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Posts Tagged ‘National Institutes of Health’

In Two-thirds of Waking Hours Older Women are Sedentary

Reporter: Aviva Lev-Ari, PhD, RN

 

Older women sedentary two-thirds of waking hours

By: MARY ANN MOON, Family Practice News Digital Network

Older women are sedentary for approximately two-thirds of their waking hours, usually in bouts lasting about 30 minutes each punctuated by brief periods of activity, according to a report published Dec. 18, 2013 in JAMA.

Recent studies suggest a high volume of sedentary behavior may be a risk factor for adverse health outcomes. However, few data exist on how this behavior is patterned (for example, does most sedentary behavior occur in a few long bouts or in many short bouts?)

In a research letter to the editor, investigators presented data collected from 7,247 older women (mean age, 71 years) participating in an ancillary study of the Women’s Health Study who wore accelerometers for 1 week to track their physical activity. Overall, the women spent 65.5% of their waking hours – the equivalent of 9.7 hours per day – in sedentary behavior, said Eric J. Shiroma of Harvard School of Public Health, Boston, and his associates.

The mean number of sedentary intervals was 85.9/day, with a mean of 9 breaks per sedentary hour. Most sedentary time occurred in short rather than long intervals, with approximately one-third of the sedentary bouts lasting roughly 30 minutes, the researchers said (JAMA 2013;310:2562-3).

Accelerometers cannot convey whether the women were sitting, standing, or lying down during sedentary periods, but it is most likely that they were sitting. “If future studies confirm the health hazards of sedentary behavior and guidelines are warranted, these data may be useful to inform recommendations on how to improve such behavior,” Mr. Shiroma and his associates said.

They noted that most participants in the Women’s Health Study were white and of higher socioeconomic statusso these findings may not apply to women of other backgrounds.

This study was supported by the National Institutes of Health. No relevant financial conflicts of interest were reported.

SOURCE

http://www.familypracticenews.com/single-view/older-women-sedentary-two-thirds-of-waking-hours/0e9af152ff0d6f3fb1f085ae175489e3.html

 

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North Americans With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: Genomics of Ventricular arrhythmias, A-Fib, Right Ventricular Dysplasia, Cardiomyopathy – Comprehensive Desmosome Mutation Analysis

Reporter: Aviva Lev-Ari, PhD, RN

Genomics of Ventricular arrhythmias, A-Fib, Right Ventricular Dysplasia, Cardiomyopathy – Comprehensive Desmosome Mutation Analysis in North Americans With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

A. Dénise den Haan, MD, Boon Yew Tan, MBChB, Michelle N. Zikusoka, MD, Laura Ibañez Lladó, MS, Rahul Jain, MD, Amy Daly, MS, Crystal Tichnell, MGC, Cynthia James, PhD, Nuria Amat-Alarcon, MS, Theodore Abraham, MD, Stuart D. Russell, MD,David A. Bluemke, MD, PhD, Hugh Calkins, MD, Darshan Dalal, MD, PhD and Daniel P. Judge, MD

Author Affiliations

From the Department of Medicine/Cardiology (A.D.d.H., B.Y.T., M.N.Z., L.I.L., R.J., A.D., C.T., C.J., N.A.-A., T.A., S.D.R., H.C., D.D., D.P.J.), Johns Hopkins University School of Medicine, Baltimore, Md; Department of Cardiology, Division of Heart and Lungs (A.D.d.H.), University Medical Center Utrecht, Utrecht, The Netherlands; and National Institutes of Health, Radiology and Imaging Sciences (D.A.B.), Bethesda, Md.

Correspondence to Daniel P. Judge, MD, Johns Hopkins University, Division of Cardiology, Ross 1049; 720 Rutland Avenue, Baltimore, MD 21205. E-mail djudge@jhmi.edu

Abstract

Background— Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited disorder typically caused by mutations in components of the cardiac desmosome. The prevalence and significance of desmosome mutations among patients with ARVD/C in North America have not been described previously. We report comprehensive desmosome genetic analysis for 100 North Americans with clinically confirmed or suspected ARVD/C.

Methods and Results— In 82 individuals with ARVD/C and 18 people with suspected ARVD/C, DNA sequence analysis was performed on PKP2, DSG2, DSP, DSC2, and JUP. In those with ARVD/C, 52% harbored a desmosome mutation. A majority of these mutations occurred in PKP2. Notably, 3 of the individuals studied have a mutation in more than 1 gene. Patients with a desmosome mutation were more likely to have experienced ventricular tachycardia (73% versus 44%), and they presented at a younger age (33 versus 41 years) compared with those without a desmosome mutation. Men with ARVD/C were more likely than women to carry a desmosome mutation (63% versus 38%). A mutation was identified in 5 of 18 patients (28%) with suspected ARVD. In this smaller subgroup, there were no significant phenotypic differences identified between individuals with a desmosome mutation compared with those without a mutation.

Conclusions— Our study shows that in 52% of North Americans with ARVD/C a mutation in one of the cardiac desmosome genes can be identified. Compared with those without a desmosome gene mutation, individuals with a desmosome gene mutation had earlier-onset ARVD/C and were more likely to have ventricular tachycardia.

SOURCE:

Circulation: Cardiovascular Genetics.2009; 2: 428-435

Published online before print June 3, 2009,

doi: 10.1161/ CIRCGENETICS.109.858217

 

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Healthcare Startups Accelerator is Reaching Out: Deadline November 11, 2013

Reporter: Aviva Lev-Ari, PhD, RN

Applications for companies are due November 11, 2013.

We are also seeking exceptional individuals looking to join a team, particularly those with software development or data science skills. Individuals interested in working with one of the startups can also apply to the program and applications for individuals are due December 16, 2013. Individuals will be matched with companies throughout January.

DreamIt Health Baltimore 2014

baltimorebrought to you byAPPLY TODAY

Applications are due November 11, 2013

Apply as a company | Apply as an individual

Follow us on Twitter | DreamIt Ventures on Facebook

DreamIt Health Baltimore is designed to speed the growth and success of early-stage health IT companies through its program in Central Maryland. Powered by the Johns Hopkins UniversityBioHealth Innovation, and DreamIt Ventures – the program gives participants access and advantages typically out-of-reach to healthcare startups.

DreamIt works with extraordinary teams to create exceptional companies, accomplishing in 3-6 months what would otherwise take years. DreamIt accelerators are characterized by seed capital, intense 1-on-1 mentorship from dedicated, previously successful tech entrepreneurs, access to key people, expertise, and information typically beyond the reach of a startup, informal education from leading industry practitioners, a robust network of DreamIt alumni, and a wide range of free services.  Following a lean startup methodology, the selected teams focus on rapid, iterative interactions with their target markets to reduce risk and find product-market fit as quickly as possible.

DreamIt Health Baltimore 2014 will select up to ten companies from around the world to participate in a four-month accelerator program. In addition to receiving up to a $50,000 stipend and professional services, the startups will be paired with and work closely with exited entrepreneurs-turned-mentors with domain expertise specific to their needs; benefit from an intense startup and healthcare curriculum taught by accomplished practitioners; meet with subject matter experts and investors; and enjoy access to executives, information systems, and data from leading industry players including providers, payers, biopharma, device makers, and federal agencies. Participating teams will also benefit from DreamIt’s extensive network and expertise in guiding the growth of young technology companies.

DreamIt Health Baltimore is expected to take advantage of many of the strengths of the region, giving participating startups the opportunity to work closely with Johns Hopkins Medicine for potential pilots and also access to key individuals throughout the region’s wealth of federal health care institutions including the Center for Medicare and Medicaid Services, the Food and Drug Administration, the National Institutes of Health and the Agency for Healthcare Research and Quality.

The program will be led by Elliot Menschik, MD PhD, a Johns Hopkins alum and successfully-exited health IT entrepreneur.

Learn more about DreamIt Health Baltimore…
Apply to DreamIt Health Baltimore
Apply as an individual
Questions? Ask us.

Press Highlights DreamIt Health Philadelphia (Held April 8th 2013-August 8th 2013)
DreamIt Ventures Teams Up with Blue Cross, Penn Medicine to Launch and Accelerator for Health Startups

Improving outcomes, speeding up diagnoses among goals of Dreamit Venture’s first health IT accelerator

New incubator DreamIt Health launches first class

Next Big Thing In Health Care May Come From Philly Business Incubator

DreamIt ‘boot camp’ boosts health-care info start-ups

DreamIt Health startup accelerator are recruiting ten healthtech startups

Founder at UACTIFY

DreamIt Health startup accelerator is reaching out in the hopes that you might be open to getting the word out among Health 2.0 Israel members about the upcoming DreamIt Health startup accelerator in partnership with Johns Hopkins.

DreamIt Health startup accelerator are recruiting for (and applications are open for) up to ten healthtech startups from around the world to come to Baltimore for a four-month program to achieve significant business milestones in delivering products that solve real problems for key healthcare stakeholders. DreamIt Health startup accelerator do this by removing as many obstacles as possible from the team’s path and providing guidance and access to people and resources otherwise out of their reach. The capstone of the program, Demo Day, gives these teams the opportunity to unveil their products and progress before a few hundred early stage investors and key industry figures.

In addition to receiving up to a $50,000 stipend, free workspace and top-shelf legal services, the startups will be paired 1-on-1 with previously successful entrepreneurs customized to the needs of each team. These mentors will contribute considerable time and effort to guide and assist the founders. Participants will also benefit from an intense startup and healthcare curriculum taught by accomplished practitioners, meet regularly with subject matter experts and investors, and enjoy access to executives, systems, and data from leading industry players including providers, payers, biopharma, device makers, and federal agencies. Participating teams will also benefit from DreamIt’s extensive network and expertise in guiding the growth of young technology companies.

DreamIt Health startup accelerator were founded in 2008 and are run by a group of successful tech entrepreneurs. To date, DreamIt has worked closely with 127 companies from around the world through accelerators in Philadelphia, New York, Austin, and Tel Aviv. These programs are characterized by seed capital, intense 1-on-1 mentorship from dedicated, previously successful tech entrepreneurs, access to key people, expertise, and information typically beyond the reach of a startup, informal education from leading industry practitioners, a robust network of DreamIt alumni, and a wide range of free services. Following a lean startup methodology, the selected teams focus on rapid, iterative interactions with their target markets to reduce risk and find product-market fit as quickly as possible. Forbes has named DreamIt among the top three accelerators in the world and DreamIt companies have gone on to raise nearly $100M in follow-on capital with an aggregate value north of $400M.

DreamIt Health startup accelerator are looking for extraordinary people and teams developing IT-based products with the potential to solve significant problems faced by key stakeholders in the industry including providers, payers, public health, biopharma, device makers, employers and patients themselves. Interested teams can apply at http://www.dreamithealth.com. Applications for companies are due November 11, 2013. We are also seeking exceptional individuals looking to join a team, particularly those with software development or data science skills. Individuals interested in working with one of the startups can also apply to the program and applications for individuals are due December 16, 2013. Individuals will be matched with companies throughout January.

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The Stanford Center for Clinical and Translational Research and Education, or Spectrum – NIH Awards Stanford $45.3M

Reporter: Aviva Lev-Ari, PhD, RN

NIH Awards Stanford $45.3M for Translational Research

October 07, 2013

NEW YORK (GenomeWeb News) – The Stanford Center for Clinical and Translational Research and Education, or Spectrum, is being awarded $45.3 million over four and a half years by the National Institutes of Health to push forward translational research in medicine.

Spectrum is one of 15 institutions to receive such an award being funded as part of the Clinical and Translational Sciences Awards, which were launched in 2006 by NIH “to help meet the nation’s urgent need to provide better healthcare to more people for less money,” the Stanford School of Medicine said.

Stanford won a first round of CTSA funding in 2008 of $30 million.

The new funding will be used to support two new programs at Stanford, one in disease diagnostics and one in population health sciences.

The diagnostics program seeks to develop new methods of testing and preventing disease through advances in omics, immune monitoring, molecular imaging, single-cell analysis, computation, and informatics, the school said. Atul Butte, chief of systems medicine and associate professor of pediatrics and genetics, will lead the program.

The Population Health Sciences Initiative will design systems to serve as a new source of practice-based evidence. The systems will be based on the daily experiences of practicing physicians and information drawn from clinical data warehouses, Stanford said.

This initiative is led by Robert Harrington, professor and chair of medicine; Mark Cullen, professor of medicine and chief of the Division of General Medical Disciplines; and Douglas Owens, professor of medicine and director of the Stanford Center for Primary Care and Outcomes Research and the Center for Health Policy.

The new CTSA award also will be used to address the shortage of qualified clinical and translational researchers across the US by funding new training programs and online courses in clinical research, Stanford said.

Related Stories

SOURCE

http://www.genomeweb.com//node/1290106?utm_source=SilverpopMailing&utm_medium=email&utm_campaign=Stanford%20Nabs%20$45M%20NIH%20Award;%20Signal%20Genetics’%20BCBS%20Coverage;%20$1.4M%20Approval%20for%20Geisinger;%20More%20-%2010/07/2013%2003:45:00%20PM

 

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

Updated on 2/17/2023

The training statement was developed in collaboration with and endorsed by the American Association for Thoracic Surgery, American Society of Echocardiography, Heart Failure Society of America, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, Society of Thoracic Surgeons, and Society for Vascular Medicine.

Primary SOURCE

Journal of the American College of Cardiology

Source Reference: opens in a new tab or window

Bass TA, et al “2023 ACC/AHA/SCAI advanced training statement on interventional cardiology (coronary, peripheral vascular, and structural heart interventions): A report of the ACC Competency Management Committee” J Am Coll Cardiol 2023; DOI: 10.1016/j.jacc.2022.11.002.

https://www.medpagetoday.com/cardiology/pci/103139?xid=nl_mpt_Cardiology_update_2023-02-17&eun=g99985d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=Automated%20Specialty%20Update%20Cardiology%20BiWeekly%20FRIDAY%202023-02-17&utm_term=NL_Spec_Cardiology_Update_Active

Interventional Cardiology Gets Codified Rules for Training

— Multi-society recommendations cover minimum procedural volumes, competencies

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

and

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

#1:

Identifying translational science within the triangle of biomedicine

http://www.translational-medicine.com/content/11/1/126

Griffin M Weber

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

 #2:

Integrated wall stress: a new methodological approach to assess ventricular

workload and myocardial contractile reserve

http://www.translational-medicine.com/content/11/1/183

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:

Introduction

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].

REFERENCES:

  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
  17. Shavelson RJ, Webb NM: Generalizability theory: 1973–1980.Br J Math Stat Psychol 1981, 34:133-166. Publisher Full Text OpenURL
  18. Chiappelli F, Navarro AM, Moradi DR, Manfrini E, Prolo P: Evidence-based research in complementary and alternative medicine III: treatment of patients with Alzheimer’s disease.Evidence-Based Comp Alter Med 2006, 3:411-424. Publisher Full Text OpenURL
  19. Montgomery C: Statistical quality control: a modern introduction. Chichester, West Sussex, UK: Johm Wiley & sons; 2009. OpenURL

 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.

BASIC DISCOVERY -T1->  CLINICAL INSIGHTS -T2-> IMPLICATIONS FOR PRACTICE -T3-> IMPLICATIONS FOR POPULATION HEALTH -T4-> IMPLICATIONS FOR GLOBAL HEALTH

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

http://www.translational-medicine.com/content/11/1/126

Methods

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.

Results

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.

Conclusions

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.

Keywords:

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

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

Background

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.

Conclusion

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.

Keywords:

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.

#1

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.

#2

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.

#3

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

#1: REFERENCES

Identifying translational science within the triangle of biomedicine

http://www.translational-medicine.com/content/11/1/126

Griffin M Weber

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

  1. 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 OpenURL
  2. Zerhouni E: The NIH roadmap.Science 2003, 302:63-72. PubMed Abstract | Publisher Full Text OpenURL
  3. 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
  4. Curry SH: Translational science: past, present, and future.Biotechniques 2008, 44:1-8. OpenURL
  5. Wehling M: Translational medicine: science or wishful thinking?J Transl Med 2008, 6:31. PubMed Abstract | BioMed Central Full Text |PubMed Central Full Text OpenURL
  6. Szilagyi PG: Translational research and pediatrics.Acad Pediatr 2009, 9:71-80. PubMed Abstract | Publisher Full Text OpenURL
  7. Khoury MJ, Gwinn M, Yoon PW, Dowling N, Moore CA, Bradley L: The continuum of translation research in genomic medicine: how can we accelerate the appropriate integration of human genome discoveries into health care and disease prevention?Genet Med 2007, 9:665-674. PubMed Abstract | Publisher Full Text OpenURL
  8. Narin F, Pinski G, Gee HH: Structure of the biomedical literature.J Am Soc Inf Sci 1976, 27:25-45. OpenURL
  9. Narin F, Rozek RP: Bibliometric analysis of U.S. pharmaceutical industry research performance.Research Policy 1988, 17:139-154. Publisher Full Text OpenURL
  10. Narin F, Olivastro D: Status report: linkage between technology and science.Research Policy 1992, 21:237-249. Publisher Full Text OpenURL
  11. Lewison G: The definition of biomedical research subfields with title keywords and application to the analysis of research outputs.Research Evaluation 1996, 6:25-36. OpenURL
  12. Webster B, Lewison G, Rowlands I: Mapping the landscape II: biomedical research in the UK, 1989–2002. London, School of Informatics: City University; 2003. OpenURL
  13. Lewison G, Paraje G: The classification of biomedical journals by research level.Scientometrics 2004, 60:145-157. OpenURL
  14. Small H: Co-citation in scientific literature: a New measure of the relationship between publications.J Am Soc Inf Sci 1973, 24:265-269. Publisher Full Text OpenURL
  15. Small H: Visualizing science by citation mapping.J Am Soc Inf Sci 1999, 50:799-813. Publisher Full Text OpenURL
  16. Morris SA, Yen GG: Crossmaps: visualization of overlapping relationships in collections of journal papers.PNAS 2004, 101(Suppl 1):5291-5296. PubMed Abstract | Publisher Full Text |PubMed Central Full Text OpenURL
  17. Morris SA, Boyack KW: Visualizing 60 years of anthrax research. In Proceedings of the 10th international conference of the international society for scientometrics and informetrics. Edited by Ingwerson P, Larsen B. Stockholm: Karolinska University Press; 2005::45-55. OpenURL
  18. Boyack KW, Klavans R, Borner K: Mapping the backbone of science.Scientometrics 2005, 64:351-374. Publisher Full Text OpenURL
  19. Klavans R, Boyack K: Quantitative evaluation of large maps of science.Scientometrics 2006, 68:475-499. Publisher Full Text OpenURL
  20. Klavans R, Boyack KW: Using global mapping to create more accurate document-level maps of research fields.Journal of the American Society for Information Science and Technology 2011, 62:1-18. Publisher Full Text OpenURL
  21. Harris RL: Information graphics: a comprehensive illustrated reference. New York: Oxford University Press; 1999. OpenURL
  22. Bakkalbasi N, Bauer K, Glover J, Wang L: Three options for citation tracking: Google scholar. Scopus and Web of science.Biomedical Digital Libraries 2006, 3:7. PubMed Abstract | BioMed Central Full Text |PubMed Central Full Text OpenURL
  23. Ioannidis JP: Materializing research promises: opportunities, priorities and conflicts in translational medicine.J Transl Med 2004, 2:5. PubMed Abstract | BioMed Central Full Text |PubMed Central Full Text OpenURL
  24. Roberts SF, Fischhoff MA, Sakowski SA, Feldman EL: Perspective: transforming science into medicine: how clinician-scientists can build bridges across research’s “valley of death”.Acad Med 2012, 87:266-270. PubMed Abstract | Publisher Full Text OpenURL
  25. Contopoulos-Ioannidis DG, Ntzani E, Ioannidis JP: Translation of highly promising basic science research into clinical applications.Am J Med 2003, 114:477-484. PubMed Abstract | Publisher Full Text OpenURL
  26. Contopoulos-Ioannidis DG, Alexiou GA, Gouvias TC, Ioannidis JP: Life cycle of translational research for medical interventions.Science 2008, 5894:1298-1299. OpenURL
  27. Zemlo T, Garrison H, Partridge N, Ley T: The physician-scientist: career issues and challenges at the year 2000.FASEB J 2000, 14:221-230. PubMed Abstract | Publisher Full Text OpenURL
  28. Ley TJ, Rosenberg LE: The physician-scientist career pipeline in, 2005: build it, and they will come.JAMA 2005, 2005(294):1343-1351. OpenURL
  29. Wehling M: Assessing the translatability of drug projects: what needs to be scored to predict success?Nat Rev Drug Discov 2009, 8:541-546. PubMed Abstract | Publisher Full Text OpenURL
  30. Wendler A, Wehling M: Translatability scoring in drug development: eight case studies.J Transl Med 2012, 10:39. PubMed Abstract | BioMed Central Full Text |PubMed Central Full Text OpenURL
  31. Fontelo P, Liu F: Finding translational science publications in MEDLINE/PubMed with translational science filters.Clin Transl Sci 2011, 4:455-459. PubMed Abstract | Publisher Full Text |PubMed Central Full Text OpenURL

 #2: REFERENCES

Integrated wall stress: a new methodological approach to assess ventricular

workload and myocardial contractile reserve

http://www.translational-medicine.com/content/11/1/183

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

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

  1. Mann DL: Mechanisms and models in heart failure: a combinatorial approach.Circulation 1999, 100:999-1008. PubMed Abstract | Publisher Full Text OpenURL
  2. Sutton MG, Sharpe N: Left ventricular remodeling after myocardial infarction: Pathophysiology and therapy.Circulation 2000, 101:2981-2988. PubMed Abstract | Publisher Full Text OpenURL
  3. Colucci WSBE: Pathophysiology of heart failure. In Heart disease. 6th edition. Edited by Braunwald E, Zipes D, Libby P. Philadelphia: Saunders; 2001::503-533. OpenURL
  4. Opie L: Ventricular function. In Heart physiology. 4th edition. Edited by Opie L. Philadelphia, Baltimore, New York, London, Buenos Aires, Hong Kong, Sydney and Tokyo: Lippincott Williams & Wilkins; 2004::351-401. OpenURL
  5. Tsuda T, Gao E, Evangelisti L, Markova D, Ma X, Chu ML: Post-ischemic myocardial fibrosis occurs independent of hemodynamic changes.Cardiovasc Res 2003, 59:926-933. PubMed Abstract | Publisher Full Text OpenURL
  6. Barbone A, Oz MC, Burkhoff D, Holmes JW: Normalized diastolic properties after left ventricular assist result from reverse remodeling of chamber geometry.Circulation 2001, 104:I229-I232. PubMed Abstract | Publisher Full Text OpenURL
  7. Cheng A, Nguyen TC, Malinowski M, Langer F, Liang D, Daughters GT, Ingels NB Jr, Miller DC: Passive ventricular constraint prevents transmural shear strain progression in left ventricle remodeling.Circulation 2006, 114:I79-I86. PubMed Abstract | Publisher Full Text OpenURL
  8. Strauer BE, Beer K, Heitlinger K, Hofling B: Left ventricular systolic wall stress as a primary determinant of myocardial oxygen consumption: Comparative studies in patients with normal left ventricular function, with pressure and volume overload and with coronary heart disease.Basic Res Cardiol 1977, 72:306-313. PubMed Abstract | Publisher Full Text OpenURL
  9. Osbakken M, Bove AA, Spann JF: Left ventricular function in chronic aortic regurgitation with reference to end-systolic pressure, volume and stress relations.Am J Cardiol 1981, 47:193-198. PubMed Abstract | Publisher Full Text OpenURL
  10. Shen WF, Fletcher PJ, Roubin GS, Harris PJ, Kelly DT: Relation between left ventricular functional reserve during exercise and resting systolic loading conditions in chronic aortic regurgitation.Am J Cardiol 1986, 58:757-761. PubMed Abstract | Publisher Full Text OpenURL
  11. Colin P, Ghaleh B, Monnet X, Su J, Hittinger L, Giudicelli JF, Berdeaux A: Contributions of heart rate and contractility to myocardial oxygen balance during exercise.Am J Physiol Heart Circ Physiol 2003, 284:H676-H682. PubMed Abstract |Publisher Full Text OpenURL
  12. Grossman W, Jones D, McLaurin LP: Wall stress and patterns of hypertrophy in the human left ventricle.J Clin Invest 1975, 56:56-64. PubMed Abstract | Publisher Full Text |PubMed Central Full Text OpenURL
  13. Gao E, Lei YH, Shang X, Huang ZM, Zuo L, Boucher M, Fan Q, Chuprun JK, Ma XL, Koch WJ: A novel and efficient model of coronary artery ligation and myocardial infarction in the mouse.Circ Res 2010, 107:1445-1453. PubMed Abstract | Publisher Full Text |PubMed Central Full Text OpenURL
  14. Kamphoven JH, Stubenitsky R, Reuser AJ, Van Der Ploeg AT, Verdouw PD, Duncker DJ:Cardiac remodeling and contractile function in acid alpha-glucosidase knockout mice.Physiol Genomics 2001, 5:171-179. PubMed Abstract OpenURL
  15. Reichek N, Wilson J, St John Sutton M, Plappert TA, Goldberg S, Hirshfeld JW:Noninvasive determination of left ventricular end-systolic stress: Validation of the method and initial application.Circulation 1982, 65:99-108. PubMed Abstract | Publisher Full Text OpenURL
  16. Grossman W: Cardiac hypertrophy: Useful adaptation or pathologic process?Am J Med 1980, 69:576-584. PubMed Abstract | Publisher Full Text OpenURL
  17. Strauer BE: Left ventricular dynamics, energetics and coronary hemodynamics in hypertrophic heart disease.Eur Heart J 1983, 4(Suppl A):137-142. PubMed Abstract | Publisher Full Text OpenURL
  18. Fontanet HL, Perez JE, Davila-Roman VG: Diminished contractile reserve in patients with left ventricular hypertrophy and increased end-systolic stress during dobutamine stress echocardiography.Am J Cardiol 1996, 78:1029-1035. PubMed Abstract | Publisher Full Text OpenURL
  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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AACR announces AACR Progress Report 2013

Stephen J. Williams: Curator

Article ID #79: AACR announces AACR Progress Report 2013. Published on 9/19/2013

WordCloud Image Produced by Adam Tubman

The American Association for Cancer Research (AACR) presented a webinar of the highlights of their yearly progress report (released yesterday and available on the AACR website) on the recent advances and current status of cancer research and cancer research’s impact on health outcomes in the United States.  This report, compiled by staff of AACR, with special thanks to the efforts of Dr. Karen Honey, Ph.D, reports on the current achievements in cancer research including developments in immunotherapies, new drug approvals, health outcomes, newly approved imaging modalities, and the current state of affairs of funding for cancer research and clinical trials.  The report also describes the impact and timeline of discoveries leading to the use of genomics and personalized medicine in cancer treatment.  The last portion of the report is an “AACR Call to Action”, imploring cancer patient activists, scientists, and citizens to write their representatives in Washington for increased funding for cancer research and clinical trials.  The report and presentation will be given to lawmakers on Capital Hill on Spetmeber 19, 2013 as part of Hill Day’s Rally for Medical Research.

The presentation, given on September 18, 2013 at the National Press Club in Washington DC) was headed by AACR CEO Dr. Marge Foti, M.D., Ph.D. with presentations given by

  • Dr. Charles Sawyers, M.D. (Memorial Sloan Kettering)
  • Dr. Drew M. Pardoll, M.D., Ph.D. (Sidney Kimmel Cancer Center, Johns Hopkins)
  • 3 cancer survivors

Below is a brief summary of each of their talks.  The downloadable AACR Progress Report 2013 can be found here and a link to the video can also be found at the AACR website.

Marge Foti, M.D., Ph.D. (Chief Executive Officer, American Association Cancer Research)

Although Dr. Foti mentioned the grim statistic in the US 580,000 this year will die of cancer, she gave multiple statistics on the great progress the US has achieved since staring the “War on Cancer” in 1971 and the future progress which lies ahead.  Notably (from the report)

  • From 1990 to 2012 over 1 million cancer patients lives have been saved
  • There are over 13 million cancer survivors today
  • For the year 2012-2013 FDA has approved
  1. 11 new cancer drugs
  2. 3 new uses of previously approved drugs
  3. 3 new imaging modalities and protocols for cancer detection

However Dr. Foti also stressed the speed of progress is being pressured by diminishing federal funds for cancer research and clinical trials.  Dr. Foti noted:

  • In mid 90’s there was a doubling of federal funds to the NCI
  • Since 2003 however funding has not kept up with “biomedical inflation” (not risen adjusted for current inflation)
  • Sequester has been a big pressure on biomedical and cancer research capacity
  • Funding cuts also decrease the number of patients that can enroll in clinical trials

Charles Sawyers, M.D. (Howard Hughes Medical Institute investigator and Director at Memorial Sloan-Lettering Cancer Center)

Dr. Sawyers’s research work involves the signaling pathways involved in conferring growth advantage to cancerous cells.  His work led to the development of numerous targeted therapies such as imatinib (Gleevec) for CML (chronic myeloid leukemia).  He referred to these therapies as “precision medicine” and noted there were only 5 such therapies 10 years ago but now 17 such precision medicines five years ago for cancer, “ a complex host of diseases”.

Dr. Sawyers reflected this is the “most serious funding crisis in decades” and we are “already losing momentum” due to the current funding crisis.

Drew M. Pardoll, M.D. Ph.D. (Professor, Co-Director Division Immunology, Johns Hopkins)

Dr. Pardoll is a leader in the fielod of immunotherapy for cancer and his work is pioneering a new clas of immunotherapies, such as PD1 inhibitors, which supports the cancer patient’s own immune system to fight and kill the patient’s own cancer cells.  Dr. Pardoll had mentioned early work on immunotherapy had revealed its potential but researchers are now realize this is the “5th pillar of cancer therapy”.  Because of research done in the early 2000’s, cancer researchers such as Dr. Pardoll figured out mechanisms how to make these immunotherapies more reproducible in clinical trials.  This led to the discovery of CTLA4 and PD1 as major regulators of the immune tolerance to cancer cells (see post Combined anti-CTLA4 and anti-PD1 immunotherapy shows promising results against advanced melanoma).

Dr. Pardoll also mentioned how he, and others, noticed that the pharmaceutical industry is now looking to academia to keep driving the science and that patient advocates are very important partner in the discovery process.

Moving presentation were also given by three cancer survivors (breast cancer, ovarian cancer, and  childhood leukemia) which all attested that without ground-breaking clinical research they might not have survived their deadly cancer.

Please see the following website below about the Rally for Medical Research to see how you can get involved in supporting cancer research in the US, and contacting your representative.

Rally for Medical Research Hill Day

September 18, 2013

Federal funding for medical research is in jeopardy, threatening the health of Americans. On September 18, 2013, a broad coalition of groups from the medical research advocacy community will meet with House and Senate offices in Washington, D.C., to urge Congress to invest in the National Institutes of Health for the health and economic security of our nation.

Sponsoring organizations will join the Rally for Medical Research Hill Day to raise awareness during a critical time about the urgent need for a sustained investment in the NIH to improve health, spur more progress, inspire more hope and save more lives.

More articles on Progress on the War on Cancer from this site include:

2013 Perspective on “War on Cancer” on December 23, 1971

2013 American Cancer Research Association Award for Outstanding Achievement in Chemistry in Cancer Research: Professor Alexander Levitzki

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ENCODE (Encyclopedia of DNA Elements) program: ‘Tragic’ Sequestration Impact on NHGRI Programs

Reporter: Aviva Lev-Ari, PhD, RN

NHGRI’s Green Sees ‘Tragic’ Sequestration Impact on NHGRI Programs

September 13, 2013

NEW YORK (GenomeWeb News) – The funding squeeze from the sequestration of the US federal budget, now more than half-a-year old, has already had a sizable impact at the National Human Genome Research Institute, leading to cuts to ongoing programs, scaling back of new ones, and the deferring of efforts that have not yet launched.

The five percent cut in funding this year at NHGRI has led not only to trimmed-down renewal grants and fewer, smaller awards broadly, but also has chopped the budget for some of the institute’s important programs, according to NHGRI Director Eric Green.

The programs that have either had their funding reduced, and in one case delayed, include the ENCODE (Encyclopedia of DNA Elements) program, projects focused on using genome sequencing in newborns and in clinical medicine, and other initiatives, Green said in his Director’s Report to the National Advisory Council on Human Genomics Research this week.

In addition, many renewal grants have been trimmed, and there are “numerous examples of detrimental cuts” to the institute’s intramural research program, said Green. These cuts to large and small NHGRI programs come at a pivotal time for genomics, he noted, as the products of such research are beginning to translate into clinical possibilities.

“It is tragic. [That] is the word I would use,” Green told GenomeWeb Daily News this week.

“[The field of genomics] is just so exciting. There are so many opportunities,” he said. “This is precisely the time that we should be pushing the accelerator hard, and we just cannot do it because we don’t have enough fuel in our fuel tank.

“It’s frustrating. I think the opportunities now are just spectacular,” said Green. “It’s tragic because it is just so obvious that we could do some remarkable things in genomics and we are not being able to do it.”

ENCODE, a decade-old flagship project at NIH that aims to identify all of the functional elements in the human genome, had its budget reduced by 16 percent.

The Genomic Sequencing and Newborn Screening Disorders program was cut by half, which left the program to fund fewer research projects than planned and its research consortium to go forward without the benefit of a data coordinating center. This new initiative, an effort to support pioneering studies on how sequencing might be used in the care of newborns and in neonatal care that was created jointly with the Eunice Kennedy Shriver National Institute of Child Health and Human Development, had its budget cut from $10 million to $5 million.

The Genomic Medicine Pilot Demonstration Projects program had its budget cut by 20 percent, and NHGRI’s Bioinformatics Resources and Analysis Research Portfolio had $5 million sliced out of its budget. The new Genomics of Gene Regulation (GGR)request for applications was bumped out of this funding year entirely, and has been delayed until 2014, according to Green.

Because the sequestration plan was concocted and agreed to well in advance of its arrival earlier this year, Green told GWDN that the institute did have some time to try to react to the sequestration and mitigate the pain from the cuts, spreading them around fairly and evenly while maintaining priorities. He said leadership at the institute tried to prepare for the possibility of sequestration by being conservative in its planning.

Programs that were already ongoing, like ENCODE, were likely to take priority over those that were not yet launched, like GGR, in part because the infrastructure is already in place for ongoing projects and because it is easier to plan for how they operate and generate outputs, like data.

“With ENCODE you know for every million dollars you invest you get so much back,” said Green. “With a program like newborn sequencing … we don’t totally know what it’s going to look like or play out like. We won’t know what we are missing because we won’t be able to launch it to the scale that we wanted to launch it originally.”

Green said some of the projects being cut or delayed were created under NHGRI’sstrategic plan, a program it laid out in 2011 that involves restructuring of the institute’s divisions and some shifting in its research portfolio to include more efforts in applying genomics to medicine and healthcare.

“Some of these RFAs that we delayed really represent key elements that we started to anticipate two years ago,” said Green. “We knew we wanted to do more in sequencing, we knew we wanted to do some pilot projects in genomic medicine. We knew we wanted to continue to accelerate efforts in understanding how the genome works … ENCODE, GGR, and so forth. It just had to be slowed down,” he said.

Anastasia Wise, program director for the Genomic Sequencing and Newborn Screening Disorders program, told GWDN that the program was supposed to be much larger than the $5 million in awards unveiled last week, which funded a consortium of four research projects.

Wise said NHGRI and NICHD were each initially planning to provide double the amount of funding they were actually awarded, which is now expected to be a total of $25 million over five years, although that total could be subject to the availability of funding.

“There were definitely more scientifically meritorious applications than we were able to fund,” she said. “Even the four awards that we made ended up being cut an additional five percent because of the sequestration.”

She said the program “wanted to be able to make more awards, and we wanted to be able to fund a coordinating center to be able to bring the network together and help provide some harmonization of data and coordination of logistics between the different members of the consortium,” but it was unable to fund that part of the effort.

Although the fractured fiscal culture in Washington engenders caution at NHGRI as the agency looks forward, Green sees many scientific opportunities right now, as genomics begins to hit the clinic.

“Some people are saying we are not even going fast enough,” he said. “Lots of people have been discussing what the world is going to look like when somebody gets their genome sequenced in the newborn period, and [they] think about what the implications of that are for the patient for the rest of their lives. We want to start studying this,” he said.

“And we are starting to … but we’re not starting as aggressively as we wanted to,” Green said. “I mean, we took a big hit this year.”

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 Matt Jones or follow GWDN’s headlines at @DailyNewsGW.

Related Stories

SOURCE

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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

and

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

Article ID #78: 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. Published on 9/13/2013

WordCloud Image Produced by Adam Tubman

INTRODUCTION

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

http://www.nih.gov/about/lmedia/goldberger.jpg

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

http://history.nih.gov/exhibits/history/assets/images/bengston_lg.jpg

cholera_sm cholera epidemic of 19th century (Koch bacillus)

http://history.nih.gov/exhibits/history/assets/images/cholera_sm.jpg

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

http://history.nih.gov/exhibits/history/assets/images/flowchart_sm.jpg

 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
Organizations.

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

http://www.nejm.org/na101/home/literatum/publisher/mms/journals/content/nejm/2013/nejm_2013.369.issue-2/nejmp1306051/20130708/images/small/nejmp1306051_f1.gif

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.

Causes_of_death_by_age_group

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
http://www.nejm.org/doi/full/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.

http://www.nejm.org/na101/home/literatum/publisher/mms/journals/content/nejm/2013/nejm_2013.368.issue-14/nejmp1303266/20130618/images/small/nejmp1303266_t1.gif

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
http://www.nejm.org/doi/full/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
http://www.nejm.org/doi/full/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.

Innovators-Prescription-New-Wave-of-Disruptive-Models-in-Healthcare

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

Medscape

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.

Introduction

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
http://www.dummies.com/how-to/content/healthcare-reform-2014-mandated-coverage-insurance.html

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
http://www.nejm.org/doi/full/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
 http://www.usatoday.com/story/news/nation/2013/09/12/health-insurance-sales-retail-stores-malls/2789897/

,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

http://www.linkedin.com/today/post/article/20130912184535-205372152-the-medical-breakthrough-nobody-s-talking-about

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.

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Issues in Personalized Medicine: Discussions of Intratumor Heterogeneity from the Oncology Pharma forum on LinkedIn

Curator and Writer: Stephen J. Williams, Ph.D.

Article ID #77: Issues in Personalized Medicine: Discussions of Intratumor Heterogeneity from the Oncology Pharma forum on LinkedIn. Published on 9/4/2013

WordCloud Image Produced by Adam Tubman

In an earlier post entitled “Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing” the heterogenic nature of solid tumors was discussed.  There resulted an excellent discussion in the Oncology Pharma forum on LinkedIn so I curated the comments (below article) to foster further discussion. To summarize the original post, this was a discussion of Dr. Charles Swanton’s paper[1] in which he and colleagues had noticed that individual biopsies from primary renal tumors displayed a variety of mutations of the same and different tumor suppressor genes (TSG), thereby not only revealing the heterogeneity of individual tumors but also how tumors can evolve.  Thus it was suggested that individual cells of a primary tumor can represent individual clones, each evolving on a distinct pathway to tumorigenicity and metastasis as each clone would have accumulated different passenger mutations.  It is these passenger mutations which have been posited to be responsible for a tumor’s continued growth (as discussed in the following post Rewriting the Mathematics of Tumor Growth; Teams Use Math Models to Sort Drivers from Passengers).  Indeed, as Dr. Swanton mentioned in the posting that it is very likely a solid tumor contains discrete clones with different driver and passenger mutations and possibly different mutated TSG but also this intra-tumor heterogeneity would have great implications for personalized chemotherapeutic strategies, not only against the primary tumor but against resistant outgrowth clones, and to the metastatic disease, as Swanton and colleagues had found that the metastatic disease displayed tremendously increased genomic instability than the underlying primary disease.

Therefore it may behoove the clinical oncologist to view solid tumors as a collection of multiple clones, each having their own mutagenic spectrum and tumorigenic phenotype.  Each of these clones may acquire further mutations which provide growth advantage over other clones in the early primary tumor.  In addition, branched evolution of a clone most likely depends more on genomic instability and epigenetic factors than on solely somatic mutation.

This is echoed in a  report in Carcinogenesis back in 2005[3] Lorena Losi, Benedicte Baisse, Hanifa Bouzourene and Jean Benhatter had shown some similar results in colorectal cancer as their abstract described:

“In primary colorectal cancers (CRCs), intratumoral genetic heterogeneity was more often observed in early than in advanced stages, at 90 and 67%, respectively. All but one of the advanced CRCs were composed of one predominant clone and other minor clones, whereas no predominant clone has been identified in half of the early cancers. A reduction of the intratumoral genetic heterogeneity for point mutations and a relative stability of the heterogeneity for allelic losses indicate that, during the progression of CRC, clonal selection and chromosome instability continue, while an increase cannot be proven.”

Therefore if a tumor had evolved in time closer to the initial driver mutation multiple therapies may be warranted while tumors which had not yet evolved much from their driver mutation may be tackled with an agent directed against that driver, hence the branched evolution as shown in the following diagram:

branced chain evolution cancer

Cancer Sequencing

Unravels clonal evolution.

From Carlos Caldas. (2012).

Nature Biotechnology V.30

pp 405-410.[2] used with

permission.

 

 

 

 

 

 

 

An article written by Drs. Andrei Krivtsov and Scott Armstron entitled “Can One Cell Influence Cancer Heterogeneity”[4] commented on a study by Friedman-Morvinski[5] in Inder Verma’s laboratory discussed how genetic lesions can revert differentiated neorons and glial cells to an undifferentiated state [an important phenotype in development of glioblastoma multiforme].

In particular it is discussed that epigenetic state of the transformed cell may contribute to the heterogeneity of the resultant tumor.  Indeed many investigators (initially discovered and proposed by Dr. Beatrice Mintz of the Institute for Cancer Research, later to be named the Fox Chase Cancer Center) show the cellular microenvironment influences transformation and tumor development[6-8].

Briefly the Friedman-Morvinski study used intra-cerebral ventricular (ICV) injection of lentivirus to introduce oncogenes within the CNS and produced tumors of multiple cell origins including neuronal and glial cell origin (neuroblastoma and glioma).  The important takeaway was differentiated somatic cells which acquire genetic lesions can transform to form multiple tumor types.  As the authors state, “cellular differentiation and specialization are accompanied by gradual changes in epigenetic programs” and that “the cell of origin may influence the epigenetic state of the tumor”.   In essence this means that the success of therapy may depend on the cellular state (whether stem cell, progenitor cell, or differentiated specialized cell) at time of transformation.  In other words tumors arising from cells with an epigenetic state seen in stem cells would be more resistant to therapy unless given an epigenetic therapy, such as azacytididne, retinoic acid or HDAC inhibitors.

 

So as the Oncology Pharma forum on LinkedIn was such an excellent discussion I would like to post the comments for curation purposes and foster further discussion.  I would like to thank everyone’s great comments below.  I would especially like to thank Dr. Emanuel Petricoin from George Mason and Dr. David Anderson for supplying extra papers which will be the subject of a future post. I had curated each comment with inserted LIVE LINKS to make it easier to refer to a paper and/or company mentioned in the comment.

The comments seemed to center on three main themes:

  1. 1.      Clinicians pondering the benefit to mutational spectrum analysis to determine personalized therapy and develop biomarkers of early disease
  2. 2.      A shift in the clinicians paradigm of cancer development, diagnoses, and treatment from strictly histologic evaluation to a genetic and altered cellular pathway view
  3. 3.      Use of proteomics, microarray and epigenetics as an alternative to mutational analysis to determine aberrant cellular networks in various stages of tumor development

 

Victor Levenson • Thanks for posting this! To be honest, I am puzzled by the insistence on sequencing as a tool for tumor analysis – we know that expression patterns rather than mutations in a limited number of genes determine tumor physiology (or, even more, physiology of any tissue). Since the AACR-2012 we know that different tumors have similar or even identical mutations, so >functional< rather than >structural< differences are important. Frankly, I’d be much more excited learning about expression pattern heterogeneity in tumors.Granted that is much more challenging than NGS sequencing, but the value of the data would be incomparable, especially in its application to biomarker development.

Stephen J. Williams, Ph.D. • Dear Dr. Levenson, thanks for your comments. I agree with you and in no way am insisting on the releiance of sequencing mutations in cancer as the sole means for determining therapy. It is extremely true that tumors will show tremendous heterogeneity of mRNA expression. There are a number of studies (one which I will post on pharmaceuticalintelligence.com) that individual tumor cells will have differing expression patterns based on the levels of regional hypoxia within the tumor as well as other microenvironmental factors. I do have two posts on pharmaceuticalintelligence.com on this matter, curating various programs around the world which are using microarray expression analysis of tumors to determine personalized strategies. I believe the reliance on mutational analysis is based on the drugs that have been developed (such as Gleevec and crizotinib) which are based on mutant forms of BCR-Abl and ALK, respectively. However (as per two posts I did based on Mike Martin on our site “Mathematical Models of Driver and Passenger mutations) where he discusses how certain driver mutations will get the senescent cell over the hump to get to fully transformed and contribute to a certain level of growth while subsequent passengers are responsible for the sustained survival and expansion of the tumor.

Victor Levenson • Dr. Williams, thanks for the comments. Driving a senescent cell into proliferative stage is a tremendous change, which >may< begin with a mutation, but involves dramatic restructuring of transcription patterns that will drive the process. Hypoxia will definitely contribute to variations in the patterns, although will probably not be the main driver of the process. As to whether a mutation or a change in transcription pattern initiate the process, I am not sure we will ever be able to determine <grin>.

Vanisree Staniforth • Thanks for posting! Certainly a thought provoking article with regard to the future of personalized cancer therapies.

 

Dr. Raj Batra • If we follow Dr Levenson’s proposed conceptual approach (which we also published in 2009 and 2010), we are MUCH more likely to significantly impact tumor morbidity and mortality.

Stephen J. Williams, Ph.D. • Thanks Vanisiree and Dr. Batra for your comments. Hopefully we will see, from the future cancer statistics, how personlized therapy have improved outcomes for the solid tumors, like the hematologic cancers. 26 days ago

Emanuel Petricoin • The issue about intra and inter tumor heterogeneity is very important however since it is unknown which mutations are true drivers, an explanation of the results found in these studies simply could be the variances are all in the inconsequential mutations and the commonality is the driver mutations. Moreover, at the end of the day, its not the mRNA expression that we really care about but the functional protein signaling -phosphoprotein driven signaling architecture, that we care about since these are the drug targets directly.

Mohammad Azhar Aziz,PhD • This article addresses the potential complexity of dealing with cancer which is apparently increasing proportionally with the amount of data generated. Intratumor heterogeneity will remain there and even multiple biopsies that are randomly chosen will offer no conclusive solution.Mutations,expression profiles and functional protein signaling (as discussed above) alone can not provide any breakthrough. It will be a composite picture of all these and many other components (e.g. microenvironment, alternative splicing, epigenetics,non-coding RNAs etc.) that will hold the promises in the future. We have made phenomenal advances in understanding each of these aspects separately but definitely lack the tools to integrate all these. Developing tools to integrate all these data may provide some breakthrough in understanding and thus treating cancer.

Emanuel Petricoin • I agree Mohammad in a systems biology approach however the current compendium of drugs largely are kinase inhibitors or enzymatic inhibitors. Since most studies have shown little correlation between gene mutation and protein levels and phosphoprotein levels, for example, it is no wonder why the recent spate of failed trials (e.g. stratification by PIK3CA mutation or PTEN mutation for AKT-mTOR inhibitors) should come as any shock. We will be publishing work using protein pathway activation mapping coupled to laser dissection of a number of intra and inter tumoral analysis that indicates that the signaling architecture appears much more stable.

Stephen J. Williams, Ph.D. • Thank you Dr. Pettricoin for your comments. I eagerly await the publication of your results concerning proteomic evaluation of multiple biopsies of a tumor. I am very interested that you found limited intratuoral heterogeneity of signaling pathways given the diversity of intratumoral microenvironmental stresses (changes in regional hypoxia, blood flow, and populations of cancer stem cells). I agree with you and Mohammed that proteomic profiling will be imperative in determining personalized approaches for targeted therapy. Dr. Swanton had informed me that they had used IHC to determine if mTOR signaling had correlated with the mutational spectrum they had seen. In addition he had mentioned that there was enhanced genomic instability in the metastatic disease relative to the primary tumor and it would be very interesting to see how signaling pathways change in cohorts of matched metastatic and primary tumors. A few years ago we were looking at genes which were completely lost upon transformation of ovarian epithelial cells and worked up one of those genes (CRBP1) in cohorts of human ovarian cancer samples, using expression analysis in conjunction with laser capture microdissection and backed up by IHC analysis, and found that the expression pattern of CRBP1 was uniform in a tumor, either there was a complete loss in all cells in a tumor of CRBP1 or all the cells expressed the protein. Therefore I am curious if intratumor heterogeneity is dependent on the cell lineage and evolution of the transformed cell into a full tumor or a function of a discrete population of stem cells with varied genomic instability. Your results might suggest a more clonal evolution rather than a branched evolution which was found in this paper.
It is interesting that you mention the tough trials with the PTEN/PI3K/AKT axis of inhibitors. In high grade serous ovarian cancer we were never able to find any PI3K, PTEN, nor AKT mutations yet PI3K activity is usually overactive. If feel both your and Mohammed’s assessment that a systems biology approach instead of just relying on DNA mutational analysis will be more important in the future. In addition, there is nice work from Dr. Jefferey Peterson at Fox Chase and the development of a database of kinase inhibitors and activity effects on the kinome, showing the vast amount of crosstalk between once thought linear enzyme systems. If TKI’s will be the brunt of pharma’s development I feel they need to quickly develop as many TKI’s as they can now before we get to a clinical problem (resistance and lack of available therapeutics).

Emanuel Petricoin • Thanks Steven- yes, we are working with Charlie Swanton and Marco on the renal sets- our other studies are from breast and colon cancers. I think one of the things we do that really no one else is doing, unfortunately, is to laser capture microdissect the tumor cells from these specimens so that we have a more pure and accurate view of the signaling architecture. One confounder from the proteomic stand-point is the fact that pre-analytical variables such as post-excision delay times where the tissue is a hypoxic wound and signaling changes fluctuating as the tissue reacts to the ex-vivo condition can really effect things. When we look at tissue sets where the tissue is biopsied and immediately frozen we really dont see big differences in the signaling – the within tumor architecture is much more similar then between. We use the reverse phase array technology we invented to provide quantitative analysis on hundreds of phosphoproteins at once – so a nice view of the functional protein activation network. Your results of CRBP1 in ovarian tumors and the IHC data are very interesting. We will see how this all plays out. Of course once other confounder with the mutational data is that we really dont know what are the drivers and what are the passengers…
Yes I know Jeff Peterson’s work- its fantastic. In the end the hope I think- and in my personal opinion- will be rationally combined therapeutics based on the signaling architecture of each individual patient.

Incidentally, we just published a paper that you may be interested in from a “systems biology” standpoint-

SYSTEMS ANALYSIS OF THE NCI-60 CANCER CELL LINES BY ALIGNMENT OF PROTEIN PATHWAY ACTIVATION MODULES WITH “-OMIC” DATA FIELDS AND THERAPEUTIC RESPONSE SIGNATURES.

Federici G, Gao X, Slawek J, Arodz T, Shitaye A, Wulfkuhle JD, De Maria R, Liotta LA, Petricoin EF 3rd. Mol Cancer Res. 2013 May

also- we published a paper that speaks directly to your point where we compared the signaling network activation of patient-matched primary colorectal cancers and synchronous liver mets. indeed there is huge systemic differences in the liver metastasis compared to the primary. there is no doubt in my mind that we will need to biopsy the metastasis to know how to treat. Looking at the primary tumor as a guide for therapy is a fools errand. here is the paper reference:

Protein pathway activation mapping of colorectal metastatic progression reveals metastasis-specific network alterations.

Silvestri A, Calvert V, Belluco C, Lipsky M, De Maria R, Deng J, Colombatti A, De Marchi F, Nitti D, Mammano E, Liotta L, Petricoin E, Pierobon M.

Clin Exp Metastasis. 2013 Mar;30(3):309-16. doi: 10.1007/s10585-012-9538-5. Epub 2012 Sep 29.

Center for Applied Proteomics and Molecular Medicine, George Mason University, 10900 University Blvd., Manassas, VA, 20110, USA.

Abstract

The mechanism by which tissue microecology influences invasion and metastasis is largely unknown. Recent studies have indicated differences in the molecular architecture of the metastatic lesion compared to the primary tumor, however, systemic analysis of the alterations within the activated protein signaling network has not been described. Using laser capture microdissection, protein microarray technology, and a unique specimen collection of 34 matched primary colorectal cancers (CRC) and synchronous hepatic metastasis, the quantitative measurement of the total and activated/phosphorylated levels of 86 key signaling proteins was performed. Activation of the EGFR-PDGFR-cKIT network, in addition to PI3K/AKT pathway, was found uniquely activated in the hepatic metastatic lesions compared to the matched primary tumors. If validated in larger study sets, these findings may have potential clinical relevance since many of these activated signaling proteins are current targets for molecularly targeted therapeutics. Thus, these findings could lead to liver metastasis specific molecular therapies for CRC.

Adrian Anghel • I think both patterns (protein phosphorylation and mRNA) should be important in this complicated equation of heterogeneity. Let’s not forget the so-called functional miRNA-mRNA regulatory modules (FMRMs). Also I think we have different patterns of this heterogeneity for different evolutive stages of the tumour.

 

Alvin L. Beers, Jr., M.D. • This is a great study, but bad news for attempting to tailor treatment based on molecular markers. Dr. Swanton’s comment: “herterogeneity is likely to complicate matters” is an understatement. Intratumoral heterogeneity, branched, instead of linear, evolution of mutational events portends a nightmare in trying to predict location and volume of biopsies. I am reminded of a series of articles in Nature 491 (22 November 2012) “Physical Scientists take on Cancer”. There is a great comment by Jennie Dusheck: “Cancer researchers now recognize that taming wild cancer cells – populations of cells that evolve, cooperate, and roam freely through the body-demand a wider-angle view than molecular biology has been able to offer. Cross-disciplinary collaborations can approach cancer a greater spatial and temporal scales, using mathematical methods more typical of engineering, physics, ecology and evolutionary biology. The sense of failure so evident five years ago is giving way to the excitement of a productive intellectual partnership.” I’m not certain how well the “productive partnership” is going, but this Swanton study confirms the limitations of molecular biology.

Stephen J. Williams, Ph.D. • Thanks Dr. Beers for adding in your comment and adding in Jennie’s comment. Certainly it is something to be aware of if a cancer center’s strategy is to rely solely on gene arrays to genotype tumors. I think Dr. Pettricoin’s work on using proteomics might give some resolution to the matter however, in communicating with Dr. Swanton, I did not get the feeling of an “all hope is lost” but just that, in the case of solid tumors like renal, that careful monitoring of tumors after treatment may be warranted and, more interestingly, from a scientific standpoint, is the genetic complexity surrounding the origin of the disease, and not simple mutational spectrum of a single clone.

Burke Lillian • This is clinically a very important issue. Right now, sequencing or massive approaches such as pan-phosphorylation studies are helpful because, although we know many of the drivers, these studies are actually identifying new genes or new pathways that are activated. After a few (or several years), we truly will know which genes are typically activated and there will be panels to look for these.

Emanuel Petricoin • yes, I agree. In fact, the company that I co-founded, Theranostics Health, Inc– is launching a CLIA based protein pathway activation mapping test at ASCO that measures actionable drug targets (e.g. phospho HER2, EGFR, HER3, AKT, ERK, JAK, STAT, p70S6) and total HER2, EGFR, HER3 and PTEN. So these tests are coming even now.

 

Alvin L. Beers, Jr., M.D. • I do not think that “all hope is lost” nor did I have the impression that Dr. Swanton feels that way with regards to molecular profiling of cancer. I certainly applaud further research into the molecular aspects of cancer biology. But I do not believe that this will be sufficient. Integrating physicial sciences into cancer biology makes perfect sense toward better understanding of this complex disease.

Eleni Papadopoulos-Bergquist • I have enjoyed reading these comments and different ideas regarding genetic testing and profiling. As a nurse and researcher at heart, this is information that will make a huge impact on drug protocols, therefore allowing the best and most specific treatment to each individual rather than having a standard treatment protocol. Even with the scientific complexity of specifying genotypes of particular cancers, there is still the question of each individuals body responding to treatment. I’d love to have some dialogue regarding immune response.

Bradford Graves • I too have enjoyed reading this discussion. I am not a clinician but as a drug discovery researcher I have been struck by some parallels to the concept of virus fitness in virology – particularly as applied to HIV. Drug discovery cannot wait for the final answers to the many important questions being addressed in the discussion initiated by Dr. Williams. The best we can do is to pursue a broad range of therapeutics that will give the clinicians the armament they will need to either cure a given cancer or to at least turn it into a chronic as opposed to an acute disease. There has been a measure of success in the HIV field and it seems like it will be achievable for cancer. Obviously, to the extent that the labels of driver and passenger mutations can be correctly applied will help to prioritize the targets we address.

David W. Anderson • I would suggest that you look at the following publications:

Horn and Pao, (2009) JCO 26: 4232-4234.

Bunn and Doebele (2011) JCO:29:1-3

Boguski et al. (2009) Customized care 2020: how medical sequencing and network biology will enable personalized medicine. F1000 Bio Report 1:7.

Jones, S et al. (2010). Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors. Genome Biology. 11:R82. Marco Marra’s group in Toronto.

Also look at how companies and organizations like Foundation Medicine, Caris, Clarient, and CollabRx who are using genomics and sequencing on a large scale to address cancer from a personalized/individual approach.

Cancer is/will be a chronic disease requiring individualized/combinatorial therapies in many cases.

Alvin L. Beers, Jr., M.D. • David. These are excellent articles by Paul Bunn and Mark Boguski regarding integrating molecular markers into diagnostic evaluation, and I’ve seen other papers of similiar elk, and likely there will be more to come. Particularly in NSC lung cancer, the SOC is to use these markers up front. Diagnosis based on histology alone can no longer be recommended. The challenge for the future is how to integrate other aspects of cell biology with these markers. It remains daunting that not only do we see heterogeneity in molecular within tumors at a particularly point in time, but that there is often an evolution of markers over time, ie, a “plasticity” of markers, whether treatment is given or not. We know that targeted agents, TKI’s, enzyme inhibitors are not curative, but do give an improvement in PFS. A great deal of this resistance has to do with this “moving target” aspect of cancer cell biology..

 

References:

1.         Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P et al: Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. The New England journal of medicine 2012, 366(10):883-892.

2.         Caldas C: Cancer sequencing unravels clonal evolution. Nature biotechnology 2012, 30(5):408-410.

3.         Losi L, Baisse B, Bouzourene H, Benhattar J: Evolution of intratumoral genetic heterogeneity during colorectal cancer progression. Carcinogenesis 2005, 26(5):916-922.

4.         Krivtsov AV, Armstrong SA: Cancer. Can one cell influence cancer heterogeneity? Science 2012, 338(6110):1035-1036.

5.         Friedmann-Morvinski D, Bushong EA, Ke E, Soda Y, Marumoto T, Singer O, Ellisman MH, Verma IM: Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science 2012, 338(6110):1080-1084.

6.         Mintz B, Cronmiller C: Normal blood cells of anemic genotype in teratocarcinoma-derived mosaic mice. Proceedings of the National Academy of Sciences of the United States of America 1978, 75(12):6247-6251.

7.         Watanabe T, Dewey MJ, Mintz B: Teratocarcinoma cells as vehicles for introducing specific mutant mitochondrial genes into mice. Proceedings of the National Academy of Sciences of the United States of America 1978, 75(10):5113-5117.

8.         Mintz B, Cronmiller C, Custer RP: Somatic cell origin of teratocarcinomas. Proceedings of the National Academy of Sciences of the United States of America 1978, 75(6):2834-2838.

 

 

Other articles on this site on “PERSONALIZED MEDICINE” and “CANCER” and “OMICS” include:

Personalized medicine-based diagnostic test for NSCLC

Personalized medicine and Colon cancer

Helping Physicians identify Gene-Drug Interactions for Treatment Decisions: New ‘CLIPMERGE’ program – Personalized Medicine @ The Mount Sinai Medical Center

Systems Diagnostics – Real Personalized Medicine: David de Graaf, PhD, CEO, Selventa Inc.

Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

Personalized Medicine: Clinical Aspiration of Microarrays

Understanding the Role of Personalized Medicine

Directions for Genomics in Personalized Medicine

Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1

Rewriting the Mathematics of Tumor Growth; Teams Use Math Models to Sort Drivers from Passengers

Diagnosing Diseases & Gene Therapy: Precision Genome Editing and Cost-effective microRNA Profiling

Breast Cancer: Genomic profiling to predict Survival: Combination of Histopathology and Gene Expression Analysis

Proteomics and Biomarker Discovery

 

 Also please see our upcoming e-book “Genomics Orientations for Individualized Medicine” in our Medical E-book Series at http://pharmaceuticalintelligence.com/biomed-e-books/genomics-orientations-for-personalized-medicine/volume-one-genomics-orientations-for-personalized-medicine/

 

 

 

 

 

 

 

 

 

 

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Reporter: Aviva Lev-Ari, PhD, RN

We reported similar observations in the past:

Watch Out SF, Boston Is Turning Into Biotech’s No. 1 Cluster

http://www.xconomy.com/national/2012/10/08/watch-out-sf-boston-is-becoming-biotechs-no-1-cluster/2/

Transforming Biotech & Pharma: LinkedIn is the Quiet Force by Timmerman

Massachusetts Continues to Lead Biopharma Industry

August 20, 2013

Annual statistics show growth in MA with other clusters on the rise

August 20, 2013 (Cambridge, MA) – Massachusetts biopharma employment continues to grow in Massachusetts, though some other clusters are outpacing the Commonwealth, according to an annual industry report published by MassBio.

The 2013 MassBio Industry Snapshot shows Massachusetts continues to lead the nation in research & development jobs, federal research funding and venture capital investment per capita, but smaller biotech clusters, such as Washington and New York are growing at faster rates as governments increasingly court the industry as an economic development engine.

“Let’s be clear, Massachusetts remains far and away the most robust cluster for industry research and investment, and we continue to grow our presence,” said MassBio President & CEO Robert K. Coughlin. “But we cannot take our eyes off the ball, as the nation and the world try to rebound from the recent recession. We must continue to advocate for policy and regulatory structures that encourage innovation and work to speed the time to market for therapies for patients in need.”

This year’s Snapshot will lay the foundation for the 2020 Report, a strategic report for the industry commissioned by MassBio every five years. The 2020 Report will be produced in partnership with Weston-based Health Advances and completed by spring 2014.

Massachusetts employment in the biopharma industry rose to 56,462 in 2012, based on data from the U.S. Bureau of Labor Statistics’ Quarterly Cen­sus of Employment and Wages (QCEW) and, for the first time, factoring medical testing laboratory employment as part of the industry.

Massachusetts still leads the nation in biotechnology R&D jobs, a segment of the larger industry employment, with more than 27,800 positions in 2012 and maintained its position as the leader in R&D in biotechnology, as defined by industry concentration.

Since 2007, Massachusetts added 3,227 jobs in biotechnology R&D. While this number of jobs added is second only to California (4,304), Massachusetts’ 13.1% growth was outpaced by other clusters, including California (+22.5%), New York  (+41.7%) and Washington (+53.8%).

New this year, MassBio looked at medical device manufacturing in Massachusetts. With 23,151 employees in 2012, the Commonwealth has paced closely to the national growth rate of 2% over the last decade. Only California and Minnesota employ more in the medical device industry, while Minnesota and Massachusetts have the strongest industry concentrations across medical instrument manufacturing industries.

Venture investment in biotech declined 15% across the nation in 2012, and venture investment in Massachusetts biotechs declined from 2011’s all-time high to $838 million in 2012.

Additional highlights from the report include:

  • Massachusetts biopharma industry employment reached an all-time high in 2012, continuing the industry’s pattern of growth, and now accounts for over $6.5 billion in payroll.
  • The estimated average salary in the biopharma industry is $115,290, 89% higher than the estimated state average salary of $60,901.
  • Nationally, biopharma manufacturing employment has declined by 8% since 2002. Massachusetts ran counter to the trend, as one of only four leading biomanufacturing states that grew employment since 2002.
  • Massachusetts-headquartered companies have a total of 1,174 drug candidates at some stage of R&D.
  1. Oncology drug candidates make up 37% of that pipeline with
  2. systemic anti-infectives,
  3. central nervous system, and
  4. musculoskeletal therapeutics as other strong areas of research.
  • Massachusetts accounts for 11.3% of the U.S.-based drug development pipeline. Massachusetts-headquartered companies account for 5% of the global biologics pipeline.
  • The top three NIH-funded independent hospitals in the U.S. in 2012 are in Boston. Nine of the top 18 are in Massachusetts.
  • On an NIH-funding per capita basis, Massachusetts continues to far exceed other leading NIH-recipient states.
  • Since 2007, just under 2.6 million square feet of commercial lab space has been added to inventory in Massachusetts. Over 2 million square feet of new lab space is currently under construction.

This year’s Snapshot was again produced in partnership with EvaluatePharma USA, Inc., the premier source for commercial analysis of the pharma and biotech sector. Snapshot statistics are compiled annually by MassBio from sources including EvaluatePharma, the U.S. Bureau of Labor Statistics, the Quarterly Census of Employment & Wages and others.

“The 2013 MassBio Industry Snapshot confirms Massachusetts biotech job growth remains strong and is fueled by the local R&D activities.” said Debbie Paul, EvaluatePharma CEO of Americas. “We are proud to support MassBio’s industry analysis, and look forward to the findings of the 2020 Report in the spring.”

The Snapshot findings will be used in MassBio’s 2020 Report in conjunction with stakeholder interviews and analysis of market factors, business trends and competitive clusters. The 2020 Report will include a plan that outlines a clearly articulated vision for the continued growth of the life sciences industry as economics, business models, policies and healthcare practices continue to shift through the next several years. It will assess the critical events, trends, policies and discoveries that will impact the life sciences sector through 2020 and make recommendations to ensure that the industry thrives in Massachusetts for generations to come.

MassBio 2013 Industry Snapshot

For more information on the Massachusetts cluster, or the 2020 Report, visitwww.MassBio.org.

 SOURCE

http://www.massbio.org/news/397-massachusetts_continues_to_lead_biopharma_industry/news_detail?goback=%2Egde_65240_member_267256778#%21

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