the original target-enrichment technique and continues to be useful in contexts such as genome finishing. “One target set is the unique gaps—the gaps in the unique sequence regions. Another is to enrich the repetitive sequences…ribosomal RNA regions, which together are about 5 kb or 6 kb.” The unique-sequence gaps targeted for PCR with 40-nucleotide primers complementary to sequences adjacent to the gaps, did not yield the several-hundred-fold enrichment expected based on previously published work. “We got a maximum of 70-fold enrichment and generally in the dozens of fold of enrichment,” noted Dr. Han.

“We enrich the genome, put the enriched fragments onto the Pacific Biosciences sequencer, and sequence the repeats,” continued Dr. Han. “In many parts of the sequence there will be a unique sequence anchored at one or both ends of it, and that will help us to link these scaffolds together.” This work, while promising, will remain unpublished for now, as the Joint Genome Institute has shifted its resources to other projects.
At the SFAF conference Dr. Jones focused on going beyond basic target enrichment and described new tools for more efficient NGS research. “Hybridization methods are flexible and have multiple stop-start sites, and you can capture very large sizes, but they require library prep,” said Jennifer Carter Jones, Ph.D., a genomics field applications scientist at Agilent. “With PCR-based methods, you have to design PCR primers and you’re doing multiplexed PCR, so it’s limited in the size that you can target. But the workflow is quick because there’s no library preparation; you’re just doing PCR.” She discussed Agilent’s recently acquired HaloPlex technology, a hybrid system that includes both a hybridization step and a PCR step. Because no library preparation is required, sequencing results can be obtained in about six hours, making it suitable for clinical uses. However, the hybridization step allows capture of targets of up to 5 megabases—longer than purely PCR-based methods can deliver. The Agilent talk also provided details on the applications of SureSelect, the company’s hybridization technology, to Methyl-Seq and RNA-Seq research. With this technology, 120-mer baits hybridize to targets, then are pulled down with streptavidin-coated magnetic beads.
These are selections from the SFAF conference, which is expected to be a boost to work on the microbiome, and lead to infectious disease therapeutic approaches.


We have finished a breathtaking ride through the genomic universe in several sessions.  This has been a thorough review of genomic structure and function in cellular regulation.  The items that have been discussed and can be studied in detail include:

  1.  the classical model of the DNA structure
  2. the role of ubiquitinylation in managing cellular function and in autophagy, mitophagy, macrophagy, and protein degradation
  3. the nature of the tight folding of the chromatin in the nucleus
  4. intramolecular bonds and short distance hydrophobic and hydrophilic interactions
  5. trace metals in molecular structure
  6. nuclear to membrane interactions
  7. the importance of the Human Genome Project followed by Encode
  8. the Fractal nature of chromosome structure
  9. the oligomeric formation of short sequences and single nucletide polymorphisms (SNPs)and the potential to identify drug targets
  10. Enzymatic components of gene regulation (ligase, kinases, phosphatases)
  11. Methods of computational analysis in genomics
  12. Methods of sequencing that have become more accurate and are dropping in cost
  13. Chromatin remodeling
  14. Triplex and quadruplex models not possible to construct at the time of Watson-Crick
  15. sequencing errors
  16. propagation of errors
  17. oxidative stress and its expected and unintended effects
  18. origins of cardiovascular disease
  19. starvation and effect on protein loss
  20. ribosomal damage and repair
  21. mitochondrial damage and repair
  22. miscoding and mutational changes
  23. personalized medicine
  24. Genomics to the clinics
  25. Pharmacotherapy horizons
  26. driver mutations
  27. induced pluripotential embryonic stem cell (iPSCs)
  28. The association of key targets with disease
  29. The real possibility of moving genomic information to the bedside
  30. Requirements for the next generation of electronic health record to enable item 29

Other Related articles on this Open Access Online Scientific Journal, include the following:

https://pharmaceuticalintelligence.com/2013/01/14/oogonial-stem-cells-purified-a-view-towards-the-future-of-reproductive-biology/   SSaha

https://pharmaceuticalintelligence.com/2012/10/22/blood-vessel-generating-stem-cells-discovered/ RSaxena

https://pharmaceuticalintelligence.com/2012/08/22/a-possible-light-by-stem-cell-therapy-in-painful-dark-of-osteoarthritis-kartogenin-a-small-molecule-differentiates-stem-cells-to-chondrocyte-healthy-cartilage-cells/   ASarkar and RSaxena

https://pharmaceuticalintelligence.com/2012/08/07/human-embryonic-pluripotent-stem-cells-and-healing-post-myocardial-infarction/    LHB

https://pharmaceuticalintelligence.com/2013/02/03/genome-wide-detection-of-single-nucleotide-and-copy-number-variation-of-a-single-human-cell/  SJWilliams

https://pharmaceuticalintelligence.com/2013/01/09/gene-therapy-into-healthy-heart-muscle-reprogramming-scar-tissue-in-damaged-hearts/ ALev-Ari

https://pharmaceuticalintelligence.com/2013/01/03/differentiation-therapy-epigenetics-tackles-solid-tumors/  SJWilliams

https://pharmaceuticalintelligence.com/2012/12/09/naotech-therapy-for-breast-cancer/  TBarliya

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Nation’s BiobanksAcademic institutions, Research institutes and Hospitals – vary by Collections Size, Types of Specimens and Applications: Regulations are Needed

Reporter: Aviva Lev-Ari, PhD, RN

On this Open Access Online Scientific Journal a series of posts address the Gemonic Research Establishment

Personalized Medicine: An Institute Profile – Coriell Institute for Medical Research: Part 3


Cancer Diagnostics by Genomic Sequencing: ‘No’ to Sequencing Patient’s DNA, ‘No’ to Sequencing Patient’s Tumor, ‘Yes’ to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities

How to Tailor Cancer Therapy to the particular Genetics of a patient’s Cancer


‘No’ to Sequencing Patient’s DNA, ‘No’ to Sequencing Patient’s Tumor, ‘Yes’ to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities

PRESENTED in the following FOUR PARTS. Recommended to be read in its entirety for completeness and arrival to the End Point of Present and Future Frontier of Research in Genomics

Part 1:

Research Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine


Part 2:

LEADERS in the Competitive Space of Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer Personalized Treatment


Part 3:

Personalized Medicine: An Institute Profile – Coriell Institute for Medical Research


Part 4:

The Consumer Market for Personal DNA Sequencing


We present the State of Affairs of Nation’s BioBank Industry
Characterizing Biobank Organizations in the U.S.: Results from a National Survey

Gail E Henderson, R Jean Cadigan, Teresa P Edwards, Ian Conlon, Anders G Nelson, James P Evans, Arlene M Davis, Catherine Zimmer and Bryan J Weiner

Abstract (provisional)


Effective translational biomedical research hinges on the operation of “biobanks,” repositories which assemble, store, and manage collections of human specimens and related data. Some are established intentionally to address particular research needs; many, however, have arisen opportunistically, in a variety of settings and with a variety of expectations regarding their functions and longevity. Despite their rising prominence, little is known about how biobanks are organized and function beyond simple classification systems (“government, academia, industry”). Methods: In 2012, we conducted the first national survey of biobanks in the U.S., collecting information on their origins, specimen collections, organizational structures, and market contexts and sustainability. From a list of 636 biobanks assembled through a multi-faceted search strategy, representatives from 456 U.S. biobanks were successfully recruited for a 30 minute online survey (72% response rate). Both closed and open-ended responses were analyzed using descriptive statistics. Results: While nearly two-thirds of biobanks were established within the last decade, 17% have been in existence for over 20 years. Fifty-three percent listed research on a particular disease as the most important reason for establishment; 29% listed research generally. Other reasons included response to a grant or gift, and intent to centralize, integrate, or harmonize existing research structures. Biobank collections are extraordinarily diverse in number and types of specimens and in sources (often multiple) from which they are obtained, including from individuals, clinics/hospitals, public health programs, and research studies. Forty-four percent of biobanks store pediatric specimens, and 36% include post-mortem specimens. Most biobanks are affiliated in one or multiple ways with other entities: 88% are part of at least one or more larger organizations (67% of these are academic, 23% hospitals, 13% research institutes). The majority of biobanks seem to fill a particular “niche” within a larger organization or research area; a minority are concerned about competition for services, although many are worried about underutilization of specimens and long term funding. Conclusions: Effective utilization of biobank collections and effective policies to govern their use will require understanding the immense diversity found in organizational features, including the very different history and primary goals that many biobanks have.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.


US Sees Boom in Diverse Range of Biobanks, But Regulations are Lacking

January 25, 2013

NEW YORK (GenomeWeb News) – The past decade has seen a dramatic rise in the number and diversity of biobanks in the US, from academic institutions to research institutes and hospitals, and any efforts at creating regulations or governing rules for them will require more than a ‘one-size-fits-all’ approach, according to a new survey.

Funded by the National Human Genome Research Institute and published today in BioMed Central‘s Genome Medicinethe survey found that nearly two-thirds of the nation’s biobanks were launched over the past decade, and they are an “extraordinarily diverse” group, from the size of their collections to the types of specimens they harbor to their fields of study and applications.

The study’s lead author, Gail Henderson, professor and chair of the Department of Social Medicine at the University of North Carolina at Chapel Hill, told GenomeWeb Daily News this week that the “rise of genomics and large-scale gene-environment studies” have led biobanks to “play an increasingly important role in biomedical research.”

“Many articles discuss the ways they are changing the research enterprise – but they have never been systematically studied,” and there is little empirical data or details “on how they are run or on the policies and practices they have to manage their work,” Henderson said.

Although it is difficult to determine the exact number of biobanks operating in the US, by hunting through a range of sources the UNC-based research team was able to create a list of nearly 800 banks. Their online survey generated responses from 456 biobanks, and the team found that 59 percent of these were established after 2001.

Nearly 50 percent of these banks said that the main biomolecule that they store is DNA, 11 percent said RNA, 7 percent said protein, 20 percent said they do not store biomolecules, and 9 percent said ‘other’.

In total, these banks may house from tens of millions to over 50 million samples, the researchers found, and 53 percent of these specimens were stored to support research on particular diseases or disease types. By far, the largest portion of these is being used for cancer research, which is followed by biospecimens stored for neurological diseases like Alzheimer’s and HIV/AIDS.

As for the types of biological specimens these repositories store, 77 percent said they hold serum/plasma, 69 percent store solid tissues, 55 percent store whole blood, and 49 percent house peripheral blood cells or bone marrow. Around 7 percent of the biobanks store pathological body fluids, and around two or three percent have hair and toenail samples.

The rise of genome-focused research after the completion of the sequencing of the human genome a decade ago appears as if it may be a key driver in the biobank explosion. Since then, biobanks have been created to facilitate research generally, rather than to support studies of single diseases or to focus on one area of human biology.

“While there are likely multiple explanations for these results, it is possible that the changing landscape of genomic technology has facilitated a broadening of scope in research pursuits, so that biobanks are not as likely to limit their work to one disease,” the authors stated in the paper.

The expansion and use of new biobanks likely is “all about genomic information,” Henderson told GWDN.

“When we talk about specimens, and look at the numbers and kinds of specimens that people are saving, and the fact that the majority of our banks are cancer banks, and cancer research is fundamentally about DNA,” it is hard not to come to the conclusion that much of this growth is about genomics, she said.

Henderson also said the survey uncovered a “huge diversity” in the types of biobanks in the US.

“They get established for a variety of reasons, some accidental, some intentional, and they vary in size, in when they were established, how formal they are as organizations, what kind of specimens they hold, and where those specimens come from,” she said.

Biobanks also are diverse in their structural affiliations, although nearly 90 percent are embedded within other institutions, and nearly 80 percent of those embedded banks are located within academic institutions. Hospitals house around a quarter of these biobanks, and around 15 percent are part of a research institute.

While they house the samples that are helping to fuel genomics and molecular research, biobanks also can bring up ethical and policy questions that have caught the eye of policy-watchers at NHGRI.

Several issues that have been flagged by the institute’s Ethical, Legal, and Social Implications Research program are stirred up by the expansion of biobanks, such as questions about policies governing data sharing and security, privacy and the identifiability of genomic information, how and when to return research results and incidental findings, how governance structures function at genomic repositories, and informed consent issues caused by the multiple uses for samples by genome researchers.

“Given the diversity in biobank organizational characteristics, it is likely that management and governance policies will have to be tailored to fit the particular context. One size will not fit all,” Henderson said.

For example, she said, the biobanks in the survey showed a range of policies regarding who may access the data, with some enabling only the researchers who run the repository to access it, and others providing nearly universal access with no applicants denied.

There currently are few or no specific guidelines and laws that specifically govern biobanks and biorepositories, she explained.

A list of voluntary best practices for biospecimen resources published by the National Cancer Institute is probably the best available guidelines for biobanks to follow, Henderson explained, but there is not enough specificity in those or other rules or guidelines to apply them to the range of biobanks that are out there now.

“It’s not as is if there are no federal regulations that affect biobanks,” she said. “Certainly, human subject regulations do, and material transfer agreements and commercialization [rules] fall under certain federal regulatory guidance, but none are specific to biobanks.”

In some ways, she said, the biobanking and biorepository boom has created a “Wild West” landscape that will require further study, Henderson said. She and her fellow investigators now plan to begin to tack their research aims toward the ethical and regulatory issues that the proliferation of and multiple new uses for biobanks have brought about.

Matt Jones is a staff reporter for GenomeWeb Daily News. He covers public policy, legislation, and funding issues that affect researchers in the genomics field, as well as the operations of research institutes. E-mail him here or follow GWDN’s headlines at@DailyNewsGW.

ACMG Issues Guidelines on Sequencing for Dx, Screening Purposes

March 29, 2012

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – The American College of Medical Genetics last night released a policy statement and guidelines for the use of genomic sequencing for diagnostic genetic screening applications.

The guidelines cover how clinical whole-genome and whole-exome sequencing should be applied, distinguishing between cases where the technology is applied to diagnose a specific condition and when it is used as a screening purpose on asymptomatic individuals. It also asserted that the guidelines are applicable to sequencing for clinical purposes, not research.

In a statement, ACMG said that it recognizes that “genomic sequencing approaches can be of great value in the clinical evaluation of individuals with suspected germ-line genetic disorders,” and there are already “instances in which genomic sequencing approaches can and should contribute to clinical care.”

The organization also distinguished between returning results directly associated with the patient’s phenotype or clinical condition and secondary findings or results generated from screening asymptomatic individuals.

For secondary findings, or returning results to asymptomatic individuals, “it is critical that the standards for what is reportable be high to avoid burdening the health care system and consumers with what could be very large numbers of false positive results,” it wrote. By contrast, “a lower threshold for reporting is appropriate” for returning “diagnostic results that are clearly related to a patient’s phenotype or clinical condition.”

ACMG said whole-genome or whole-exome sequencing should be considered as a diagnostic test for individuals when the phenotype or family history data strongly implicate a genetic etiology, but the disorder is unknown and a specific genetic test is not available; when a patient presents with a defined genetic disorder with a high degree of genetic heterogeneity, making multiple single-gene tests less practical; when a patient has a likely genetic disorder, but available tests have failed at diagnosing the disorder; and when a fetus has a likely genetic disorder, but available tests have failed to diagnose it.

Prior to testing, ACMG recommends patients and families receive genetic counseling and be informed about the expected outcomes, likelihood of finding incidental results, and what types of results will be returned. Labs performing the tests should have clear policies related to disclosing secondary findings, and patients should also have the option of not receiving certain results.

Additionally, patients should be informed if a laboratory’s institutional review board has approved a protocol that allows variants of unknown significance to be used for further research, and patients should consent to this use of their data.

The test itself, and every component of it, including the bioinformatics and interpretation, should be performed in a lab directed by a board-certified individual with broad medical genetics and genomics training, ACMG said.

Regarding what results it recommends returning, ACMG said that test results could include variants known to be associated with the patient’s condition; novel variants whose “genetic, biological, and pathological features” indicate that they are likely involved with the patient’s phenotype; and secondary findings not associated with the patient’s condition, but that are known to be associated with a phenotype.

ACMG has different recommendations for whole-genome or whole-exome sequencing done not for diagnostic purposes, but as a screen of asymptomatic individuals. In these instances, it stresses that the threshold for determining which results should be returned should be “significantly higher” than when the technology is used for a specific diagnostic purpose.

Additionally, it said that individuals should be informed of the “virtual certainty of finding variants of unknown significance.”

While many in the field assume that everyone will eventually have their genomes sequenced at birth, the ACMG’s current position is that sequencing should not be used as a first-tier approach for newborn screening. Whole-genome or whole-exome sequencing should also not be used as a method for prenatal screening, it wrote.

However, whole-genome or whole-exome sequencing could be considered for preconception carrier screening to “focus on genetic variants known to be associated with significant phenotypes in homozygous or hemizygous progeny,” ACMG said.

ACMG acknowledged that the field is rapidly evolving and said that its recommendations would likely be revised over time.

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Reporter: Aviva Lev-Ari, PhD, RN

Gordon H. Sun, M.D., Jeffrey D. Steinberg, Ph.D., and Reshma Jagsi, M.D., D.Phil.

N Engl J Med 2012; 367:687-690   August 23, 2012

Since the founding of the National Institutes of Health (NIH) and the National Science Foundation (NSF) more than six decades ago, the United States has maintained a preeminent position as a government sponsor of medical research. That primacy is being tested, however, by potent economic challenges. The NIH’s proposed budget for fiscal year 2013 would freeze baseline funding at 2012 levels, continuing a decade-long failure to keep pace with the rising costs of conducting medical research. Across-the-board cuts mandated by the Budget Control Act (BCA) of 2011 will also affect medical research, with the NIH, NSF, and other federal research sponsors sustaining budgetary reductions of about 8% next year.

Cuts to government-funded research will have adverse long-term effects on the health care system and the economy and may irreversibly compromise the work of laboratories long accustomed to receiving stable federal support. Moreover, many medical researchers could transfer their knowledge and resources abroad. In fact, five emerging Asian economic or technological powers — China, India, South Korea, Taiwan, and Singapore — already have medical research policies in place that are filling the void being created by ever more restrictive U.S. funding.

Several U.S.-based economists have justified increasing research budgets on the premise that medical discoveries have intrinsically high economic value. For example, Murphy and Topel have suggested that eliminating deaths related to heart disease had an estimated worth of $48 trillion, and a 1% reduction in cancer-related mortality could save $500 billion.1 Beyond these ambitious goals, however, are more practical arguments favoring support for medical research.

Local and regional economic benefits are one example. A June 2008 analysis by Families USA showed that during the NIH’s fiscal year 2007, nearly $23 billion in grants and contracts supported more than 350,000 jobs, with each dollar generating more than twice as much in direct state economic output in the form of goods and services. The NIH reported that almost 1 million Americans worked in for-profit medical businesses in 2008, earning $84 billion and generating $90 billion in goods and services, reinforcing the importance of preserving the U.S. position as a “knowledge hub” for medical research.2 Nevertheless, BCA cuts next year could result in at least 2500 fewer NIH grants, 33,000 fewer jobs, and a $4.5 billion loss in economic activity.3 Since the NIH’s budget represents less than 1% of overall federal spending, policymakers must reconsider whether shaving 8% from NIH outlays will have a noticeable positive effect on the national deficit or economy.

Fallout from funding cuts could include shifts in the U.S. medical research workforce. In 2000, the National Research Council noted both an overall shortage of medical researchers and inadequate funding for scientists working in the United States, which coincided with a decline in the number of funded NIH grant applications from 31% in fiscal year 2002 to 19% in 2010. This change is particularly critical for postdoctoral researchers, who represent the majority of the U.S. biomedical science workforce. According to the NSF, nearly half the 14,601 new postdoctoral-level researchers who were trained in the United States in 2009 were not U.S. citizens or permanent residents. If U.S. institutions are willing to devote money, training, and infrastructure to support talented, committed researchers, it would be an illogical waste of resources and poor long-term strategy to reduce federal grant mechanisms and wipe out potential job opportunities. Indeed, declining financial support may well encourage medical researchers to seek employment elsewhere.

As compared with the United States, China, India, South Korea, Taiwan, and Singapore have taken a sharply different view of medical research and have developed policies that foster medical research as an engine for economic growth and intellectual innovation (see tableMajor Government Agencies in Asia and Their Budgets for Medical Research.). Their national budgets are heavily based on scientific research and development, and funding is increasing, with budgetary targets ranging from 2 to 5% of their gross domestic products (GDPs). India’s funding goal for medical research alone is 2% of its GDP.

Increased funding for research infrastructure attracts scientists and organizations interested in high-quality research, including clinical trials. During the past two decades, increasing numbers of clinical trials have moved overseas, where benefits can include decreased costs of doing business, fewer administrative regulations, and greater enrichment of international relationships among researchers. The average annual rate of growth in clinical trials has been highest in China — 47% — while the number conducted in the United States has decreased by an average of 6.5% annually.4 In addition, the increased attention paid to Asia by private firms and other nongovernmental organizations has spurred rapid policy-level responses to concerns about the lack of informed consent, transparency, and other ethical issues, thus further strengthening the appeal of conducting research in the region.

Asian policies reflect a recognition of the extrinsic economic benefits of medical research. China and India have advocated for more government-funded medical research to improve health-related outcomes. China has espoused increased spending as part of achieving xiaokang, a Confucian term meaning a moderately prosperous society. In 2007, India inaugurated its Department of Health Research, which coordinates biomedical science and health-services research programs and translates their findings to address public health concerns. Since the signing of the Korean War Armistice Agreement in 1953, South Korea has leaned heavily on government-funded research to reduce poverty, allowing the country to gradually acquire advanced technologies and expertise. Medical research is part of at least two core technology areas in South Korea’s “577 Initiative”: medical technologies, such as neuroimaging, to address the needs of an aging population and research on issues pertaining to national safety and public health, such as infectious-disease preparedness and food safety.

National research and development programs have been a fundamental component of Taiwan’s economic policy for at least five decades. In 2005, the country began developing “intelligent medical care” — similar to earlier U.S. initiatives — which integrates medical information technology with quality-improvement measures. In Singapore, medical research and economic oversight are administratively linked. For example, the Biomedical Sciences Group of the Economic Development Board supports researchers financially and designs strategies that enhance Singapore’s status as a knowledge center, and the private firm Bio*One Capital invests directly in promising medical technologies.

The diverse strategies outlined above allow Asian countries to systematically recruit medical researchers from both home and abroad. China is particularly proactive in enticing Chinese-born, U.S.-educated researchers to return to their native country by offering generous financial and material incentives under its Knowledge Innovation Program. As the vice president of the Chinese Academy of Sciences stated more than a decade ago, modern “research and development is actually a war for more talented people.”5 In 2000, Singapore jump-started its Biomedical Sciences Initiative to attract medical researchers worldwide with a direct $2 billion investment, as well as with tax incentives for internal biotechnology start-ups and global pharmaceutical firms. In Singapore and India, English is the primary language for scientific communications, which alleviates concerns about language barriers.

For two decades, emerging Asian countries have been designing long-term strategies to reap the benefits of medical research. Meanwhile, the United States is relying on short-term solutions to support its medical research infrastructure, such as those offered by the Patient Protection and Affordable Care Act and the American Recovery and Reinvestment Act. Decreased investment in U.S. medical research could lead to long-term economic damage for the United States and the loss of its stature as a global leader in the field. Powerful incentives that can retain an elite biomedical-research workforce are necessary to strengthen the U.S. health care system and economy.

The views expressed in this article are those of the authors and do not necessarily reflect those of the Robert Wood Johnson Foundation, the Department of Veterans Affairs, or the Agency for Science, Technology, and Research.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.


From the Robert Wood Johnson Foundation Clinical Scholars Program (G.H.S., R.J.), the Department of Otolaryngology (G.H.S.), and the Department of Radiation Oncology (R.J.), University of Michigan, and the Health Services Research and Development Service, VA Ann Arbor Healthcare System (G.H.S.) — both in Ann Arbor, MI; and the Singapore Bioimaging Consortium, Agency for Science, Technology, and Research, Singapore (J.D.S.).




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