This issue of JAMA is a theme issue on professionalism and self-governance in medicine across the spectrum of physician education and clinical practice, with particular attention to maintenance of certification, which has become highly contentious. Nineteen Viewpoints and 3 Editorials by leading scholars and academic leaders consider the roles and responsibilities of governing and accrediting bodies and of professional organizations and societies for ensuring effective governance and professionalism in medicine.

The following Viewpoints and Editorials are available pre-embargo at https://media.jamanetwork.com/.

Viewpoints Appearing in this Issue of JAMA

Embargoed for Release: 11 a.m. ET Tuesday, May 12, 2015

Self-Governance and Self-Regulation

Ensuring Competency and Professionalism Through State Medical Licensing

Humayun J. Chaudhry, D.O., M.S., Federation of State Medical Boards, Euless, Texas, and colleagues

Professionalism, Self-Regulation, and Motivation – How Did Health Care Get This So Wrong?

James L. Madara, M.D., and Jon Burkhart, American Medical Association, Chicago

Aiming Higher to Enhance Professionalism – Beyond Accreditation and Certification

Mark R. Chassin, M.D., M.P.P., M.P.H., and David W. Baker, M.D., M.P.H., The Joint Commission, Oakbrook Terrace, Il.

Education and Professionalism

Undergraduate Medical Education and the Foundation of Physician Professionalism

Darrell G. Kirch, M.D., Association of American Medical Colleges, Washington, D.C., and colleagues

Enhancing Professionalism Through Management

Ezekiel J. Emanuel, M.D., Ph.D., University of Pennsylvania, Philadelphia

Professionalism and its Implications for Governance and Accountability of Graduate Medical Education in the United States

Thomas J. Nasca, M.D., M.A.C.P., Accreditation Council for Graduate Medical Education, ACGME International, Chicago

Postgraduate Education of Physicians – Professional Self-Regulation and External Accountability

Donald M. Berwick, M.D., M.P.P., Institute for Healthcare Improvement, Cambridge, Mass.

Board Certification and Lifelong Learning

Of the Profession, by the Profession, and for Patients, Families, and Communities – ABMS Board Certification and Medicine’s Professional Self-Regulation

Lois Margaret Nora, M.D., J.D., M.B.A., American Board of Medical Specialties, Chicago, and colleagues

Professional Self-Regulation in a Changing World – Old Problems Need New Approaches

Richard J. Baron, M.D., American Board of Internal Medicine, Philadelphia

The Role of Maintenance of Certification Programs in Governance and Professionalism

Paul S. Teirstein, M.D., and Eric J. Topol, M.D., Scripps Health, La Jolla, Calif.

Medicine’s Continuous Improvement Imperative

Robert S. Huckman, Ph.D., and Ananth Raman, Ph.D., M.B.A., Harvard Business School, Boston

Reforming the Continuing Medical Education System

Steven E. Nissen, M.D., Cleveland Clinic, Cleveland, Ohio

Professionalism and Employment

Redesigning Metrics to Integrate Professionalism Into the Governance of Health Care

Vivian S. Lee, M.D., Ph.D., M.B.A., University of Utah, Salt Lake City

Physician Professionalism in Employed Practice

Francis J. Crosson, M.D., former executive director of the Permanente Federation, Kaiser Permanente

Professionalism, Fiduciary Duty, and Health-Related Business Leadership

Joshua D. Margolis, Ph.D., M.A., Harvard Business School, Boston

Perspectives on Medical Professionalism

The Transformation of U.S. Physicians

Victor R. Fuchs, Ph.D., and Mark R. Cullen, M.D., Stanford University, Stanford, Calif.

Governance and Professionalism in Medicine – A UK Perspective

Harvey Marcovitch, F.R.C.P., F.R.C.P.C.H., Honeysuckle House, Oxfordshire, England

Maintaining Physician Competence and Professionalism – Canada’s Fine Balance

1. David Naylor, M.D., D.Phil., University of Toronto, Canada

Medical Professionalism and the Future of Public Trust in Physicians

Noam N. Levey, Los Angeles Times/Tribune Washington Bureau, Washington, D.C.

Editorials Appearing in this Issue of JAMA

Embargoed for Release: 11 a.m. ET Tuesday, May 12, 2015

Professionalism, Governance, and Self-Regulation of Medicine

Howard Bauchner, M.D., JAMA, Chicago

Medical Professionalism

Catherine D. DeAngelis, M.D., M.P.H., Johns Hopkins Schools of Medicine and Public Health, Baltimore

Tasking the “Self” in the Self-Governance of Medicine

Jordan J. Cohen, M.D., Arnold P. Gold Foundation, Englewood Cliffs, N.J.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 12, 2015

Media Advisory: To contact Kate Smolina, Ph.D., call Heather Amos at 604-822-3213 or email heather.amos@ubc.ca.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.3642

Public Health Advisories Associated With Reductions in Dispensing of Codeine to Postpartum Women

Public health advisories from the U.S. Food and Drug Administration (FDA) and Health Canada were associated with significant reductions in the rate of dispensing of codeine to postpartum women, according to a study in the May 12 issue of JAMA.

Some patients are ultra-rapid metabolizers of codeine, with prevalence ranging from 2 percent to 40 percent. Nursing mothers who take codeine may be putting their infant at risk if they carry the gene variants for elevated activity of an enzyme that metabolizes codeine to morphine. High levels of morphine in breast milk may lead to infant death from a drug-induced respiratory problem. The U.S. FDA released a public health advisory in August 2007 warning about the potentially life-threatening adverse effects in infants of breast-feeding mothers taking codeine. Health Canada published a similar advisory in October 2008, according to background information in the article.

Kate Smolina, Ph.D., of the University of British Columbia, Vancouver, Canada, and colleagues examined postpartum codeine use among all women with live births between January 2002 and December 2011 in British Columbia to evaluate the rate of codeine dispensations before and after the two regulatory advisories. Information about prescription dispensations came from BC PharmaNet, a comprehensive database of every prescription filled outside of acute care hospitals, regardless of patient age or insurance status.

During the study period, there were 320,351 live births to 225,532 women. Of these, new mothers filled at least 1 codeine prescription during 47,095 postpartum periods. Before the FDA advisory, the monthly average for the proportion of postpartum mothers filling at least 1 codeine prescription was 17 percent, which declined to a monthly average of 9 percent from September-December 2011, a 45 percent relative reduction over 4 years.

The authors write that the reduction may reflect the adoption of the recommendations by clinicians. “Some of the reduction could also reflect changes in patient behavior, including not filling written prescriptions, not asking for codeine, or both. The speed and the magnitude of the response suggests that regulatory warnings regarding postpartum drug safety can have a strong influence on prescribing patterns.”

(doi:10.1001/jama.2015.3642; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by a Canadian Institutes for Health Research (CIHR) grant. Dr. Smolina is funded in part by a CIHR Banting postdoctoral fellowship. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 10 A.M. (ET) MONDAY, MAY 4, 2015

Media Advisory: To contact Rahul Rajkumar, M.D., J.D., call Raymond Thorn of CMS Media Relations at 202-690-6145 or email press@cms.hhs.gov. To contact Lawrence P. Casalino, M.D., Ph.D., email Jennifer Gundersen at jeg2034@med.cornell.edu. To contact Mark McClellan, M.D., Ph.D., email Michelle Shaljian at mshaljian@brookings.edu.

To place an electronic embedded link to this study and editorials in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.4930. This will be the link to the 1^st editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.5086. This will be the link to the 2^nd editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.5087.

Pioneer Accountable Care Organization Model Shows Smaller Increases in Medicare Spending

In the first 2 years of the Pioneer Accountable Care Organization (ACO) Model, beneficiaries aligned with these ACOs, as compared with general Medicare fee-for-service beneficiaries, showed smaller increases in total Medicare expenditures, with an estimated savings of approximately $385 million, according to a study published by JAMA. The study is being released to coincide with an announcement by the Centers for Medicare & Medicaid Services (CMS) about the performance of the Pioneer ACO model.

In 2012, the CMS launched the Pioneer ACO Model and the Medicare Shared Savings Program as alternative payment approaches to engage physicians and health care organizations willing to assume collective responsibility for the cost and quality outcomes of a specified population of fee-for-service (FFS) Medicare beneficiaries. As part of the incentive to participate, Pioneer ACOs with an annual spending level lower than a projected spending level can receive a portion of the difference between their spending and the projection as shared savings with CMS, conditional on their performance on a set of 33 quality measures. The Pioneer ACO Model is one of several attempts to test the viability of the ACO concept as means to improve quality of care and reduce spending in the U.S. health care system, according to background information in the article.

Rahul Rajkumar, M.D., J.D., of the Centers for Medicare & Medicaid Services, Baltimore, and colleagues determined whether FFS beneficiaries aligned with 32 Pioneer ACOs (n = 675,712 in 2012; n = 806,258 in 2013) had smaller increases in spending and utilization than other FFS beneficiaries (a comparison group of alignment-eligible beneficiaries in the same markets [n = 13,203,694 in 2012; n = 12,134,154 in 2013]) while retaining similar levels of care satisfaction in the first 2 years of the Pioneer ACO Model.

The researchers found that total spending for beneficiaries aligned with Pioneer ACOs in 2012 or 2013 increased from baseline (2010-2011) to a lesser degree relative to comparison populations. Differential changes in spending were approximately -$35.62 per-beneficiary-per-month (PBPM) in 2012 and -$11.18 PBPM in 2013, which amounted to aggregate reductions in increases of approximately -$280 million in 2012 and -$105 million in 2013.

A large portion of the smaller increase in spending was from decreases in inpatient utilization among ACO-aligned beneficiaries, although greater decreases in primary care evaluation and management office visits, and smaller increases in the use of tests, procedures, and imaging services also were related to the observed differences in changes in spending. There was no difference in all-cause readmissions within 30 days of discharge, but follow-up visits after hospital discharge increased more for ACO-aligned beneficiaries.

Compared with other Medicare beneficiaries, ACO-aligned beneficiaries reported higher average scores for timely care and for clinician communication.

“These results are encouraging, given how historically challenging it has been for physicians to achieve spending reductions in Medicare demonstration projects,” the authors write. “Despite decreases in spending growth, results from this study and previously reported data on Pioneer ACOs’ performance on clinical quality measures suggest it is possible to reduce expenditure growth while maintaining or improving quality in a FFS payment environment.”

(doi:10.1001/jama.2015.4930; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Pioneer Accountable Care Organizations – Traversing Rough Country

Lawrence P. Casalino, M.D., Ph.D., of Weill Cornell Medical College, Healthcare Policy and Research, New York, comments on the findings of this study in an accompanying editorial.

“Nyweide et al estimated that Pioneer ACOs achieved savings for CMS of $280 million in their first year. This represents a savings of approximately 4 percent. This amount may seem small, but if this rate of savings could be sustained, and achieved throughout a large part of the U.S. health care system, it would be more than enough to ‘bend the cost curve’ so that health care expenditures do not continue to increase as a percentage of the gross domestic product and the federal budget.”

“Can this rate of savings be sustained? The Pioneer ACOs produced savings in year 2 that were one-third of year 1 savings. It is possible that during the first year these ACOs were able to ‘grasp the low hanging fruit’—to address relatively easy ways to control costs—and that the savings they generate will be much smaller, at best, in subsequent years. Alternatively, it may be that it will take time for ACOs to develop better processes to improve the care of their patients and that they will be able to continue to lower costs for years to come.”

“The number of ACO­like contracts between private insurers is increasing rapidly. The next 5 years will be critical in determining if ACOs can indeed maintain or improve quality of care at a time when new therapies are emerging and simultaneously control the rise of health care costs.”

(doi:10.1001/jama.2015.5086; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

Editorial: Accountable Care Organizations and Evidence-Based Payment Reform

“This early evidence moves the effects of ACOs from speculation to reality and highlights the importance of further evaluation as alternative payment models are refined,” writes Mark McClellan, M.D., Ph.D., of The Brookings Institution, Washington, D.C., in an accompanying editorial. “Payment reform moving away from FFS is now part of the policy landscape, but the exact form it will take is less clear. Evaluations like this derived from actual payment reforms can provide more clarity.”

“Incorporating evaluations like this alongside the implementation of further ACO payment reforms would help ensure that many health care organizations do not end up in alternative payment models that are not improving care and also would provide more evidence that clinicians could use to succeed in ACOs. Payment reform has a long way to go, but it is possible for further steps to be guided by the development of better evidence. Reforming care to achieve better outcomes and lower costs is not easy, even with financing that is better aligned. Nonetheless, an increasing number of diverse health care organizations are demonstrating that it is possible.”

(doi:10.1001/jama.2015.5087; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 5, 2015

Media Advisory: To contact Fred Poordad, M.D., call Rosanne Fohn at 210-567-3026 or email fohn@uthscsa.edu. To contact Andrew J. Muir, M.D., call Samiha Khanna at 919-419-5069 or email samiha.khanna@duke.edu. To contact editorial author Hari Conjeevaram, M.D., M.Sc., call Shantell Kirkendoll at 734-764-2220 or email smkirk@umich.edu.

To place an electronic embedded link to these studies and editorial in your story This link to the 1^st study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.3860. This link to the 2^nd study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.3868. This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.4368.

Studies Show Effectiveness of New Combination Treatment for HCV Patients With or Without Cirrhosis

In two studies appearing in the May 5 issue of JAMA, patients with chronic hepatitis C virus (HCV) genotype 1 infection and with or without cirrhosis achieved high rates of sustained virologic response after 12 weeks of treatment with a combination of the direct-acting-antiviral drugs daclatasvir, asunaprevir, and beclabuvir.

Current estimates indicate that 130 million to 150 million people worldwide are chronically infected with HCV, resulting in up to 350,000 deaths per year. Of the 7 HCV genotypes identified, genotype 1 is the most prevalent worldwide, accounting for approximately 60 percent of infections. Treatment options for HCV genotype 1 are evolving rapidly from interferon-based regimens to all-oral, direct-acting antiviral only regimens.

In one study, Fred Poordad, M.D., of the University of Texas Health Science Center, San Antonio, Texas, and colleagues determined the rates of sustained virologic response (SVR) in patients receiving a twice-daily combination of daclatasvir, asunaprevir and beclabuvir (DCV-TRIO regimen). The study included both treatment-naive (n = 312) and patients who had previously received treatment (n = 103) for HCV genotype 1 infection and who did not have cirrhosis. This international study (UNITY-1) was conducted at 66 sites in the United States, Canada, France, and Australia. Sustained virologic response was defined as HCV-RNA <25 IU/ml at post-treatment week 12 (SVR12).

Overall, SVR12 was observed in 379 of 415 patients (91.3 percent): 287 of 312 treatment-naive patients (92 percent) and 92 of 103 treatment-experienced patients (89.3 percent). Virologic failure occurred in 8 percent of patients.

One patient died at post-treatment week 3: this was not considered related to study medication. There were 7 serious adverse events, all considered unrelated to study treatment, and 3 adverse events (<1 percent) leading to treatment discontinuation. The most common adverse events (in ≥ 10 percent of patients) were headache, fatigue, diarrhea, and nausea.

“This study demonstrates that 12 weeks of therapy with the DCV-TRIO regimen without ribavirin was associated with high rates of SVR12 in patients with HCV genotype 1 infection,” the authors write.

(doi:10.1001/jama.2015.3860; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by Bristol-Myers Squibb. Editorial support was provided by Andrew Street, Ph.D., of Articulate Science and was funded by Bristol-Myers Squibb. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

In another study, Andrew J. Muir, M.D., of the Duke University Medical Center, Durham, N.C., and colleagues evaluated the effectiveness of treatment with daclatasvir, asunaprevir, and beclabuvir in patients who were treatment-naive and treatment-experienced with chronic HCV genotype 1 infection and cirrhosis.

An estimated 20 percent of patients with chronic HCV infection will develop cirrhosis, with the prevalence increasing. Patients with cirrhosis are at increased risk for liver cancer and death. Effective and well-tolerated, interferon-free regimens are needed for these patients.

This study (UNITY-2) was conducted at 49 outpatient sites in the United States, Canada, France and Australia. Patients were treated for 12 weeks with the 3-drug combination regimen, with 24 weeks of follow-up after completion of treatment. Patients with cirrhosis were enrolled in 2 cohorts: HCV treatment-naive or HCV treatment-experienced; patients within each cohort were also stratified according to HCV genotype 1 subtype (1a or 1b) and randomly assigned to receive weight-based ribavirin (1,000-1,200 mg/d) or matching placebo.

One hundred twelve patients in the treatment-naive group and 90 patients in the treatment-experienced group were treated and included in the analysis. In the treatment-naive group, sustained virologic response at post-treatment week 12 (SVR₁₂) was achieved by 93 percent of patients receiving DCV-TRIO alone and by 98 percent of patients with ribavirin added; and corresponding SVR₁₂ rates for the treatment­ experienced group were 87 percent for patients receiving DCV-TRIO alone and 93 percent for patients with ribavirin added. SVR₁₂ was achieved by 51 of 52 patients (98 percent) with genotype 1b infection overall; and SVR₁₂ rates in patients with genotype 1a were 86 percent to 97 percent across all treatment groups.

Three serious adverse events were considered to be treatment related and there were 4 adverse event-related discontinuations.

The authors note that the contribution of ribavirin to SVR₁₂ remains uncertain because of the small sample sizes; results suggest that inclusion of ribavirin with the regimen may be considered for patients with genotype 1a infection.

“In this open-label, uncontrolled study, patients with chronic HCV genotype 1 infection and cirrhosis who received a 12-week oral fixed-dose regimen of daclatasvir, asunaprevir, and beclabuvir, with or without ribavirin, achieved high rates of SVR₁₂.”

(doi:10.1001/jama.2015.3868; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by Bristol-Myers Squibb. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Continued Progress Against Hepatitis C Infection

“These 2 studies add to the armamentarium of all-oral interferon-free regimens that have revolutionized management of hepatitis C, not only for patients who are treatment naive with no significant liver disease but also for those who are treatment experienced and those with cirrhosis,” writes Hari Conjeevaram, M.D., M.Sc., of the University of Michigan, Ann Arbor, in an accompanying editorial.

“Despite the progress and the success of viral eradication, numerous questions remain unanswered such as response based on race, still difficult-to-treat situations such as patients with end-stage liver disease or undergoing hemodialysis, access to and affordability of these therapies, improvement in quality of life, and cost-effectiveness. It is time to reflect on these challenges and find solutions because the influence of HCV infection on global society is an ongoing challenge.”

(doi:10.1001/jama.2015.4368; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 5, 2015

Media Advisory: To contact Dale N. Gerding, M.D., call Stasia Thompson at 708-216-5155 or email thoms@lumc.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.3725.

Oral Administration of Non-Aggressive Strain of C difficile Reduces Risk of Recurrence of C difficile Infection

Among patients with Clostridium difficile infection (CDI) who recovered following standard treatment with the antibiotics metronidazole or vancomycin, oral administration of spores of a strain of C difficile that does not produce toxins colonized the gastrointestinal tract and significantly reduced CDI recurrence, according to a study in the May 5 issue of JAMA.

C difficile is the cause of one of the most common and deadly health care–associated infections, linked to 29,000 U.S. deaths each year. Rates of CDI remain at unprecedented high levels in U.S. hospitals. Clinical infection also has a recurrence rate of 25 percent to 30 percent among affected patients. Not all strains of C difficile produce toxins. Nontoxigenic C difficile strains that lack the genes for toxin production are also found in the hospital environment and can colonize hospitalized patients, although patients are usually asymptomatic. Gastrointestinal colonization by these nontoxigenic C difficile strains (in both humans and hamsters) has shown promising results as a potential way to prevent CDI, according to background information in the article.

Dale N. Gerding, M.D., of the Edward Hines Jr. VA Hospital, Hines, Il., and Loyola University Chicago, Maywood, Il., and colleagues randomly assigned 173 adult patients who were diagnosed as having CDI (first episode or first recurrence) to receive 1 of 4 treatments: oral liquid formulation of nontoxigenic C difficile strain M3 (VP20621; NTCD-M3), 10⁴ spores/d for 7 days (n = 43), 10⁷ spores/d for 7 days (n = 44), 10⁷ spores/d for 14 days (n = 42), or placebo for 14 days (n = 44). Prior to enrollment, these patients had all successfully completed treatment with metronidazole, oral vancomycin, or both at 44 study centers in the United States, Canada, and Europe.

Among 168 patients who started treatment, 157 completed treatment. Clostridium difficile infection recurrence was 30 percent among patients receiving placebo compared with 11 percent among all patients receiving NTCD-M3. The lowest recurrence was in 5 percent of patients receiving 10⁷ spores/d for 7 days. Fecal colonization with NTCD-M3 occurred in 69 percent of NTCD-M3 patients: 71 percent with 10⁷ spores/d and 63 percent with 10⁴ spores/d. Colonization with NTCD correlated with reduced recurrence of CDI: recurrence occurred in 2 percent patients who were colonized vs 31 percent of patients who received NTCD-M3 but were not colonized.

One or more treatment-emergent adverse events were reported in 78 percent of patients receiving NTCD-M3 and 86 percent of patients receiving placebo. Diarrhea and abdominal pain were reported in 46 percent and 17 percent of patients receiving NTCD-M3 and 60 percent and 33 percent of placebo patients, respectively. Serious treatment-emergent adverse events were reported in 7 percent of patients receiving placebo and 3 percent of all patients who received NTCD-M3. Headache was reported in 10 percent of patients receiving NTCD-M3 and 2 percent of placebo patients.

The researchers write that the mechanism by which NTCD prevents recurrent CDI is not known; however, there may be an association with the presence of NTCD in the stool (colonization) with reduced infection from toxigenic C difficile and in animal models with prevention of CDI when challenged with toxigenic strains. “The most likely hypothesized mechanism of action of NTCD-M3 is that it occupies the same metabolic or adherence niche in the gastrointestinal tract as does toxigenic C difficile and, once established, is able to outcompete resident or newly ingested toxigenic strains.”

The authors note that the sample size of the study was small, so many of the findings should be confirmed in larger studies.

(doi:10.1001/jama.2015.3725; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was sponsored by ViroPharma Incorporated, which is now part of the Shire group of companies. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 28, 2015

Media Advisory: To contact Gail D’Onofrio, M.D., M.S., call Ziba Kashef at 203-436-9317 or email ziba.kashef@yale.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.3474

Emergency Department Intervention Improves Rate of Treatment for Opioid Dependence

Among opioid-dependent patients presenting for emergency care, treatment with buprenorphine initiated in the emergency department, compared with a brief intervention and referral, significantly increased the likelihood of receiving formal addiction treatment, reduced self-reported illicit opioid use, and decreased use of inpatient addiction treatment services but did not significantly decrease the rates of urine samples that tested positive for opioids or of HIV risk, according to a study in the April 28 issue of JAMA. Buprenorphine is a medication for opioid use disorder that decreases withdrawal symptoms, craving, and opioid use.

Dependence on prescription opioids and heroin is a major public health problem that is increasing in the United States and internationally. Opioid agonist treatment, including methadone and buprenorphine, is the most effective treatment. Patients with opioid dependence are at increased risk of adverse health consequences and often seek medical care in emergency departments (EDs). Currently, the primary option available to the ED for opioid dependence is referral to addiction treatment services. The introduction of buprenorphine/naloxone may provide ED physicians the opportunity to initiate effective medication treatment in conjunction with a brief intervention and referral, according to background information in the article.

Gail D’Onofrio, M.D., M.S., of the Yale School of Medicine, New Haven, Conn., and colleagues randomly assigned opioid-dependent patients who were treated at an urban teaching hospital ED to screening and referral to treatment (referral; n = 104); screening, brief intervention and facilitated referral (brief intervention; n = 111), or screening, brief intervention, ED-initiated treatment with buprenorphine/naloxone, and referral to primary care for 10-week follow-up (buprenorphine; n = 114).

The primary outcome for the study was enrollment in and receiving addiction treatment 30 days after randomization. Eighty-nine of 114 patients (78 percent) in the buprenorphine group were engaged in treatment at significantly higher rates than patients in the referral group (37 percent) or patients in the brief intervention group (45 percent). The buprenorphine group reported greater reductions in the average number of days of illicit opioid use per week—from 5.4 days to 0.9 days, compared to the referral group, which decreased from 5.4 days to 2.3 days, and the brief intervention group, which decreased from 5.6 days to 2.4.

The rates of opioid negative urine toxicology test results did not differ statistically across the treatment groups, with 54 percent in the referral group, 43 percent in the brief intervention group, and 58 percent in the buprenorphine group having tested negative for opioid use. There were no statistically significant differences in HIV risk across groups.

Eleven percent of patients in the buprenorphine group used inpatient addiction treatment services, whereas 37 percent in the referral group and 35 percent in the brief intervention group used these services.

“Our findings demonstrate that ED-initiated buprenorphine with coordinated follow-up for ongoing treatment was more effective than referral with or without brief intervention,” the authors write. “Although this single-site study supports this ED-initiated treatment strategy, these findings require replication in other centers before widespread adoption.”

(doi:10.1001/jama.2015.3474; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The study was supported by a grant from the National Institute on Drug Abuse (NIDA), and Reckitt-Benckiser Pharmaceuticals provided buprenorphine through NIDA. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 28, 2015

Media Advisory: To contact Nicolas Stettler, M.D., M.S.C.E., email Christine Farazi at christine.farazi@optum.com or Stephen Puleo at steve.puleo@optum.com.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.3075

Medication to Treat Frequent Pain Crises in Sickle Cell Anemia Underused

Despite evidence demonstrating the benefits of the medication hydroxyurea for patients with sickle cell anemia and frequent pain crises, an analysis suggests that more than 3 of 4 patients who might benefit were not treated with this safe and inexpensive drug, according to a study in the April 28 issue of JAMA.

The recommendation from the 2014 National Heart, Lung, and Blood Institute guidelines to treat all adults with sickle cell anemia (SCA) and 3 or more moderate to severe pain crises within 1 year with hydroxyurea was rated as strong based on high-quality evidence reviewed in 2008. Despite benefits in reducing pain crises, hospitalizations, and blood transfusions, it is thought that hydroxyurea is underused, although the extent of its use is unknown, according to background information in the article.

Nicolas Stettler, M.D., M.S.C.E., of the Lewin Group, Falls Church, Va., and colleagues examined the use of hydroxyurea when indicated for SCA in the Optum Normative Health Informatics database, a nationwide sample of commercial health and pharmacy claims from more than 36 million residents in all 50 states and Washington, D.C. Adults (18 years or older) with 1 or more inpatient or outpatient claims between January 2009 and June 2013 for SCA were identified. Patients were selected when they had 3 or more hospitalizations, emergency department (ED) visits, or both within 12 months that included 1 of the 5 most frequent diagnosis codes used for patients with SCA and pain crises. Treatment was defined as filling 1 or more hydroxyurea prescriptions during the 3, 6, or 12 months of continued enrollment following the third episode.

Of an enrolled population of 26,631,901, the researchers identified 2,086 adults with probable SCA. Of these, 677 had at least 3 pain-related hospitalizations or ED visits within 12 months and 570 had at least 3 months of coverage after the third episode. Among them, 86 (15 percent) were treated with hydroxyurea within 3 months of their third encounter. The percentage of treated patients increased slightly to 18 percent at 6 months and to 23 percent at 12 months.

The authors write that several barriers to treatment have been identified, including fear of adverse events, lack of clinician training, and failure to engage in shared decision making. “Our estimate reflects the combined effect of all barriers to treatment, regardless of source.”

“Our data do not include the large uninsured or publicly insured population who may have more limited access to health care or awareness of treatment options. Therefore, these findings may not be representative of the entire U.S. population with SCA and may be a conservative estimate of the hydroxyurea treatment gap. To address this gap, it may be necessary to enhance patient outreach and clinician training and develop health care quality measures aimed at increasing the use of hydroxyurea for all patients who would benefit.”

(doi:10.1001/jama.2015.3075; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 28, 2015

Media Advisory: To contact Anne Barton, Ph.D., F.R.C.P., email anne.barton@manchester.ac.uk. To contact editorial co-author David T. Felson, M.D., M.P.H., call Gina DiGravio at 617-638-8480 or email ginad@bu.edu.

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Certain Genetic Factors Associated With Rheumatoid Arthritis Severity, Risk of Death and Response to Treatment

Genetic variations associated with the risk of susceptibility to rheumatoid arthritis are also associated with responsiveness to treatment, the risk of death, and severity of the disease as measured by imaging, according to a study in the April 28 issue of JAMA.

Advances have been made in identifying genetic susceptibility loci (the specific site of a particular gene on its chromosome) for autoimmune diseases, but evidence is needed regarding their association with disease prognosis and treatment response, according to background information in the article.

Anne Barton, Ph.D., F.R.C.P., of the University of Manchester, England, and colleagues examined whether specific HLA-DRBl (a gene) haplotypes (a set of DNA or genetic variations) associated with rheumatoid arthritis (RA) susceptibility are also associated with severity (as measured by radiological imaging), death, and response to medications (tumor necrosis factor [TNF] inhibitor drugs). For the analysis, the researchers used data from several sources that totaled 2,112 patients to evaluate radiologic severity; 2,432 patients to assess mortality; and 1,846 patients to examine treatment response to TNF inhibitor therapy. All patients were from the United Kingdom.

The researchers found that the HLA-DRBl locus was associated with radiological severity of RA, risk of death, and response to treatment with TNF inhibitor therapy.

“Replication of these findings in other cohorts is needed as a next step in evaluating the role of HLA-DRBl haplotype analysis for management of RA,” authors write.

(doi:10.1001/jama.2015.3435; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: The Genetics of Rheumatoid Arthritis

The results of this study are important for 3 reasons, write David T. Felson, M.D., M.P.H., of the Boston University School of Medicine, and Lars Klareskog, M.D., Ph.D., of the Karolinska Institutet/Karolinska University Hospital, Stockholm, in an accompanying editorial.

“First, these findings may add to the ability to predict outcomes of RA, thus helping to optimize therapeutic strategies for different patients. Second, the findings may add to the understanding of the molecular mechanisms that determine disease course and mortality. … Third, the findings by Viatte et al also help to inform understanding of disease pathogenesis by strongly implicating HLA-dependent immune events not only for the onset of RA, but also for disease course and mortality.”

“Although the findings reported by Viatte and colleagues may not have immediate clinical implications, identification of the precise HLA variants that influence disease course is of great interest. These observations open the door to further research, including replication for this haplotype and discovery related to its combination with other determinants of disease development and progression. Such discoveries will prove helpful both to understand and predict the variable disease course and response to therapy that occurs in patients with rheumatoid arthritis.”

(doi:10.1001/jama.2015.1710; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Supported by a grant from the National Institutes of Health. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 28, 2015

Media Advisory: To contact Patrick Mismetti, M.D., Ph.D., email patrick.mismetti2@chu-st-etienne.fr.

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Use of Vena Cava Filter Does Not Reduce Risk of Recurrent Blood Clot for Patients Receiving Anticoagulant

Among hospitalized patients with severe acute pulmonary embolism (a life-threatening blood clot in a lung), the use of a retrievable inferior vena cava filter plus anticoagulation compared with anticoagulation alone did not reduce the risk of recurrent pulmonary embolism or death, according to a study in the April 28 issue of JAMA.

An inferior vena cava (the largest vein in the body) filter is a type of vascular filter that is implanted to prevent blood clots. Observational studies show a sharp increase in the placement of inferior vena cava filters over the past 3 decades, including their use as add-on therapy to anticoagulant therapy in patients presenting with a blood clot. However, due to the lack of reliable data, the benefit vs risk is uncertain, according to background information in the article.

Patrick Mismetti, M.D., Ph.D., of the Centre Hospitalier Universitaire de Saint-Etienne, France and colleagues randomly assigned hospitalized patients with acute, symptomatic pulmonary embolism associated with lower-limb vein thrombosis and at least 1 criterion for severity to retrievable inferior vena cava filter implantation plus anticoagulation (n = 200) or anticoagulation alone with no filter implantation (control group; n = 199). Initial hospitalization with ambulatory follow-up occurred in 17 French centers; follow-up was 6-months. Filter retrieval was planned at 3 months from placement.

In the filter group, the filter was successfully inserted in 193 patients and was retrieved as planned in 153 of the 164 patients in whom retrieval was attempted. By 3 months, pulmonary embolism had recurred in 6 patients (3.0 percent) in the filter group and 3 patients (1.5 percent) in the control group. All episodes in the filter group and 2 of 3 in the control group were fatal. One additional pulmonary embolism recurrence was observed in each group between 3 and 6 months.

No difference was observed between the 2 treatment groups for deep vein thrombosis, major bleeding, or death from any cause at 3 and 6 months.

“The availability of retrievable inferior vena cava filters has probably contributed to the increasing use of filters for managing acute venous thromboembolism, including their use in addition to full-dose anticoagulant therapy in patients with pulmonary embolism, a large clot burden, a poor cardiopulmonary reserve, or a suspected increased risk for recurrence, as advocated by several guidelines. The results of the present study do not support such a strategy,” the authors write. “These findings do not support the use of this type of filter in patients who can be treated with anticoagulation.”

(doi:10.1001/jama.2015.3780; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 21, 2015

Media Advisory: To contact Anjali Jain, M.D., call Christine Farazi at 952-500-0592 or email christine.farazi@optum.com; or call Stephen Puleo at 617-774-9322 or email steve.puleo@optum.com. To contact editorial author Bryan H. King, M.D., M.B.A., call Leila Gray at 206-685-0381 or email leilag@uw.edu.

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No Association Found Between MMR Vaccine and Autism, Even Among Children at Higher Risk

In a study that included approximately 95,000 children with older siblings, receipt of the measles-mumps-rubella (MMR) vaccine was not associated with an increased risk of autism spectrum disorders (ASD), regardless of whether older siblings had ASD, findings that indicate no harmful association between receipt of MMR vaccine and ASD even among children already at higher risk for ASD, according to a study in the April 21 issue of JAMA, a theme issue on child health.

Although a substantial body of research over the last 15 years has found no link between the MMR vaccine and ASD, parents and others continue to associate the vaccine with ASD. Surveys of parents who have children with ASD suggest that many believe the MMR vaccine was a contributing cause. This belief, combined with knowing that younger siblings of children with ASD are already at higher genetic risk for ASD compared with the general population, might prompt these parents to avoid vaccinating their younger children, according to background information in the article.

Anjali Jain, M.D., of the Lewin Group, Falls Church, Va., and colleagues examined ASD occurrence by MMR vaccine status in a large sample of U.S. children who have older siblings with and without ASD. The researchers used an administrative claims database associated with a large commercial health plan. Participants included children continuously enrolled in the health plan from birth to at least 5 years of age during 2001-2012 who also had an older sibling continuously enrolled for at least 6 months between 1997 and 2012.

Of the 95,727 children included in the study, 1,929 (2.01 percent) had an older sibling with ASD. Overall, 994 (1.04 percent) children in the cohort had ASD diagnosed during follow-up. Among those who had an older sibling with ASD, 134 (6.9 percent) were diagnosed with ASD, compared with 860 (0.9 percent) diagnosed with ASD among those with siblings without ASD. The MMR vaccination rate (l dose or more) for the children with unaffected siblings (siblings without ASD) was 84 percent (n = 78,564) at 2 years and 92 percent (n = 86,063) at age 5 years. In contrast, the MMR vaccination rates for children with older siblings with ASD were lower (73 percent at age 2 years and 86 percent at age 5 years). Analysis of the data indicated that MMR vaccine receipt was not associated with an increased risk of ASD at any age.

“Consistent with studies in other populations, we observed no association between MMR vaccination and increased ASD risk among privately insured children. We also found no evidence that receipt of either 1 or 2 doses of MMR vaccination was associated with an increased risk of ASD among children who had older siblings with ASD. As the prevalence of diagnosed ASD increases, so does the number of children who have siblings diagnosed with ASD, a group of children who are particularly important as they were undervaccinated in our observations as well as in previous reports,” the authors write.

(doi:10.1001/jama.2015.3077; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This project was funded by the National Institute of Mental Health, National Institutes of Health, and the U.S. Department of Health and Human Services. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Promising Forecast for Autism Spectrum Disorders

In an accompanying editorial, Bryan H. King, M.D., M.B.A., of the University of Washington and Seattle Children’s Hospital, Seattle, comments on the findings of this study.

“Some parents of children with ASD may have chosen to delay immunization in subsequent children until they were certain any risk had passed. Such behavior, which arguably could enrich the immunization rate in the nonautism subgroup relative to the group that may have been showing early atypical development, might create the impression that MMR vaccine is actually reducing risk for ASD. Indeed, Jain et al report relative risks of less than 1.0. Even so, short of arguing that MMR vaccine actually reduces the risk of ASD in those who were immunized by age 2 years, the only conclusion that can be drawn from the study is that there is no signal to suggest a relationship between MMR and the development of autism in children with or without a sibling who has autism.”

“Taken together, some dozen studies have now shown that the age of onset of ASD does not differ between vaccinated and unvaccinated children, the severity or course of ASD does not differ between vaccinated and unvaccinated children, and now the risk of ASD recurrence in families does not differ between vaccinated and unvaccinated children.”

(doi:10.1001/jama.2015.2628; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 21, 2015

Media Advisory: To contact Lawrence Scahill, M.S.N., Ph.D., call Holly Korschun at 404-727-3990 or email hkorsch@emory.edu. To contact editorial author Bryan H. King, M.D., M.B.A., call Leila Gray at 206-685-0381 or email leilag@uw.edu.

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Parent Training Program Helps Reduce Disruptive Behavior of Children with Autism

A 24 week parent training program, which provided specific techniques to manage disruptive behaviors of children with autism spectrum disorder, resulted in a greater reduction in disruptive and noncompliant behavior compared to parent education, according to a study in the April 21 issue of JAMA, a theme issue on child health.

Autism spectrum disorder (ASD) affects an estimated 6 per 1,000 children worldwide and is a major public health challenge. As many as 50 percent of children with ASD exhibit behavioral problems, including tantrums, noncompliance, aggression, and self-injury. Behavioral interventions are used to treat disruptive behavior but have not been evaluated in large-scale randomized trials, according to background information in the article.

Lawrence Scahill, M.S.N., Ph.D., of Children’s Healthcare of Atlanta and Emory University, Atlanta, and colleagues conducted a study in which children (age 3-7 years) with ASD were randomly assigned to parent training (n = 89) or parent education (n = 91) at 6 centers (Emory University, Indiana University, Ohio State University, University of Pittsburgh, University of Rochester, Yale University).

Parent training provided specific strategies to manage disruptive behavior and was delivered individually to the parents in 11 core sessions of 60 to 90 minutes’ duration, up to 2 optional sessions, 1 home visit, and up to 6 parent-child coaching sessions over 16 weeks. Parent training also included 1 home visit and 2 telephone booster sessions between weeks 16 and 24. Parent education provided information about autism but no behavior management strategies and included 12 sessions of 60 to 90 minutes and 1 home visit over 24 weeks.

On parent-rated measures of disruptive and noncompliant behavior, parent training, compared to parent education, showed a greater reduction on two scales: a 48 percent vs 32 percent decline on the Aberrant Behavior Checklist-Irritability subscale; and a 55 percent vs 34 percent decline on the Home Situations Questionnaire-Autism Spectrum Disorder.  Both treatment groups improved over time, although neither measure met the prespecified minimal clinically important difference. The authors suggest that one possible explanation for the smaller than anticipated differences between groups is the larger than predicted improvement in the parent education group.

Parent training was superior to parent education on a measure of overall improvement as judged by a clinician who was blinded to research assignment (69 percent vs 40 percent).

The authors write that the cost-effectiveness of the 2 interventions needs to be investigated, and that future analyses may identify child and family characteristics that predict success with parent training or parent education.

“To our knowledge, this is the largest randomized trial of any behavioral intervention for children with ASD. The results of this multisite study provide empirical support for wider implementation of this structured, relatively brief parent training intervention for young children with ASD.”

(doi:10.1001/jama.2015.3150; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Promising Forecast for Autism Spectrum Disorders

“Although specific behavioral training was superior, both groups reported considerable improvement over baseline, suggesting that even regular intensive education about autism provided value to parents and translated to perceived behavioral improvements in their children,” writes Bryan H. King, M.D., M.B.A., of the University of Washington and Seattle Children’s Hospital, Seattle, in an accompanying editorial.

“Some challenges for the future include what can be learned about the children who did not respond to behavioral intervention and why some children of parents who were not educated about behavioral principles also improved. Autism is a diverse condition, and a better understanding of how psychosocial interventions work will be critical for determining how to personalize treatment.”

(doi:10.1001/jama.2015.2628; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 21, 2015

Media Advisory: To contact Ezio Bonifacio, Ph.D., email ezio.bonifacio@crt-dresden.de. To contact editorial author Jay S. Skyler, M.D., email Jennifer Smith at Jennifer.Smith@med.miami.edu.

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High-Dose Oral Insulin Shows Potential for Preventing Type 1 Diabetes in High-Risk Children

In a pilot study that included children at high risk for type 1 diabetes, daily high-dose oral insulin, compared with placebo, resulted in an immune response to insulin without hypoglycemia, findings that support the need for a phase 3 trial to determine whether oral insulin can prevent islet autoimmunity and diabetes in high-risk children, according to a study in the April 21 issue of JAMA, a theme issue on child health.

A few specific proteins are often the trigger for immune responses that cause autoimmune diseases. This has led to the experimental use of antigen­specific therapies (using a substance to initiate an immune response) to prevent, stabilize, or reverse immune­related diseases, such as allergies and multiple sclerosis. Type 1 diabetes is an autoimmune disease that can be detected in asymptomatic individuals by the presence of islet autoantibodies that develop in children. Antigen-specific therapy using insulin before the development of autoantibodies may induce protective immune responses that prevent the emergence of autoimmunity and subsequent type 1 diabetes in genetically at-risk children, according to background information in the article.

Ezio Bonifacio, Ph.D., of the DFG Center for Regenerative Therapies Dresden, Technische Universitat Dresden, Germany and colleagues randomly assigned autoantibody-negative, genetically at-risk children to receive oral insulin at varying doses (n = 15) or placebo (n = 10) once daily for 3 to 18 months to assess whether oral insulin can induce a potentially protective immune response without causing adverse effects. The study (Pre-POINT) was performed between 2009 and 2013 in Germany, Austria, the United States, and the United Kingdom and enrolled children age 2 to 7 years with a family history of type 1 diabetes.

Immune responses to insulin were observed in 2 of 10 (20 percent) placebo-treated children, in 1 of 6 (16.7 percent) children treated with 2.5 mg of insulin, 1 of 6 (16.7 percent) treated with 7.5 mg, 2 of 6 (33.3 percent) treated with 22.5 mg, and 5 of 6 (83.3 percent) treated with 67.5 mg of insulin.

The incidence and type of adverse events were not different between children who received placebo and children who received oral insulin, regardless of the insulin dose. Hypoglycemia was not observed at any of the tested doses.

“The Pre-POINT pilot study demonstrated that daily oral administration of 67.5 mg of insulin to genetically at-risk healthy children without signs of islet autoimmunity resulted in an immune response without hypoglycemia. The immune response observed in insulin-treated children did not display the features typically associated with type 1diabetes,” the authors write.

(doi:10.1001/jama.2015.2928; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Toward Primary Prevention of Type 1 Diabetes

“It is now possible to identify children at increased risk for type 1 diabetes at birth, and there is an identifiable sequence of events that culminates in impaired insulin secretion and overt type 1 diabetes,” writes Jay S. Skyler, M.D., of the University of Miami Miller School of Medicine, in an accompanying editorial.

“What is missing are interventions to arrest this process prior to irreversible damage to the pancreatic beta cell. The promise of autoantigen-specific therapy for prevention of type 1 diabetes in humans has yet to be realized. The Pre-POINT study provides additional evidence to inform trial design and increases enthusiasm for cautiously moving forward with a study of primary prevention in genetically screened children.”

(doi:10.1001/jama.2015.2054; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 21, 2015

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Incidence of Serious Diabetes Complication May Be Increasing Among Youth in U.S.

The incidence of a potentially life-threatening complication of diabetes, diabetic ketoacidosis, in youth in Colorado at the time of diagnosis of type 1 diabetes increased by 55 percent between 1998 and 2012, suggesting a growing number of youth may experience delays in diagnosis and treatment, according to a study in the April 21 issue of JAMA, a theme issue on child health.

Diabetic ketoacidosis (DKA) at the time of type 1 diabetes (T1D) diagnosis has detrimental long-term effects and is characterized by dangerously high blood sugar and the presence of substances in the blood known as ketones. It may reflect delayed access to health care, lower quality of care, or income inequality. Little is known about long-term trends of DKA in the United States, according to background information in the article.

Arleta Rewers, M.D., Ph.D., of the University of Colorado School of Medicine, Aurora, and colleagues examined trends in DKA at T1D diagnosis between 1998 and 2012 in Colorado and factors associated with DKA. Between this time period, youth diagnosed with T1D before age 18 years at any medical facility were included in the study if a Colorado resident and followed up at the Barbara Davis Center for Diabetes in Denver, which serves more than 80 percent of youth with diabetes in Colorado. Standard criteria were used to define DKA. Data were extracted from medical records.

Diabetic ketoacidosis was present in 1,339 of 3,439 youth (39 percent) at T1D diagnosis. Youth with DKA had a median age of 9.4 years, 54 percent were male, and 76 percent were white. The proportions with DKA increased significantly, especially after 2007 (30 percent in 1998; 35 percent in 2007; 46 percent in 2012). The only characteristic that changed over time was insurance, with those covered by public insurance increasing from 17.1 percent in 2007 to 37.5 percent in 2012. Younger age and African American race were associated with higher risk, whereas private insurance and history of T1D in a first-degree relative were associated with lower risk.

The authors note that the incidence of DKA found in this study is consistent with incidences in countries with poor access to health care and low community and physician awareness of diabetes, and is much higher than incidences reported in Canada or the United Kingdom.

“Some of the factors associated with DKA at diagnosis are potentially modifiable. For example, the association with family history suggests the importance of awareness of diabetic symptoms. However, economic factors are more difficult to modify. Increasing incidence of DKA correlated temporally with an increase in Colorado child poverty prevalence from 10 percent in 2000 to 18 percent in 2012. The recent increase of DKA incidence among youth with private insurance may be related to proliferation of high-deductible health plans.”

“To our knowledge, this is the only report of increasing incidence of DKA in the developed world. Further research on the reasons for the increase and interventions to decrease the incidence are warranted.”

(doi:10.1001/jama.2015.1414; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases and by funding from the Children’s Diabetes Foundation in Denver. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 21, 2015

Media Advisory: To contact Marina Cavazzana, M.D., Ph.D., email m.cavazzana@nck.aphp.fr. To contact editorial author Harry L. Malech, M.D., email the NIAID Office of Communications at niaidnews@niaid.nih.gov.

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Study Shows Feasibility of Using Gene Therapy to Treat Rare Immunodeficiency Syndrome

In a small study that included seven children and teens with Wiskott-Aldrich syndrome, a rare immunodeficiency disorder, use of gene therapy resulted in clinical improvement in infectious complications, severe eczema, and symptoms of autoimmunity, according to a study in the April 21 issue of JAMA, a theme issue on child health.

Wiskott-Aldrich syndrome (WAS) is caused by loss-of-function mutations in the WAS gene. The condition is characterized by thrombocytopenia (low platelet count), eczema, and recurring infections. In the absence of definitive treatment, patients with classic WAS generally do not survive beyond their second or third decade of life. Partially human leucocyte antigen (HLA) antigen-matched allogeneic (donated from another individual) hematopoietic stem cell (HSC) transplantation is often curative, but is associated with a high incidence of complications. Gene therapy based on transplantation of autologous (from the same individual) gene­corrected HSCs may be an effective and potentially safer alternative. This procedure involves the removal and treatment of the patient’s own blood stem cells, and their return to the patient by intravenous injection.

Marina Cavazzana, M.D., Ph.D., of Necker Children’s Hospital, Paris, France, and colleagues assessed the outcomes and safety of autologous HSC gene therapy in patients with Wiskott-Aldrich syndrome. Gene-corrected autologous HSCs were infused in 7 patients (age range, 0.8-15.5 years) with severe Wiskott-Aldrich syndrome lacking HLA antigen-matched related or unrelated HSC donors. Patients were enrolled in France and England and treated between December 2010 and January 2014. Follow-up of patients in this intermediate analysis ranged from 9 to 42 months.

Among 6 of the 7 patients, there was clinical improvement after gene therapy, which was well tolerated. One patient died of preexisting, treatment-refractory infectious disease. In the 6 surviving patients, the infectious complications resolved after gene therapy, and prophylactic (preventative) antibiotic therapy was successfully discontinued in 3 cases. Severe eczema resolved in all affected patients, as did signs and symptoms of autoimmunity.

No severe bleeding episodes were recorded after treatment, and at last follow-up, all 6 surviving patients were free of blood product support. Hospitalization days were reduced from a median of 25 days during the 2 years before treatment to a median of 0 days during the 2 years after treatment.

The authors note that the interpretation of the results of this type of study is constrained by the small number of patients. “We therefore cannot draw conclusions on long-term outcomes and safety. Further follow-up of these patients and those reported in a similar study last year, together with additional clinical trials of this therapy, are therefore necessary.”

(doi:10.1001/jama.2015.3253; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was sponsored by Genethon, Evry, France. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: An Emerging Era of Clinical Benefit From Gene Therapy

In an accompanying editorial, Harry L. Malech, M.D., of the National Institutes of Health, Bethesda, Md., and Hans D. Ochs, M.D., of the University of Washington and Seattle Children’s Research Institute, Seattle, write that this study provides strong evidence that this type of gene therapy achieves substantial restoration of immune function associated with prolonged clinical benefit to patients with severe Wiskott­Aldrich syndrome.

They add that the impressive clinical response seen in the study was achieved in the context of a long line of research by many groups of investigators striving toward the goal of clinically beneficial gene therapy. “Taken together, the available evidence demonstrates substantial sustained clinical benefit following gene therapy for certain diseases.”

“At a time when many are championing personalized medicine, no advance is as representative of that fundamental biological approach as gene therapy.”

(doi:10.1001/jama.2015.2055; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 14, 2015

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No Long-Term Survival Difference Found Between Types of Mitral Valve Replacements

In a comparison of mechanical prosthetic vs bioprosthetic mitral valves among patients 50 to 69 years of age undergoing mitral valve replacement, there was no significant difference in survival at 15 years, although there were differences in risk of reoperation, bleeding and stroke, according to a study in the April 14 issue of JAMA.

In patients with severe, symptomatic mitral valve disease unsuitable for surgical repair, mitral valve replacement reduces symptoms and improves survival.  Bioprosthetic valves (made primarily with tissue) are recommended in patients older than 70 years, in whom the likelihood of needing reoperation because of valve degeneration is low. In nonelderly patients requiring valve replacement, deciding between bioprosthetic and mechanical prosthetic valves is challenging because long-term survival and other outcomes have not been well defined, according to background information in the article.

Joanna Chikwe, M.D., of the Icahn School of Medicine at Mount Sinai, New York, and colleagues compared long-term survival, stroke, reoperation, and bleeding events after bioprosthetic vs mechanical prosthetic mitral valve replacement among 3,433 patients (age 50-69 years) who underwent mitral valve replacement in New York State hospitals from 1997-2007. Propensity score matching for 19 baseline characteristics yielded 664 patient pairs. Follow-up ended November 2013; median duration was 8.2 years.

The researchers found there was no difference in long-term survival between the mechanical prosthetic and bioprosthetic mitral valve replacement: 15-year survival was 57.5 percent vs. 59.9 percent, respectively. The cumulative incidence of stroke at l5 years after mitral valve replacement was significantly higher in the mechanical prosthesis group (14.0 percent) compared with the bioprosthesis group (6.8 percent), as was the cumulative incidence of bleeding events (14.9 percent vs. 9.0 percent).

The cumulative incidence of mitral valve reoperation at 15 years was significantly lower in the mechanical prosthesis group (5.0 percent) compared with the bioprosthesis group (11.1 percent).

“Consensus guidelines have increasingly emphasized patient preference in preoperative decision making. Quality-of-life surveys indicate that many patients view the distant possibility of reoperation as a reasonable trade-off for freedom from lifelong anticoagulation, reduced quality of life, and poorer perceived health status associated with mechanical prosthetic valves,” the researchers write. “Our data strongly suggest that the incremental risks of stroke and bleeding associated with mechanical prosthetic valve replacement should also be a major consideration in any discussion of prosthesis choice.”

The authors note that even though these findings suggest bioprosthetic mitral valve replacement may be a reasonable alternative to mechanical prosthetic valve replacement in patients aged 50 to 69 years, the 15-year follow-up was insufficient to fully assess lifetime risks, particularly of reoperation.

(doi:10.1001/jama.2015.3164; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 14, 2015

Media Advisory: To contact Mintu P. Turakhia, M.D., M.A.S., email Michael Hill-Jackson at Michael.Hill-Jackson@va.gov.

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Study Identifies Factors Linked to Greater Adherence to Use of Anticoagulant

Among patients with atrial fibrillation who filled prescriptions for the anticoagulant dabigatran at Veterans Health Administration sites, there was variability in patient medication adherence across sites, with appropriate patient selection and pharmacist-led monitoring associated with greater adherence to the medication, according to a study in the April 14 issue of JAMA.

Atrial fibrillation is the most common cardiac arrhythmia, affecting more than 3 million patients and necessitating treatment with oral anticoagulation in moderate- to high-risk patients to reduce stroke risk. Warfarin was the only treatment available until the recent introduction of target-specific oral anticoagulants (TSOACs), including dabigatran. Unlike warfarin, for which periodic laboratory testing is required, TSOACs do not require routine testing to evaluate anticoagulation effect. A previous study reported that suboptimal adherence to dabigatran was associated with increased risk of stroke and death, according to background information in the article.

Mintu P. Turakhia, M.D., M.A.S., of the VA Palo Alto Health Care System and Stanford University School of Medicine, and colleagues examined site-level variation in patient adherence to dabigatran and modifiable site-level practices associated with improved adherence in the Veterans Health Administration (VHA). The study included 67 VHA sites with 20 or more patients filling dabigatran prescriptions between 2010 and 2012 for nonvalvular atrial fibrillation (4,863 total patients; median, 51 patients per site), and also included 47 pharmacists from 41 eligible sites.

The median proportion of patients adherent to dabigatran was 74 percent, with variation in patient adherence across VHA sites. The authors write that the principal finding of their study was that appropriate patient selection was associated with better dabigatran adherence. Similarly, pharmacist-led monitoring (such as determining how medication was taken and stored, frequency of missed doses with timely laboratory testing) was associated with higher adherence with a progressive increase in adherence with longer duration of monitoring. In addition, pharmacist collaboration with clinicians for patients who were nonadherent was associated with higher adherence rates.

“These findings suggest that such site-level practices provide modifiable targets to improve patient adherence to dabigatran as opposed to patient characteristics that frequently cannot be modified.”

“Our results highlight the importance of selecting patients and monitoring strategies to translate the efficacy of TSOACs in randomized trials to clinical practice. Prior studies have described variation in patient performance on warfarin across sites further highlighting the importance of management strategies in improving patient performance to anticoagulants,” the researchers write. They add that the higher adherence rates associated with provision of dedicated monitoring even for a short time is potentially due to consistent contact made with patients.

(doi:10.1001/jama.2015.2761; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 14, 2015

Media Advisory: To contact Vincent Liu, M.D., M.S., email Maureen McInaney (Maureen.Mcinaney@kp.org) or Ann Wallace (Ann.M.Wallace@kp.org). To contact editorial co-author David Blumenthal, M.D., M.P.P., email Mary Mahon at mm@cmwf.org.

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Increase Seen in Data Breaches of Health Information

Between 2010 and 2013, data breaches of protected health information reported by HIPAA-covered entities increased and involved approximately 29 million records, with most data breaches resulting from overt criminal activity, according to a study in the April 14 issue of JAMA.

Reports of data breaches have increased during the past decade. Compared with other industries, these breaches are estimated to be the most costly in health care; however, few studies have detailed their characteristics and scope. Vincent Liu, M.D., M.S., of the Kaiser Permanente Division of Research, Oakland, Calif., and colleagues evaluated an online database maintained by the U.S. Department of Health and Human Services describing data breaches of unencrypted protected health information (i.e., individually identifiable information) reported by entities (health plans and clinicians) covered under the Health Insurance Portability and Accountability Act (HIPAA). The researchers included breaches affecting 500 individuals or more reported as occurring from 2010 through 2013, accounting for 82 percent of all reports.

The authors identified 949 breaches affecting 29.1 million records. Six breaches involved more than 1 million records each and the number of reported breaches increased over time (from 214 in 2010 to 265 in 2013). Breaches were reported in every state, the District of Columbia, and Puerto Rico. Five states (California, Texas, Florida, New York, and Illinois) accounted for 34 percent of all breaches. However, when adjusted by population estimates, the states with the highest adjusted number of breaches and affected records varied.

Most breaches occurred via electronic media (67 percent), frequently involving laptop computers or portable electronic devices (33 percent). Most breaches also occurred via theft (58 percent). The combined frequency of breaches resulting from hacking and unauthorized access or disclosure increased during the study period (12 percent in 2010 to 27 percent in 2013). Breaches involved external vendors in 29 percent of reports.

The authors note that the study was limited to breaches that were already recognized, reported, and affecting at least 500 individuals. “Therefore, our study likely underestimated the true number of health care data breaches occurring each year.”

“Given the rapid expansion in electronic health record deployment since 2012, as well as the expected increase in cloud­based services provided by vendors supporting predictive analytics, personal health records, health-related sensors, and gene sequencing technology, the frequency and scope of electronic health care data breaches are likely to increase. Strategies to mitigate the risk and effect of these data breaches will be essential to ensure the well-being of patients, clinicians, and health care systems.”

(doi:10.1001/jama.2015.2252; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Dr. Liu was supported by the Permanente Medical Group and a grant from the National Institutes of Health. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Keeping Personal Health Information Safe

In an accompanying editorial, David Blumenthal, M.D., M.P.P., of The Commonwealth Fund, New York, and Deven McGraw, J.D., L.L.M., M.P.H., of Manatt Phelps & Phillips LLP, Washington, D.C., write that “if patients have concerns that their digitized personal health information will be compromised, they will resist sharing it via electronic means, thus reducing its value in their own care and its availability for research and performance measurement.”

“Concerned patients may also withhold sensitive information about issues such as mental health, substance abuse, human immunodeficiency virus status, and genetic predispositions. Surveys suggest this may already be happening to some degree. Loss of trust in an electronic health information system could seriously undermine efforts to improve health and health care in the United States.”

“The stakes associated with the privacy and security of personal health information are huge. Threats to the safety of health care data need much more focused attention than they have received in the past from both public and private stakeholders.”

(doi:10.1001/jama.2015.2746; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 14, 2015

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Intrauterine Exposure to Maternal Gestational Diabetes Associated With Increased Risk of Autism

Among a group of more than 320,000 children, intrauterine exposure to gestational diabetes mellitus diagnosed by 26 weeks’ gestation was associated with risk of autism spectrum disorders (ASDs), according to a study in the April 14 issue of JAMA. Maternal pre-existing type 2 diabetes was not significantly associated with risk of ASD in offspring.

Exposure of fetuses to maternal hyperglycemia may have long-lasting effects on organ development and function. Previous studies have revealed long-term risks of obesity and related metabolic disorders in offspring of women who had diabetes prior to pregnancy as well as women with hyperglycemia first detected during pregnancy (gestational diabetes mellitus [GDM]). Whether such exposure can disrupt fetal brain development and heighten risk of neurobehavioral developmental disorders in offspring is less clear, according to background information in the article.

Anny H. Xiang, Ph.D., of Kaiser Permanente Southern California, Pasadena, Calif., and colleagues analyzed data from a single health care system to assess the association between maternal diabetes, both known prior to pregnancy and diagnosed during pregnancy, and the risk of ASD in children. The study included 322,323 children born from 1995-2009 at Kaiser Permanente Southern California (KPSC) hospitals. Children were tracked from birth until the first of the following: date of clinical diagnosis of ASD, last date of continuous KPSC health plan membership, death due to any cause, or December 31, 2012.

Of the children included in the study, 6,496 (2.0 percent) were exposed to pre-existing type 2 diabetes, 25,035 (7.8 percent) were exposed to GDM, and 290,792 (90.2 percent) were unexposed. Following birth (median of 5.5 years), 3,388 children were diagnosed as having ASD (115 exposed to pre-existing type 2 diabetes, 130 exposed to GDM at 26 weeks or less, 180 exposed to GDM at more than 26 weeks, and 2,963 unexposed). After adjustment for various factors, including maternal age, household income, race/ethnicity, and sex of the child, GDM diagnosed by 26 weeks was significantly associated with risk of ASD in offspring, but maternal pre-existing type 2 diabetes was not.

The increased ASD risk was independent of maternal smoking, prepregnancy body mass index, and gestational weight gain. Antidiabetic medication use was not independently associated with ASD risk in offspring.

The authors write that potential biological mechanisms linking intrauterine hyperglycemia and ASD risk in offspring may include multiple pathways, such as hypoxia (a lower-than-normal concentration of oxygen in the blood) in the fetus, oxidative stress in cord blood and placental tissue, chronic inflammation, and epigenetics (something that affects a cell, organ or individual without directly affecting its DNA).

(doi:10.1001/jama.2015.2707; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by Kaiser Permanente Southern California Direct Community Benefit Funds. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 7, 2015

Media Advisory: To contact Andrew B. Cohen, M.D., D.Phil., email Ziba Kashef at ziba.kashef@yale.edu.

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Default Surrogate Consent Statutes May Differ With Wishes of Patients

Among a sample of veterans in Connecticut, a substantial number had individuals listed as next of kin who were not nuclear family members, according to a study in the April 7 issue of JAMA. State default consent statutes do not universally recognize such persons as decision makers for incapacitated patients.

For patients who lose capacity and have no legally appointed surrogate decision maker, most states have laws that specify a hierarchy of persons who may serve as surrogate decision makers by default. A patient’s spouse is usually given priority, followed by adult children, parents, and siblings (members of the nuclear family). Even though an increasing number of adults are unmarried and live alone, state default surrogate consent statutes vary in their recognition of important relationships beyond the nuclear family, such as friends, more distant relatives, and intimate relationships outside marriage. Little has been known about how often patients identify a person who is not a nuclear family member as their next of kin, according to background information in the article.

Andrew B. Cohen, M.D., D.Phil., of the Yale University School of Medicine, New Haven, Conn., and colleagues reviewed the next-of-kin relationships for patients receiving care at Connecticut Veterans Health Administration (VHA) facilities from 2003-2013. Patients receiving care at VHA facilities are asked for information about their next of kin, which is entered into the electronic record along with a description of the relationship between the patient and next of kin.

From 2003-2013, 134,241 veterans received care at Connecticut VHA facilities, of whom 109,803 were included in the analysis. For most patients (93 percent), the next of kin was a nuclear family member. For 7.1 percent of the patients, a person outside the patient’s nuclear family was listed as next of kin. There were 3,190 patients (2.9 percent) with a more distant relative and 4.2 percent for whom the individual was not a blood or legal relative. This was most often a friend or an intimate relationship outside marriage (e.g., “common law spouse,” “live-in soul mate,” and “same-sex partner”). Veterans younger than 65 years were more likely than those 65 years or older (9.2 percent vs 6.0 percent) to have a next of kin who was not a nuclear family member.

Even though some patients use advance directives to identify decision makers who differ from their next of kin, completion rates remain low.

“Clinicians may be uncertain about whether a next of kin outside the nuclear family may make decisions for an incapacitated person, particularly when difficult choices arise during life-limiting illness. Such uncertainty may interfere with timely clinical care. In some circumstances, a guardian must be appointed, which is a slow and costly process,” the authors write.

If the finding that a substantial number of veterans have a next- of-kin relationship outside the nuclear family is confirmed in other populations, “states should consider adopting uniform default consent statutes, and these statutes should be broad and inclusive to reflect the evolving social ties in the United States.”

(doi:10.1001/jama.2015.2409; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 7, 2015

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Risk of Breast and Ovarian Cancer May Differ By Type of BRCA1, BRCA2 Mutation

In a study that involved more than 31,000 women who are carriers of disease-associated mutations in the BRCA1 or BRCA2 genes, researchers identified mutations that were associated with significantly different risks of breast and ovarian cancers, findings that may have implications for risk assessment and cancer prevention decision making among carriers of these mutations, according to a study in the April 7 issue of JAMA.

Women who have inherited mutations in BRCA1 or BRCA2 (BRCA1/2) have an increased risk of breast and ovarian cancers. Little has been known about how cancer risks differ by BRCA1/2 mutation type, according to background information in the article.

Timothy R. Rebbeck, Ph.D., of the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and colleagues evaluated whether BRCA1 and BRCA2 mutation type or location is associated with variation in breast and ovarian cancer risk. The study included 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 33 countries.

Among BRCA1 mutation carriers, 9,052 women (46 percent) were diagnosed with breast cancer, 2,317 (12 percent) with ovarian cancer, 1,041 (5 percent) with breast and ovarian cancer, and 7,171 (37 percent) without cancer. Among BRCA2 mutation carriers, 6,180 women (52 percent) were diagnosed with breast cancer, 682 (6 percent) with ovarian cancer, 272 (2 percent) with breast and ovarian cancer, and 4,766 (40 percent) without cancer. Analysis of the data indicated that the risk of breast and ovarian cancer varied by the type and location of BRCA1/2 mutations.

“This study is the first step in defining differences in risk associated with location and type of BRCA1 and BRCA2 mutations. Pending additional mechanistic insights into the observed associations, knowledge of mutation-specific risks could provide important information for clinical risk assessment among BRCA1/2 mutation carriers, but further systematic studies will be required to determine the absolute cancer risks associated with different mutations,” the authors write.

“It is yet to be determined what level of absolute risk change will influence decision making among carriers of BRCA1/2 mutations. Additional research will be required to better understand what level of risk difference will change decision making and standards of care, such as preventive surgery, for carriers of BRCA1 and BRCA2 mutations.”

(doi:10.1001/jama.2014.5985; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MARCH 24, 2015

Media Advisory: To contact Osama O. Zaidat, M.D., M.S., email Maureen Mack at mmack@mcw.edu. To contact editorial co-author Colin P. Derdeyn, M.D., email Judy Martin at martinju@wustl.edu.

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Use of Stent, Compared to Medications, Increases Risk of Stroke in Patients With Narrowed Artery Within the Brain

Among patients with symptomatic intracranial arterial stenosis (narrowing of an artery inside the brain), the use of a balloon-expandable stent compared with medical therapy (clopidogrel and aspirin) resulted in an increased of stroke or transient ischemic attack (TIA), according to a study in the March 24/31 issue of JAMA.

Intracranial arterial stenosis is a common cause of stroke worldwide. The recurrent stroke risk with severe symptomatic intracranial stenosis may be as high as 23 percent at 1 year, despite medical therapy, according to background information in the article.

Osama O. Zaidat, M.D., M.S., of the Medical College of Wisconsin/Froedtert Hospital, Milwaukee, and colleagues randomly assigned 112 patients with symptomatic intracranial stenosis (narrowing of 70 percent or greater) to receive a balloon-expandable stent plus medical therapy (stent group; n = 59) or medical therapy alone (medical group; n = 53). Medical therapy consisted of clopidogrel (75 mg daily) for the first 3 months after enrollment and aspirin (81-325 mg daily) for the study duration. This international trial (VISSIT) enrolled patients from 27 sites (January 2009-June 2012) with last follow-up in May 2013. Enrollment was halted by the sponsor after negative results from another trial prompted an early analysis of outcomes, which suggested futility after 112 patients of a planned sample size of 250 were enrolled.

The 30-day safety end point of any stroke within 30 days or hard TIA (defined as a transient episode of neurological dysfunction caused by focal brain or retinal ischemia lasting at least 10 minutes but resolving within 24 hours) within 2 to 30 days was 9.4 percent (5/53) in the medical group and 24.1 percent (14/58) in the stent group. Ischemic stroke was observed in 3 patients (5.7 percent) in the medical group and in 10 patients (17.2 percent) in the stent group. Intracranial hemorrhage occurred in 5 patients (8.6 percent) in the stent group and in 0 in the medical group. The 1-year outcome of stroke or hard TIA occurred in more patients in the stent group (36.2 percent) vs the medical group (15.1 percent).

Thirty day all-cause death was 3 of 58 patients (5.2 percent) in the stent group and 0 in the medical group. A measure of disability worsened in more patients in the stent group than in the medical group.

“These findings do not support the use of a balloon-expandable stent for patients with intracranial arterial stenosis,” the authors conclude.

(doi:10.1001/jama.2015.1693; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The trial was initiated and funded by Micrus Endovascular. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Endovascular Therapy for Atherosclerotic Intracranial Arterial Stenosis – Back to the Drawing Board

Marc I. Chimowitz, M.B.Ch.B., of the Medical University of South Carolina, Charleston, and Colin P. Derdeyn, M.D., of the Washington University School of Medicine, St. Louis, comment in an accompanying editorial.

“For endovascular therapy (e.g., angioplasty alone or new stents) to have any role, multicenter pilot studies will be required to establish the safety and potential efficacy of these devices in carefully defined patient populations. Given the disappointing performance of intracranial stenting in both VISSIT and SAMMPRIS [a trial with similar results], it is difficult to foresee how these necessary steps will happen anytime soon.”

(doi:10.1001/jama.2015.1276; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MARCH 24, 2015

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Pay Gap Between Male and Female RNs Has Not Narrowed

An analysis of the trends in salaries of registered nurses (RNs) in the United States from 1988 through 2013 finds that male RNs outearned female RNs across settings, specialties, and positions, with no narrowing of the pay gap over time, according to a study in the March 24/31 issue of JAMA.

Fifty years after the Equal Pay Act, the male-female salary gap has narrowed in many occupations. Yet pay inequality persists for certain occupations, including medicine and nursing. Studies have documented higher salaries for male registered nurses, although analyses have not considered employment factors that could explain salary differences and have not been based on recent data, according to background information in the article.

Ulrike Muench, Ph.D., R.N., of the University of California, San Francisco, and colleagues examined salaries of males and females in nursing over time using nationally representative data from the last 6 (1988-2008) quadrennial National Sample Survey of Registered Nurses (NSSRN; discontinued in 2008) and data from the American Community Survey (ACS; 2001-2013).

The NSSRN sample included 87,903 RNs, of whom 7 percent were men; the ACS sample included 205,825 RNs, of whom 7 percent were men. Both surveys showed that male RN salaries were higher than female RN salaries during every year. No significant changes in female vs male salary were found over time. Analysis estimated an overall adjusted earnings difference of $5,148.

The salary gap was $7,678 for ambulatory care and $3,873for hospital settings. The gap was present in all specialties except orthopedics, ranging from $3,792 for chronic care to $6,034 for cardiology. Salary differences also existed by position (such as for middle management, nurse anesthetists).

“The roles of RNs are expanding with implementation of the Affordable Care Act and emphasis on team-based care delivery. A salary gap by gender is especially important in nursing because this profession is the largest in health care and is predominantly female, affecting approximately 2.5 million women. These results may motivate nurse employers, including physicians, to examine their pay structures and act to eliminate inequities,” the authors write.

(doi:10.1001/jama.2015.1487; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MARCH 17, 2015

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Study Raises Concerns About Reporting of Noninferiority Trials

An examination of the reporting of noninferiority clinical trials raises questions about the adequacy of their registration and results reporting within publicly accessible trial registries, according to a study in the March 17 issue of JAMA.

Noninferiority clinical trials are designed to determine whether an intervention is not inferior to a comparator by more than a prespecified difference (known as the noninferiority margin). Selection of an appropriate margin is fundamental to noninferiority trial validity, yet a point of frequent ambiguity. Given the increasing use of noninferiority trial designs, maintaining high standards for conduct and reporting is a priority, according to background information in the article.

Joseph S. Ross, M.D., M.H.S., of the Yale University School of Medicine, New Haven, Conn., and colleagues examined registration records and results of noninferiority clinical trials posted on ClinicalTrials.gov, as well as their corresponding publications, for information about the noninferiority margin and statistical analyses. Because ClinicalTrials.gov does not require registration of noninferiority-specific information, the authors searched MEDLINE for noninferiority trials published between January 2012 and June 2014, then selected publications reporting primary analyses of noninferiority trials indexed with a Clinical Trials.gov identifier. The researchers recorded details on trial design (including specification and justification of the noninferiority margin) and results (including reporting of noninferiority statistical analyses) from both ClinicalTrials.gov and corresponding publications.

The authors identified and characterized 344 unique trials registered on ClinicalTrials.gov, published in 338 articles (6 described multiple trials) that reported primary results of noninferiority trials. All publications described noninferiority designs and nearly all (98.8 percent) provided noninferiority margins. However, any justification for choosing margins was provided for only 28 percent. On ClinicalTrials.gov, approximately one­quarter described noninferiority designs, among which 15 (4.4 percent of total) specified noninferiority margins.

Nearly all publications reported noninferiority analyses and results (99.4 percent). On ClinicalTrials.gov, 38 percent had posted summary results, among which 76 (22 percent of total) reported that noninferiority analyses were performed and provided appropriate confidence intervals or P values to interpret results.

“Our findings raise concerns about the adequacy of noninferiority trial registration and results reporting within publicly accessible trial registries and highlight the need for continued efforts to improve its quality,” the authors write.

They add that even though ClinicalTrials.gov does not provide specific registration data elements for specifying noninferiority trial designs, it does provide specific elements for reporting noninferiority results. “Nevertheless, modifications may improve reporting and temper the possibility of post hoc distortion of design and margins, facilitating transparency and accountability for noninferiority trial conduct.”

(doi:10.1001/jama.2015.1697; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MARCH 17, 2015

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Longer Duration Antiplatelet Therapy Following Coronary Stent Placement Does Not Reduce Risk of Adverse Events

An additional 18 months of dual antiplatelet therapy among patients who received a bare metal coronary stent did not result in significant differences in rates of stent thrombosis (formation of a blood clot), major adverse cardiac and cerebrovascular events, or moderate or severe bleeding, compared to patients who received placebo, according to a study in the March 17 issue of JAMA. The authors note that limitations in sample size may make definitive conclusions regarding these findings difficult.

Current clinical practice guidelines recommend a minimum of only 1 month of dual antiplatelet therapy (DAPT) after bare metal stent (BMS) placement following elective percutaneous coronary intervention (PCI; a procedure used to open narrowed coronary arteries, such as stent placement), compared with 6 to 12 months for drug-eluting stents (DES). Although randomized trial results showed a reduction in stent thrombosis and non­stent-related heart attack with thienopyridine therapy (a class of antiplatelet agents) beyond 12 months after DES placement, few trials have assessed optimal duration of DAPT after BMS, according to background information in the article.

Dean J. Kereiakes, M.D., of the Christ Hospital Heart and Vascular Center, Cincinnati, and Laura Mauri, M.D., M.Sc., of the Harvard Clinical Research Institute and Brigham and Women’s Hospital, Boston, and colleagues randomly assigned 11,648 patients who received a bare metal stent (n = 1,687;) or drug eluting stent (n = 9,961), were treated with aspirin and who completed 12 months of DAPT without bleeding or ischemic events to continued thienopyridine or placebo at months 12 through 30.

Among the patients treated with BMS who were randomized to continued thienopyridine vs placebo, rates of stent thrombosis were 0.5 percent vs 1.11 percent; rates of major adverse cardiac and cerebrovascular events (MACCE; composite of death, heart attack, or stroke) were 4.04 percent vs 4.69 percent; and rates of moderate/severe bleeding were 2.03 percent vs 0.90 percent, respectively.

Among all 11,648 randomized patients (both BMS and DES), stent thrombosis rates were 0.41 percent vs 1.32 percent; rates of MACCE were 4.29 percent vs 5.74 percent, and rates of moderate/severe bleeding were 2.45 percent vs 1.47 percent.

The results comparing continued thienopyridine vs placebo in the cohort treated with DES were previously reported and demonstrated significant reductions in stent thrombosis and MACCE.

The authors write that fewer patients treated with BMS were enrolled and randomized because of the prevailing use of DES in clinical practice. “The BMS subset may have been underpowered to identify such differences [in adverse events], and further trials are suggested.”

(doi:10.1001/jama.2015.1671; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MARCH 17, 2015

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Early Imaging for Back Pain in Older Adults Not Associated With Better Outcomes

Older adults who had spine imaging within 6 weeks of a new primary care visit for back pain had pain and disability over the following year that was not different from similar patients who did not undergo early imaging, according to a study in the March 17 issue of JAMA.

When to image older adults with back pain remains controversial. Many guidelines recommend that older adults undergo early imaging because of the higher prevalence of serious underlying conditions.  However, there is not strong evidence to support this recommendation. Adverse consequences of early imaging are more substantial in an older population because the prevalence of incidental findings on spine imaging increases with age, which may lead to a cascade of subsequent interventions that increase costs without benefits, according to background information in the article.

Jeffrey G. Jarvik, M.D., M.P.H., of the University of Washington, Seattle, and colleagues compared function and pain at the 12-month follow-up visit among older adults who received early imaging (within 6 weeks) with those who did not. The study included 5,239 patients (65 years or older) with a new primary care visit for back pain in three U.S. health care systems, who did not have radiculopathy (a condition affecting the spinal nerve roots and spinal nerves). Diagnostic imaging (plain films, computed tomography [CT], magnetic resonance imaging [MRI]) was of the lumbar or thoracic spine.

Among the patients studied, 1,174 had early radiographs and 349 had early MRI/CT. At 12 months, neither the early radiograph group nor the early MRI/CT group differed significantly from controls on measures of back or leg pain–related disability.

In contrast, there were marked differences in 1-year resource use and costs. Estimated monetary differences in 1-year total payments (payer and patient contributions) were $1,380 higher for patients with early radiographs and $1,430 higher for patients with early MRI/CTs.

“Among older adults with a new primary care visit for back pain, early imaging was not associated with better 1-year outcomes. The value of early diagnostic imaging in older adults for back pain without radiculopathy is uncertain.”

(doi:10.1001/jama.2015.1871; Available pre-embargo to the media at https://media.jamanetwork.com)

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MARCH 17, 2015

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Study Examines Diagnostic Accuracy of Pathologists Interpreting Breast Biopsies

In a study in which pathologists provided diagnostic interpretation of breast biopsy slides, overall agreement between the individual pathologists’ interpretations and that of an expert consensus panel was 75 percent, with the highest level of concordance for invasive breast cancer and lower levels of concordance for ductal carcinoma in situ and atypical hyperplasia, according to a study in the March 17 issue of JAMA.

Approximately 1.6 million women in the United States have breast biopsies each year. The accuracy of pathologists’ diagnoses is an important and inadequately studied area. Although nearly one-quarter of biopsies demonstrate invasive breast cancer, the majority are categorized by pathologists according to a diagnostic spectrum ranging from benign to pre-invasive disease. Breast lesions with atypia or ductal carcinoma in situ (DCIS; abnormal breast cells that have not spread outside the duct into the normal surrounding breast tissue) are associated with significantly higher risks of subsequent invasive carcinoma, and women with these findings may require additional surveillance, prevention, or treatment to reduce their risks. The incidence of atypical ductal hyperplasia (atypia; a benign lesion of the breast that indicates an increased risk of breast cancer) and DCIS breast lesions has increased over the past 3 decades as a result of widespread mammography screening. Misclassification of breast lesions may contribute to either overtreatment or undertreatment, according to background information in the article.

Joann G. Elmore, M.D., M.P.H., of the University of Washington, Seattle, and colleagues examined the extent of diagnostic disagreement among pathologists compared with a consensus panel reference diagnosis. The study included 115 pathologists who interpret breast biopsies in clinical practices in 8 U.S. states. Participants independently interpreted slides between November 2011and May 2014 from test sets of 60 breast biopsies (240 total cases, 1 slide per case), including 23 cases of invasive breast cancer, 73 DCIS, 72 with atypical hyperplasia (atypia), and 72 benign cases without atypia. Participants were blinded to the interpretations of other study pathologists and the three consensus panel members, who were experienced pathologists internationally recognized for research and continuing medical education on diagnostic breast pathology. Among the consensus panel members, unanimous agreement of their independent diagnoses was 75 percent, and concordance with the consensus-derived reference diagnoses was 90 percent.

For all the cases, the participants provided 6,900 total individual interpretations for comparison with the consensus-derived reference diagnoses. Participating pathologists agreed with the consensus panel diagnosis for 75 percent of the interpretations. The overall concordance rate for the invasive breast cancer cases was 96 percent. The participants agreed with the consensus-derived reference diagnosis on less than half of the atypia cases, with a concordance rate of 48 percent. The overall concordance rate for benign without atypia was 87 percent; for DCIS, it was 84 percent.

Although overinterpretation of DCIS as invasive carcinoma occurred in only 3 percent, overinterpretation of atypia was noted in 17 percent and overinterpretation of benign without atypia was noted in 13 percent. Underinterpretation of invasive breast cancer was noted in 4 percent, whereas underinterpretation of DCIS was noted in 13 percent and underinterpretation of atypia was noted in 35 percent.

Disagreement with the consensus-derived reference diagnosis was significantly more frequent when breast biopsies were interpreted by pathologists with lower weekly case volume, from non-academic settings, or smaller practices; and from women with dense breast tissue on mammography (vs low density), although the absolute differences in rates according to these factors were generally small.

“The variability of pathology interpretations is relevant to concerns about overdiagnosis of atypia and DCIS. When a biopsy is overinterpreted (e.g., interpreted as DCIS by a pathologist when the consensus-derived reference diagnosis is atypia), a woman may undergo unnecessary surgery, radiation, or hormonal therapy. In addition, overinterpretation of atypia in a biopsy with otherwise benign findings can result in unnecessary heightened surveillance, clinical intervention, costs, and anxiety,” the researchers write. “Given our findings, clinicians and patients may want to obtain a formal second opinion for breast atypia prior to initiating more intensive surveillance or risk reduction using chemoprevention or surgery.”

The authors conclude that further research is needed to understand the relationship of these findings with patient management.

(doi:10.1001/jama.2015.1405; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Expertise vs Evidence in Assessment of Breast Biopsies – An Atypical Science

“An undesirable short-term outcome from the study by Elmore et al will undoubtedly be heightened anxiety among women who undergo breast biopsy and concern among their physicians about the accuracy of the pathologic diagnosis,” write Nancy E. Davidson, M.D., of the University of Pittsburgh Cancer Institute and UPMC CancerCenter, Pittsburgh, and David L. Rimm, M.D., Ph.D., of the Yale University School of Medicine, New Haven, Conn., in an accompanying editorial.

“However, this study confirms that the majority of diagnoses, especially at either end of the spectrum from benign to invasive cancer, are readily and accurately made by practicing pathologists. It also identifies areas of uncertainty that must be addressed, providing a framework for process improvement in the pathology and scientific communities, especially in the diagnosis of atypia. The study supports the value of a second opinion in cases of ambiguity. Indeed, it is axiomatic [unquestionable] that an abnormal breast biopsy is certainly a cause for concern but does not constitute a medical emergency. Extra time and care devoted to confirmation of the histologic diagnosis and a thoughtful discussion of the treatment options are imperative.”

“Importantly, breast pathology is a biological continuum from normal to invasive cancer whereas prescription of treatment requires categorization into specific diagnoses. The goal should be to match emerging biological understanding about breast carcinogenesis with opportunities for tailored treatment in an era of ever more precise, evidence-based medicine.”

(doi:10.1001/jama.2015.1945; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MARCH 17, 2015

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Effect of Aspirin, NSAIDs on Colorectal Cancer Risk May Differ, According to Genetic Variations

Among approximately 19,000 individuals, the use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with an overall lower risk of colorectal cancer, although this association differed according to certain genetic variations, according to a study in the March 17 issue of JAMA.

Considerable evidence demonstrates that use of aspirin and other NSAIDs is associated with a lower risk of colorectal cancer. However, the mechanisms behind this association are not well understood. Routine use of aspirin, NSAIDs, or both for prevention of cancer is not currently recommended because of uncertainty about the risk-benefit profile. Understanding the relationship between genetic markers and use of aspirin and NSAIDs, also known as gene by environment interactions, can help to identify population subgroups defined by genetic background that may benefit most from use of these agents to prevent cancer, according to background information in the article.

Andrew T. Chan, M.D., M.P.H., of Massachusetts General Hospital, Boston, Li Hsu, Ph.D., of the Fred Hutchinson Cancer Research Center, Seattle, and colleagues conducted a genome-wide analysis of gene by environment interactions between regular use of aspirin, NSAIDs, or both and single-nucleotide polymorphisms (SNPs; genetic variations) in relation to risk of colorectal cancer.  The researchers used data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia, and Germany and included colorectal cancer case patients (n = 8,634) and matched controls (n = 8,553) ascertained between 1976 and 2011. Participants were all of European descent.

An analysis of the overall data indicated that regular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer compared with nonregular use. But among individuals with two less common genotypes of rs16973225 (AC or CC, 9 percent of participants), no association was found between regular use and risk of colorectal cancer. And among participants with two rare genotypes of rs2965667 (TA or AA, 4 percent of participants), aspirin and/or NSAID use was associated with a higher risk of colorectal cancer.

In this genome-wide investigation of gene by environment interactions, “use of aspirin, NSAIDs, or both was associated with lower risk of colorectal cancer, and the association of these medications with colorectal cancer risk differed according to genetic variation at 2 SNPs at chromosomes 12 and 15. Validation of these findings in additional populations may facilitate targeted colorectal cancer prevention strategies,” the authors write.

(doi:10.1001/jama.2015.1815; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Aspirin and NSAID Chemoprevention, Gene-Environment Interactions, and Risk of Colorectal Cancer

“In the not-too-distant future it will be possible to affordably and efficiently conduct genetic testing in healthy individuals to more accurately define benefits and risks of interventions intended to decrease risk of disease,” writes Richard C. Wender, M.D., of the American Cancer Society, Atlanta, in an accompanying editorial.

“It will be important for primary care clinicians to understand genetic risk and to have informed, clear, literacy-adjusted, culturally competent discussions with their patients about how to use this information; otherwise, the goal of using genetic information to enhance decision making about prevention will remain elusive. Research needs to test different approaches to translating this complex information into practical methods to share information and improve clinical decisions. The ability to translate genetic profiling into tailored preventive care plans for individuals is still years away, but with the study by Nan et al, the road, arduous as it may be, is more clearly illuminated.”

(doi:10.1001/jama.2015.1032; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 1:45 P.M. (ET) SUNDAY, MARCH 15, 2015

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Folic Acid Supplementation Among Adults with Hypertension Reduces Risk of Stroke

In a study that included more than 20,000 adults in China with high blood pressure but without a history of stroke or heart attack, the combined use of the hypertension medication enalapril and folic acid, compared with enalapril alone, significantly reduced the risk of first stroke, according to a study appearing in JAMA. The study is being released to coincide with its presentation at the American College of Cardiology Annual Scientific Session.

Stroke is the leading cause of death in China and second leading cause of death in the world. Primary prevention (prevention prior to a first episode) is particularly important because about 77 percent of strokes are first events.  Uncertainty remains regarding the efficacy of folic acid therapy for primary prevention of stroke because of limited and inconsistent data, according to background information in the article.

Yong Huo, M.D., of Peking University First Hospital, Beijing, China, and colleagues had 20,702 adults with hypertension without history of stroke or heart attack randomly assigned to receive daily treatment with a single-pill combination containing enalapril (10 mg) and folic acid (0.8 mg; n = 10,348), or a tablet containing enalapril alone (10 mg; n = 10,354). The trial was conducted from May 2008 to August 2013 in 32 communities in Jiangsu and Anhui provinces in China. Participants were tested for variations in the MTHFR C677T gene (CC, CT, and TT genotypes) that may affect folate levels.

During a median treatment duration of 4.5 years, first stroke occurred in 282 participants (2.7 percent) in the enalapril-folic acid group compared with 355 participants (3.4 percent) in the enalapril group, representing an absolute risk reduction of 0.7 percent and a relative risk reduction of 21 percent. Analyses also showed significant reductions among participants in the enalapril-folic acid group in the risk of ischemic stroke (2.2 percent vs 2.8 percent) and composite cardiovascular events (cardiovascular death, heart attack and stroke) (3.1 percent vs 3.9 percent).

There was no significant difference between groups in the risk of hemorrhagic stroke, heart attack, or all-cause death, or in the frequencies of adverse events.

The authors write that this trial (China Stroke Primary Prevention Trial; CSPPT), with data on individual baseline folate levels and MTHFR genotypes, has provided convincing evidence that baseline folate level is an important determinant of efficacy of folic acid therapy in stroke prevention. “The CSPPT is the first large-scale randomized trial to test the hypothesis using individual measures of baseline folate levels. In this population without folic acid fortification, we observed considerable individual variation in plasma folate levels and clearly showed that the beneficial effect appeared to be more pronounced in participants with lower folate levels.”

“We speculate that even in countries with folic acid fortification and widespread use of folic acid supplements such as in the United States and Canada, there may still be room to further reduce stroke incidence using more targeted folic acid therapy—in particular, among those with the TT genotype and low or moderate folate levels.”

(doi:10.1001/jama.2015.2274; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Folate Supplements for Stroke Prevention

“The trial by Huo et al has important implications for stroke prevention worldwide,” write Meir Stampfer, M.D., Dr.P.H., and Walter Willett, M.D., Dr.P.H., of the Harvard T. H. Chan School of Public Health and Channing Division of Network Medicine, Boston, in an accompanying editorial.

“Although the trial participants all had hypertension, there is little reason to doubt that the results would apply to normotensive persons, although the absolute effect would be smaller. It is possible to debate the ethics of whether a replication trial should be performed, especially because folic acid supplementation (or fortification) is safe and inexpensive, and carries other benefits. Large segments of the world’s population, potentially billions of people, including those living in northern China, Bangladesh, and Scandinavia, have low levels of folate.”

“Individuals with the TT genotype might particularly benefit, although it seems unlikely that genotyping for that purpose would be cost-effective. Also, some persons in the United States on the low end of the distribution of folate intake may benefit; effects in this subgroup would not have been detected in previous trials. Ideally, adequate folate levels would be achieved from food sources such as vegetables (especially dark green leafy vegetables), fruits and fruit juices, nuts, beans, and peas. However, for many populations, achieving adequate levels from diet alone is difficult because of expense or availability. This study seems to support fortification programs where feasible, and supplementation should be considered where fortification will take more time to implement.”

(doi:10.1001/jama.2015.1961; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) MONDAY, MARCH 16, 2015

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For Heart Attack Patients Undergoing Procedure Such as Stent Placement, Anticoagulant Bivalirudin May Improve Outcomes Compared to Heparin

Among patients who experienced a heart attack and underwent a percutaneous coronary intervention (PCI; a procedure used to open narrowed coronary arteries, such as stent placement), the use of the anticoagulant bivalirudin following the procedure resulted in a decrease in adverse clinical events, primarily due to a reduction in bleeding events, compared with heparin alone or heparin plus the antiplatelet agent tirofiban, according to a study appearing in JAMA.

Antithrombotic therapy is essential to prevent adverse ischemic events, especially stent thrombosis (formation of a blood clot) and the occurrence of a subsequent heart attack during and after primary PCI in patients who had a heart attack (acute myocardial infarction; AMI). The benefits of antithrombotic (anticlotting) agents must be weighed against their risk of hemorrhagic (bleeding) complications, which have been associated with subsequent death. Anticoagulation during primary PCI is most commonly achieved with heparin or with bivalirudin. Because of mixed results in trials involving these drugs, the safety and efficacy of bivalirudin in patients with AMI undergoing PCI is still uncertain, especially compared with heparin alone, according to background information in the article.

Yaling Han, M.D., Ph.D., of the General Hospital of Shenyang Military Region, Shenyang Liaoning Province, China, and colleagues randomly assigned 2,194 patients with AMI undergoing primary PCI at 82 centers in China to receive bivalirudin with a post-PCI infusion (n = 735), heparin alone (n = 729), or heparin plus tirofiban with a post-PCI infusion (n = 730).

Net adverse clinical events at 30 days (a composite of major adverse cardiac or cerebral events [all-cause death, subsequent heart attack, ischemia-driven target vessel revascularization, or stroke] or bleeding) occurred in 8.8 percent of patients treated with bivalirudin, compared with 13.2 percent of patients treated with heparin, and 17 percent of patients treated with heparin plus tirofiban.

Bleeding at 30 days was reduced by bivalirudin compared with heparin and heparin plus tirofiban (4.1 percent vs 7.5 percent vs 12.3 percent, respectively). Bivalirudin also reduced bleeding requiring medical intervention.

There were no statistically significant differences between treatments in the 30-day rates of major adverse cardiac or cerebral events, stent thrombosis, acquired thrombocytopenia (decrease in platelets in the blood), or in acute (<24-hour) stent thrombosis. At the 1-year follow-up, the results remained similar.

“In this multicenter randomized trial [the BRIGHT trial], by reducing bleeding with comparable rates of major adverse cardiac or cerebral events and stent thrombosis, bivalirudin significantly reduced 30-day and 1-year rates of net adverse clinical events compared with both heparin alone and heparin plus tirofiban in patients with AMI undergoing primary PCI. The reduction in net adverse clinical events was consistent across multiple subgroups,” the authors write.

(doi:10.1001/jama.2015.2323; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Can BRIGHT Restore The Glow of Bivalirudin?

Patients undergoing PCI should have a tailored approach with regards to their antithrombotic regimen, write Matthew A. Cavender, M.D., M.P.H., and David P. Faxon, M.D., of Brigham and Women’s Hospital, Harvard Medical School, Boston, in an accompanying editorial.

“Patients in whom the risk of bleeding is high such as women, patients with renal dysfunction, or patients for whom femoral access is needed may benefit from an antithrombotic regimen that decreases the risk of bleeding. In contrast, patients at high risk of thrombotic complications may benefit from regimens that reduce the risk of thrombosis while conceding that the risk of bleeding may increase. Understanding how to optimize outcomes for each individual patient remains the ultimate goal—a goal that is only achieved with the help of more studies like BRIGHT.”

(doi:10.1001/jama.2015.2345; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Cavender reports consulting fees from AstraZeneca and Merck. Dr. Faxon did not report any conflicts of interest.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MARCH 10, 2015

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No Significant Difference in Outcomes Found for Surgical vs Non-Surgical Treatment of Displaced Fracture of Upper Arm

Among patients with a displaced fracture in the upper arm near the shoulder (proximal humeral), there was no significant difference between surgical treatment and nonsurgical treatment in patient-reported outcomes over two years following the fracture, results that do not support the trend of increased surgery for patients with this type of fracture, according to a study in the March 10 issue of JAMA.

Proximal humeral fractures account for 5 percent to 6 percent of all adult fractures; an estimated 706,000 occurred worldwide in 2000. The majority occur in people older than 65 years, and the age-specific incidence of these fractures is increasing. Approximately half of these fractures are displaced, the majority of which involve the surgical neck (located on the upper portion of the humerus). Surgical treatment is being increasingly used, contributing to increased treatment costs for upper limb fractures. A review of results from randomized clinical trials found insufficient evidence to conclude whether surgical intervention produces consistently better outcomes than nonsurgical treatment, according to background information in the article.

Amar Rangan, F.R.C.S. (Tr. & Orth.), of James Cook University Hospital, Middlesbrough, England, and colleagues randomly assigned 250 patients (average age, 66 years) who sustained a displaced fracture of the proximal humerus involving the surgical neck to surgical treatment (fracture fixation or humeral head replacement) or nonsurgical treatment (sling immobilization). Standardized outpatient and community-based rehabilitation was provided to both groups. Patients were followed up for 2 years and 215 had complete follow-up data. The data for 231 patients (114 in surgical group and 117 in nonsurgical group) were included in the primary analysis.

The researchers found that there were no statistically or clinically significant differences between surgical and non-surgical treatment either overall or at individual time points (at 6, 12, and 24 months) for the Oxford Shoulder Score (OSS), a shoulder-specific outcome measure that provides a total score based on the patient’s subjective assessment of pain and function. In addition, there were no clinically or significant differences on measures of health-related quality of life, complications related to surgery or shoulder fracture, complications requiring secondary surgery or treatment, and death.

Ten medical complications (2 cardiovascular events, 2 respiratory events, 2 gastrointestinal events, and 4 others) occurred in the surgical group during the postoperative hospital stay.

“These results do not support the trend of increased surgery for patients with displaced fractures of the proximal humerus,” the authors conclude.

(doi:10.1001/jama.2015.1629; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MARCH 10, 2015

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Lower Prevalence of Diabetes Found Among Patients With Inherited High Cholesterol Disorder

The prevalence of type 2 diabetes among 25,000 patients with familial hypercholesterolemia (a genetic disorder characterized by high low-density lipoprotein [LDL] cholesterol levels) was significantly lower than among unaffected relatives, with the prevalence varying by the type of gene mutation, according to a study in the March 10 issue of JAMA.

Statins have been associated with increased risk for diabetes, but the cause for this is not clear. One theory is that statins increase expression of LDL receptors and increase cholesterol uptake into cells including the pancreas, which could cause pancreatic dysfunction. Familial hypercholesterolemia causes decreased LDL transport into cells. Researchers have hypothesized that with familial hypercholesterolemia, decreased pancreatic LDL transport would lessen cell death and ultimately lead to lower rates of diabetes.

John J. P. Kastelein, M.D., Ph.D., of the Academic Medical Centre, Amsterdam, the Netherlands, and colleagues assessed the prevalence of type 2 diabetes between patients with familial hypercholesterolemia and their unaffected relatives. The study included all individuals (n = 63,320) who underwent DNA testing for familial hypercholesterolemia in the national Dutch screening program between 1994 and 2014.

The prevalence of type 2 diabetes was 1.75 percent in familial hypercholesterolemia patients (n = 440/25,137) vs 2.93 percent in unaffected relatives (n = 1,119/38,183), with adjusted figures indicating that patients with familial hypercholesterolemia had a 51 percent lower odds of having type 2 diabetes. Prevalence varied by the type of gene mutation. The researchers observed an inverse dose-response relationship between the severity of the familial hypercholesterolemia causing mutation and prevalence of type 2 diabetes.

“The small absolute difference in prevalence of type 2 diabetes between patients with familial hypercholesterolemia and unaffected relatives will not have a major influence on individual risk for type 2 diabetes. However, the substantial relative difference of 50 percent, together with previous findings, might suggest an effect of intracellular cholesterol metabolism on pancreatic beta cell function. Nevertheless, a plethora of pathways contribute to development of type 2 diabetes, and therefore, the mechanism we discuss here can only be 1 part of the pathogenesis of this highly complex disease,” the authors write.

“If these findings are confirmed in longitudinal studies, they might provide support for development of new approaches to the prevention and treatment of type 2 diabetes by improving function and survival of pancreatic beta cells.”

(doi:10.1001/jama.2015.1206; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Does the LDL Receptor Play a Role in the Risk of Developing Type 2 Diabetes?

David Preiss, M.D., Ph.D., and Naveed Sattar, M.D., Ph.D., of the University of Glasgow, United Kingdom, comment on the findings of this study in an accompanying editorial.

“What are the implications of these findings? This report adds to the growing literature of a complex interplay between lipids, glycemia, and adiposity, in which statins and other lipid-modifying agents appear to affect diabetes risk. The study also provides mechanistic insight into the potential roles of the LDL receptor and intracellular cholesterol accumulation. From a clinical perspective, the findings should allay any concerns about the potential diabetogenic effect of statins when treating patients with familial hypercholesterolemia from childhood or young adulthood given that these patients appear to be at a low risk for diabetes.”

“The study by Besseling et al contributes important evidence to strengthen the previously observed relationship between statin therapy and diabetes risk. However, this does not, and should not, alter guidance regarding the use of these important medications in patients at elevated cardiovascular risk given the clear overall benefit of statin therapy.”

(doi:10.1001/jama.2015.1275; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MARCH 10, 2015

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Study Examines Outcomes for Patients One Year After Transcatheter Aortic Valve Replacement

In an analysis of outcomes of about 12,000 patients who underwent transcatheter aortic valve replacement, death rate after one year was nearly one in four; of those alive at 12 months, almost half had not been rehospitalized and approximately 25 percent had only one hospitalization, according to a study in the March 10 issue of JAMA.

Following U.S. Food and Drug Administration approval in 2011, transcatheter aortic valve replacement (TAVR) has been used with increasing frequency for the treatment of severe aortic stenosis in patients who have high risks with conventional surgical AVR. TAVR, a less invasive procedure than open heart-valve surgery, involves replacing the aortic valve using a catheter inserted in the patient’s groin. Introducing new medical devices into routine practice raises concerns because patients and outcomes may differ from those in clinical trials, according to background information in the article.

David R. Holmes Jr., M.D., of Mayo Clinic, Rochester, Minn., and colleagues examined 1-year outcomes for TAVR patients who had 30-day outcomes previously reported. Data from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapies Registry were linked with patient-specific Centers for Medicare & Medicaid Services administrative claims data. The authors identified 12,182 patients with linked CMS data that underwent TAVR procedures at 299 U.S. hospitals from November 2011 through June 2013; the end of the follow-up period was June 30, 2014.

The median age of patients was 84 years and 52 percent were women. Following the TAVR procedure, 60 percent were discharged to home and the 30-day mortality rate was 7.0 percent. By 1 year, the overall mortality rate was 24 percent, the stroke rate was 4.1 percent, and the rate of the composite outcome of mortality and stroke was 26 percent. In addition, 47 percent of patients who remained alive at 12 months had not been rehospitalized, 24 percent were rehospitalized once and 12.5 percent were rehospitalized twice. Readmission for a composite of stroke, heart failure, or repeat aortic valve intervention occurred in 19 percent of patients.

Characteristics significantly associated with 1-year mortality included advanced age, male sex, end-stage renal disease and severe chronic obstructive pulmonary disease. Compared with men, women had a higher risk of stroke.

The authors note that the rate of l-year mortality reported with this registry is similar to that in other comprehensive reports. “Although this study includes only patients considered to have high risks with AVR, the majority of this mortality does not represent periprocedural complications, as 30-day mortality was only 7.0 percent. As such, this makes it imperative to focus on better prediction of the overall risks and benefits of the procedure, particularly given the existing comorbidities of the group of patients being considered for TAVR.”

They add that it may be possible to identify patients who may not benefit from this procedure and who should be counseled accordingly.

“Although 3 randomized trials and multiple single-center and multicenter registry studies have been published, the profile and longer-term outcomes of U.S. TAVR cases in routine clinical practice remains limited,” the researchers write. “These findings should be helpful in discussions with patients undergoing TAVR.”

(doi:10.1001/jama.2015.1474; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MARCH 10, 2015

Media Advisory: To contact Hallie C. Prescott, M.D., M.Sc., email Kara Gavin at kegavin@med.umich.edu.

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Hospital Readmissions Following Severe Sepsis Often Preventable

In an analysis of about 2,600 hospitalizations for severe sepsis, readmissions within 90 days were common, and approximately 40 percent occurred for diagnoses that could potentially be prevented or treated early to avoid hospitalization, according to a study in the March 10 issue of JAMA.

Patients are frequently rehospitalized within 90 days after having severe sepsis. Little is known, however, about the reasons for readmission and whether they can be reduced. Hallie C. Prescott, M.D., M.Sc., of the University of Michigan, Ann Arbor, and colleagues examined the most common readmission diagnoses after hospitalization for severe sepsis, the extent to which readmissions may be potentially preventable by posthospitalization ambulatory care, and whether the pattern of readmission diagnoses differs compared with that of other acute medical conditions.

The study included participants in the nationally representative U.S. Health and Retirement Study, a sample of households with adults 50 years of age or older, that is linked to Medicare claims (1998-2010). For the analysis, the researchers identified 2,617 hospitalizations for severe sepsis, which were matched to hospitalizations for other acute medical conditions. To gauge what proportion of rehospitalizations may be potentially preventable, ambulatory care sensitive conditions (ACSCs) were measured, which are diagnoses for which effective outpatient care may reduce hospitalization rates.

There were 1,115 severe sepsis survivors (42.6 percent) rehospitalized within 90 days. The 10 most common readmission diagnoses following severe sepsis included several ACSCs (e.g., heart failure, pneumonia, chronic obstructive pulmonary disease exacerbation, and urinary tract infection). Collectively, ACSCs accounted for 22 percent of 90-day readmissions.

Readmissions for a primary diagnosis of infection (sepsis, pneumonia, urinary tract, and skin or soft tissue infection) occurred in 12 percent of severe sepsis survivors compared with 8.0 percent of matched acute medical conditions. Readmissions for ACSCs were more common after severe sepsis (22 percent) vs matched  acute conditions (19 percent) and accounted for a greater proportion of all 90-day readmissions (42 percent vs 37 percent, respectively).

“The high prevalence and concentration of specific diagnoses during the early postdischarge period suggest that further study is warranted of the feasibility and potential benefit of postdischarge interventions tailored to patients’ personalized risk for a limited number of common conditions,” the authors write.

(doi:10.1001/jama.2015.1410; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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 EMBARGOED FOR RELEASE: 11 A.M. (ET) THURSDAY, MARCH 5, 2015

Media Advisory: To contact Mark J. Mulligan, M.D., email Vincent Dollard at vdollar@emory.edu. To contact editorial author Thomas W. Geisbert, Ph.D., email Raul Reyes at rareyes@utmb.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.1995

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Researchers Examine Effect of Experimental Ebola Vaccine After High-Risk Exposure

A physician who received an experimental Ebola vaccine after experiencing a needle stick while working in an Ebola treatment unit in Sierra Leone did not develop Ebola virus infection, and there was strong Ebola-specific immune responses after the vaccination, although because of its limited use to date, the effectiveness and safety of the vaccine is not certain, according to a study appearing in JAMA.

On September 26, 2014, a 44-year-old physician from the United States caring for patients in an Ebola treatment unit in Sierra Leone experienced an accidental needle stick, which was estimated to pose a significant risk of infection. Given the concern about potentially lethal Ebola virus disease, the patient was offered, and provided his consent for, postexposure vaccination with an experimental vaccine, VSVΔG-ZEBOV (which has entered a clinical trial for the prevention of Ebola in West Africa). Forty-three hours after exposure, the patient boarded a jet for medical evacuation to the United States and received the vaccine intramuscularly.

Mark J. Mulligan, M.D., of Emory University, Atlanta, and colleagues assessed the patient’s response to the vaccine. The patient developed malaise, nausea and fever 12 hours after the vaccination while on the transport jet. A physical exam in the U.S. approximately 14 hours postvaccination (performed at the National Institutes of Health Special Clinical Studies Unit) indicated the patient was in mild to moderate distress from fever, nausea, malaise, myalgia (muscle pain), and chills. On day 2, the fever declined; however, severe symptoms continued along with mild nausea and arthralgia (joint pain). On days 3 through 5, the patient experienced resolution of symptoms and laboratory abnormalities. By day 7, he was completely asymptomatic.

Blood tests detected Ebola virus glycoprotein-specific antibodies and strong Ebola-specific adaptive immune responses. “The clinical syndrome and laboratory evidence were consistent with vaccination response and no evidence of Ebola virus infection was detected,” the authors write.

“In the current patient, a self-limited, moderate to severe clinical syndrome began at 12 hours postvaccination. Future decision making about using this experimental vaccine for postexposure vaccination will need to balance the risks of harm from the vaccine or possible Ebola infection (both were unknowns at the time of the patient’s exposure) against the possible benefit of vaccination (also unknown at the time of the patient’s treatment).”

“Neither the safety nor the efficacy of the VSVΔG-ZEBOV vaccine for postexposure protection can be learned from this single case, but the clinical and laboratory parameters are informative at a time when there is a need to garner all information available on Ebola vaccines.”

(doi:10.1001/jama.2015.1995; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Emergency Treatment for Exposure to Ebola Virus

Thomas W. Geisbert, Ph.D., of the University of Texas Medical Branch, Galveston, writes in an accompanying editorial that the most effective way to prevent and control outbreaks and to protect high-risk personnel, including medical staff and laboratory workers, is through the use of preventive vaccines along with use of appropriate personal protective equipment.

“Historically, there has been a small global market for developing an Ebola virus vaccine and there was no financial interest for large pharmaceutical companies to become involved. The current epidemic has spurred substantial scientific activity to develop vaccines.”

“Although it is not possible to know with absolute certainty whether the first-generation VSVΔG-ZEBOV vaccine used to treat the potential high-risk exposure had any influence on survival of the exposed patient in the report by Lai et al, this incident serves as an example of how important it is to have safe and effective countermeasures available in sufficient quantities that can be rapidly deployed for emergency use for both medical workers and affected populations.”

(doi:10.1001/jama.2015. 2057; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

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