EMBARGOED FOR RELEASE: 9 A.M. (ET) SUNDAY, APRIL 3, 2016

Media Advisory: To contact Steven E. Nissen, M.D., call Andrea Pacetti at 216-316-3040 or email pacetta@ccf.org.

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Steven E. Nissen, M.D., of the Cleveland Clinic, and colleagues identified patients with muscle-related adverse effects from statins and compared lipid-lowering efficacy for two nonstatin therapies, ezetimibe and evolocumab. The study was published online by JAMA, and is being released to coincide with its presentation at the American College of Cardiology’s 65th Annual Scientific Session & Expo.

A significant proportion of patients with clinical indications for statin treatment report inability to tolerate evidence-based doses, most commonly because of muscle-related adverse effects, reported by 5 percent to 20 percent of patients. These patients typically report muscle pain or weakness when treatment is initiated or dosage increased and relief when the drug is discontinued or the dosage reduced. Patients with muscle-related intolerance often refuse to take statins despite elevated low-density lipoprotein cholesterol (LDL-C) levels and a high risk of major cardiovascular events. Current management may include very low or intermittent administration of statins or use of ezetimibe, but these strategies seldom achieve reductions recommended by current guidelines.

For this study, the researchers conducted a two-stage randomized clinical trial that included 511 adult patients with uncontrolled LDL-C levels and a history of intolerance to 2 or more statins. Phase A involved a 24-week crossover procedure in which patients were randomly assigned to atorvastatin (20 mg) or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, patients were randomly assigned to evolocumab (420 mg monthly, by injection) or oral ezetimibe (10 mg daily) for 24 weeks.

In phase A, the researchers observed a 43 percent rate of discontinuation for intolerable muscle symptoms with atorvastatin but not placebo. However, 27 percent of patients reported similar symptoms with placebo but not atorvastatin, demonstrating that reported muscle symptoms are not always related to statin use. “Since statin-associated muscle symptoms are dose-related, the rate observed in [this trial] for atorvastatin (20 mg) may underestimate the problem, particularly for patients needing high-intensity statin therapy, such as those enrolled in the trial.”

During the second phase of the study, the authors found that evolocumab produced significantly larger reductions in levels of LDL-C and other lipoproteins compared to ezetimibe. Both coprimary end points (the average percent change in LDL-C level from baseline to the average of weeks 22 and 24 levels and from baseline to week 24 levels) showed a 17 percent reduction with ezetimibe and a more than 50 percent reduction with evolocumab. Despite very high baseline values, the LDL-C goal of less than 70 mg/dL was achieved in nearly 30 percent of evolocumab-treated patients and 1.4 percent of ezetimibe-treated patients.

Muscle symptoms were reported in 29 percent of ezetimibe-treated patients and 21 percent of evolocumab-treated patients. Active study drug was stopped for muscle symptoms in 7 percent of ezetimibe-treated patients and 0.7 percent of evolocumab-treated patients.

“These findings demonstrate that both drugs are unlikely to provoke muscle symptoms and can be administered successfully in such patients, although with significant differences in lipid-lowering efficacy. Since a minority of patients achieved optimal LDL-C levels despite treatment with evolocumab, it may be worth exploring the addition of ezetimibe to evolocumab for those patients requiring further LDL-C reduction. It should be noted that neither ezetimibe nor evolocumab is approved for reduction of major adverse cardiovascular events,” the authors write.

“Further studies are needed to assess long-term efficacy and safety.”

(doi:10.1001/jama.2016.3608; this study is available pre-embargo at the For The Media website.)

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

EMBARGOED FOR RELEASE: 9 A.M. (ET) MONDAY, APRIL 4, 2016

Media Advisory: To contact Michelle L. O’Donoghue, M.D., M.P.H., call Johanna Younghans at 617-525-6373 or email Jyounghans@partners.org.

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Michelle L. O’Donoghue, M.D., M.P.H., of Brigham and Women’s Hospital, Boston, and colleagues evaluated the efficacy and safety of the anti-inflammatory drug losmapimod on cardiovascular outcomes in patients hospitalized after a heart attack. The study was published online by JAMA, and is being released to coincide with its presentation at the American College of Cardiology’s 65th Annual Scientific Session & Expo.

Inflammation stimulated by the enzyme p38 mitogen-activated protein kinase (MAPK) is implicated in atherogenesis (the process of forming atheromas, plaques in the inner lining of arteries) and plaque destabilization. Pilot data in a phase 2 trial in patients with non-ST elevation myocardial infarction (NSTEMI; a certain pattern on an electrocardiogram following a heart attack) indicated that the p38 MAPK inhibitor losmapimod lessens inflammation and may improve outcomes. In this phase 3 trial, Dr. O’Donoghue and colleagues randomly assigned patients who had been hospitalized with an acute MI and had at least 1 additional predictor of cardiovascular risk to either twice-daily losmapimod (n = 1,738) or matching placebo (n = 1,765) on a background of guideline-recommended therapy. Patients were treated for 12 weeks and followed up for an additional 12 weeks. The study was conducted at 322 sites in 34 countries. Part A of the trial consisted of a group (n = 3,503) to provide an initial assessment of safety and exploratory efficacy before considering progression to part B (approximately 22,000 patients).

Among the 3,503 patients in part A, the primary end point (a composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization with the principal analysis specified at week 12) occurred by 12 weeks in 123 patients treated with placebo (7 percent) and 139 patients treated with losmapimod (8.1 percent). The on-treatment rates of serious adverse events were 16 percent with losmapimod and 14.2 percent with placebo.

The authors write that the results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population.

“In this trial, losmapimod did not reduce the risk of recurrent major adverse cardiovascular events through 12 weeks of treatment in patients hospitalized with acute MI. Furthermore, there was no evidence that losmapimod reduced the incidence of any secondary outcomes including all-cause mortality. Therefore, our findings do not support a strategy of p38 MAPK inhibition with losmapimod in patients hospitalized with MI.”

“Because inflammation is believed to play a key role in atherogenesis, there remains intense interest to identify an anti-inflammatory therapeutic that will reduce the risk of cardiovascular events. However, because inflammation acts along multiple redundant and interconnected pathways, the identification of an appropriate target may be difficult, and it is challenging to predict clinical efficacy prior to phase 3 testing.”

(doi:10.1001/jama.2016.3609; this study is available pre-embargo at the For The Media website.)

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

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EMBARGOED FOR RELEASE: 10 A.M. (ET) TUESDAY, MARCH 29, 2016

Media Advisory: To contact Robert W. Yeh, M.D., M.Sc., email Jennifer Kritz at jkritz@bidmc.harvard.edu

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JAMA

In a study published online by JAMA, Robert W. Yeh, M.D., M.Sc., of Beth Israel Deaconess Medical Center, Boston, and colleagues conducted a study to identify factors that would predict whether the expected benefit of reduced ischemia would outweigh the expected increase in bleeding associated with continued dual antiplatelet therapy (aspirin plus thienopyridine) more than one year after coronary stent placement.

Dual antiplatelet therapy after percutaneous coronary intervention (PCI; commonly known as coronary angioplasty, a non-surgical procedure used to open narrow or blocked coronary arteries) reduces ischemia (inadequate blood supply to an area due to blockage of blood vessels leading to that area) but increases risk of bleeding. It remains unclear which patients are at high risk for late ischemic events and may thus benefit most from longer-term dual antiplatelet therapy vs those who are at high risk for late bleeding events and may be harmed.

Among 11,648 randomized DAPT (Dual Antiplatelet Therapy) Study patients from 11 countries, a prediction rule was derived stratifying patients into groups to distinguish ischemic and bleeding risk 12 to 30 months after PCI. The clinical prediction score was validated among 8,136 patients from 36 countries randomized in the PROTECT (Patient Related Outcomes With Endeavor vs Cypher Stenting) trial.

After adding or subtracting points for patients for factors such as heart attack at presentation, prior heart attack or PCI; diabetes; smoking; and older age, the researchers developed a clinical prediction score that showed modest accuracy assessing ischemic and bleeding risks.

“Use of this prediction score should be cautious until further validation is performed, and optimal clinical and procedural care to reduce overall bleeding and ischemic risks should be practiced independent of score,” the authors write.

(doi:10.1001/jama.2016.3775; this study is available pre-embargo at the For The Media website.)

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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For more information, contact JAMA Network Media Relations at 312-464-JAMA (5262) or email mediarelations@jamanetwork.org.

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MARCH 22, 2016

Media Advisory: To contact Daniel C. Cherkin, Ph.D., call Rebecca Hughes at 206-287-2055 or email hughes.r@ghc.org. To contact editorial co-author Madhav Goyal, M.D., M.P.H., call Marin Hedin at 410-502-9429 or email mhedin2@jhmi.edu.

To place an electronic embedded link to this study and editorial in your story These links will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.2323; https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.2437

Among adults with chronic low back pain, both mindfulness-based stress reduction and cognitive behavioral therapy resulted in greater improvement in back pain and functional limitations when compared with usual care, according to a study appearing in the March 22/29 issue of JAMA.

Low back pain is a leading cause of disability in the United States. There is need for treatments with demonstrated effectiveness that are low risk and have potential for widespread availability. Mindfulness-based stress reduction (MBSR) focuses on increasing awareness and acceptance of moment-to-moment experiences including physical discomfort and difficult emotions. Only 1 large randomized clinical trial has evaluated MBSR for chronic low back pain, and that trial was limited to older adults.

Daniel C. Cherkin, Ph.D., of Group Health Research Institute, Seattle, and colleagues randomly assigned 342 adults age 20 to 70 years with chronic low back pain to receive MBSR (n = 116), cognitive behavioral therapy (CBT; n = 113), or usual care (n = 113). CBT (training to change pain-related thoughts and behaviors) and MBSR (training in mindfulness meditation and yoga) were delivered in 8 weekly 2-hour groups. Usual care included whatever other treatment, if any, the participants received. The average age of the participants was 49 years; the average duration of back pain was 7.3 years.

The researchers found that at 26 weeks, the percentage of participants with clinically meaningful improvement on a measure of functional limitations was higher for those who received MBSR (61 percent) and CBT (58 percent) than for usual care (44 percent). The percentage of participants with clinically meaningful improvement in pain bothersomeness at 26 weeks was 44 percent in the MBSR group and 45 percent in the CBT group, vs 27 percent in the usual care group. Findings for MBSR persisted with little change at 52 weeks for both primary outcomes.

“The effects were moderate in size, which has been typical of evidence-based treatments recommended for chronic low back pain. These benefits are remarkable given that only 51 percent of those randomized to receive MBSR and 57 percent of those randomized to receive CBT attended at least 6 of the 8 sessions,” the authors write.

“These findings suggest that MBSR may be an effective treatment option for patients with chronic low back pain.”

(doi:10.1001/jama.2016.2323; this study is available pre-embargo at the For The Media website.)

Editor’s Note: Research reported in this article was supported by the National Center for Complementary and Integrative Health of the National Institutes of Health. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Is It Time to Make Mind-Body Approaches Available for Chronic Low Back Pain?

“Although understanding the specificity of treatment effects, mechanisms of action, and role of mediators are important issues for researchers, they are merely academic for many clinicians and their patients. For patients with chronic painful conditions, options are needed to help them live with less pain and disability now,” write Madhav Goyal, M.D., M.P.H., and Jennifer A. Haythornthwaite, Ph.D., of Johns Hopkins University School of Medicine, Baltimore.

“The challenge is how to ensure that these mind-body interventions are available, given the existing evidence demonstrating they may work for some patients with chronic low back pain. Most physicians encounter numerous obstacles finding appropriate referrals for mind-body therapies that their patients can access and afford. High-quality studies such as the clinical trial by Cherkin et al create a compelling argument for ensuring that an evidence-based health care system should provide access to affordable mind-body therapies.”

(doi:10.1001/jama.2016.2437; this editorial is available pre-embargo at the For The Media website.)

Editor’s Note: 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, MARCH 22, 2016

Media Advisory: To contact Jeffrey S. Gerber, M.D., Ph.D., email Natalie Virgilio at VIRGILION@email.chop.edu.

To place an electronic embedded link to this study in your story This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.2395

Exposure to antibiotics within the first 6 months of life compared with no exposure among nearly 40,000 children was not associated with a significant difference in weight gain through age 7, according to a study appearing in the March 22/29 issue of JAMA.

Antibiotics are the most commonly prescribed medications for children, with the long-term health effects relatively unknown. Early-life antibiotic exposure has been associated with increased adiposity (body fat) in animal models. Studies of the association between infant antibiotics and childhood weight gain have reported inconsistent results. Jeffrey S. Gerber, M.D., Ph.D., of The Children’s Hospital of Philadelphia, and colleagues conducted a study that included 38,522 children and 92 twins (46 matched pairs) with differences in antibiotic exposure and assessed the association between early-life exposure and childhood weight gain. The children were of diverse racial and socioeconomic backgrounds from Pennsylvania, New Jersey, and Delaware.

Of the children in the study, 5,287 (14 percent) were exposed to antibiotics during the first 6 months of life (at an average age of 4.3 months). Antibiotic exposure was not significantly associated with rate of weight change (0.7 percent; equivalent to approximately 1.8 ounce). Among 92 twins, the 46 twins who were exposed to antibiotics during the first 6 months of life received them at an average age of 4.5 months, and exposure was not significantly associated with a weight difference (-3.2 ounces).

“These findings do not support a clinically meaningful association of early-life antibiotic use with childhood weight gain,” the authors write. “There are many reasons to limit antibiotic exposure in young, healthy children, but weight gain is likely not one of them.”

(doi:10.1001/jama.2016.2395; this study is available pre-embargo at the For The Media website.)

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 22, 2016

Media Advisory: To contact Deborah W. Neklason, Ph.D., or N. Jewel Samadder, M.D., M.S., call Linda Aagard at 801-587-7639 or email Linda.Aagard@hci.utah.edu.

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In a study appearing in the March 22/29 issue of JAMA, Deborah W. Neklason, Ph.D., N. Jewel Samadder, M.D., M.S., of the Huntsman Cancer Institute, University of Utah, Salt Lake City, and colleagues randomly assigned 92 patients with familial adenomatous polyposis to the drugs sulindac twice daily and erlotinib daily (n = 46) or placebo (n = 46) for 6 months.

Familial adenomatous polyposis (FAP) is an inherited disorder, and patients with FAP are at markedly increased risk for duodenal (part of the small intestine) polyps and cancer. Surgical and endoscopic management of duodenal neoplasia is difficult and chemoprevention has not been successful.

The researchers found that sulindac in combination with erlotinib effectively reduced the total duodenal polyp burden and polyp number in participants with FAP compared with placebo. This effect was significant after 6 months of therapy.

Grade 1 and 2 adverse events were more common in the sulindac-erlotinib group, with an acne-like rash observed in 87 percent of participants receiving treatment and 20 percent of participants receiving placebo. “Adverse events may limit the use of these medications at the doses used in this study,” the authors write.

“Further research is necessary to evaluate these preliminary findings in a larger study population with longer follow-up to determine whether the observed effects will result in improved clinical outcomes.”

(doi:10.1001/jama.2016.2522; this study is available pre-embargo at the For The Media website.)

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 22, 2016

Media Advisory: To contact Ann Marie Navar, M.D., Ph.D., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu.

To place an electronic embedded link to this study in your story This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.2374

In a study appearing in the March 22/29 issue of JAMA, Ann Marie Navar, M.D., Ph.D., of Duke University Medical Center, Durham, N.C., and colleagues examined how shared clinical trial data are being used. Concerns over bias in clinical trial reporting have stimulated calls for more open data sharing. In response, multiple pharmaceutical companies have created mechanisms for investigators to access patient-level clinical trials data.

The researchers evaluated how many clinical trials were publicly available to investigators through 3 open access platforms, and found that a total of 3,255 clinical trials were available in the platforms. The median number of trials requested by each proposal was 2. Only 505 unique trials (15.5 percent of available trials) had ever been requested. “Reasons for underutilization of clinical trials data may include lack of knowledge about these resources, possibly due to lack of publication of results from proposals, or lack of funding to support analyses.”

“Early use of platforms designed to provide access to individual patient data, developed to increase transparency of clinical trial data, has been limited. Availability of shared clinical trial data should be promoted and use of individual patient data for validation studies encouraged.”

(doi:10.1001/jama.2016.2374; this study is available pre-embargo at the For The Media website.)

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

Note: An accompanying editorial, “Data Sharing – An Ethical and Scientific Imperative,” by Howard Bauchner, M.D., Editor in Chief, JAMA, Chicago, and colleagues is available pre-embargo at the For The Media website.

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EMBARGOED FOR RELEASE: 1:30 P.M. (ET) TUESDAY, MARCH 15, 2016

Media Advisory: To contact corresponding author Deborah Dowell, M.D., M.P.H., call 404-639-3286 or email media@cdc.gov.

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The Centers for Disease Control and Prevention (CDC) has issued recommendations about opioid prescribing for primary care clinicians treating adult patients with chronic pain, recommendations that are intended to improve communication about the benefits and risks, improve safety and effectiveness of pain treatment, and reduce risks associated with long-term opioid therapy, according to a report published online by JAMA.

The number of people experiencing chronic pain is substantial, with U.S. prevalence estimated at 11.2 percent of the adult population. Opioids are commonly prescribed for pain, with approximately 3 percent to 4 percent of the adult U.S. population prescribed long-term opioid therapy. Opioid pain medication use presents serious risks. From 1999 to 2014, more than 165,000 persons died from overdose related to opioid pain medication in the U.S. In 2013 alone, an estimated 1.9 million persons abused or were dependent on prescription opioid pain medication. Primary care clinicians find managing chronic pain challenging. Evidence on long-term efficacy of opioids for chronic pain is limited.

For the development of these recommendations and guideline, which are for chronic pain outside of active cancer treatment, palliative care, and end-of-life care, the CDC updated a 2014 systematic review on effectiveness and risks of opioids and conducted a supplemental review on benefits and harms, values and preferences, and costs. Evidence consisted of observational studies or randomized clinical trials with notable limitations, characterized as low quality using Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology.

There are 12 recommendations for 3 areas: determining when to initiate or continue opioids for chronic pain; opioid selection, dosage, duration, follow-up, and discontinuation; and assessing risk and addressing harms of opioid use. Among the recommendations:

— Of primary importance, nonopioid therapy is preferred for treatment of chronic pain.

— Opioids should only be used when benefits for pain and function are expected to outweigh risks.

— Before starting opioids, clinicians should establish treatment goals with patients and consider how opioids will be discontinued if benefits do not outweigh risks.

— When opioids are used, clinicians should prescribe the lowest effective dosage, carefully reassess benefits and risks when considering increasing dosage to 50 morphine milligram equivalents or more per day, and avoid concurrent opioids and benzodiazepines whenever possible.

— Clinicians should evaluate benefits and harms of continued opioid therapy with patients every 3 months or more frequently and review prescription drug monitoring program data, when available, for high-risk combinations or dosages.

— For patients with opioid use disorder, clinicians should offer or arrange evidence-based treatment, such as medication-assisted treatment with buprenorphine or methadone.

The authors write that to inform future guideline development, more research is needed to fill critical evidence gaps. “Yet given that chronic pain is a significant public health problem, the risks associated with long-term opioid therapy, the availability of effective alternative treatment options for pain, and the potential for improvement in the quality of health care with the implementation of recommended practices, a guideline for prescribing is warranted with currently available evidence.”

They add that the “CDC is committed to evaluating the guideline to identify effects on clinician and patient outcomes, both intended and unintended, and will revisit the guideline to determine if evidence gaps have been sufficiently addressed to warrant an update of the guideline and revise the recommendations in future updates when warranted.”

(doi:10.1001/jama.2016.1464; The full report is available pre-embargo at the For The Media website.)

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: 1:30 P.M. (ET) TUESDAY, MARCH 15, 2016

Media Advisory: To contact Brian T. Bateman, M.D., M.Sc., call Elaine St. Peter at 617-525-6375 or email estpeter@partners.org.

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In a study published online by JAMA, Brian T. Bateman, M.D., M.Sc., of Brigham and Women’s Hospital, Boston, and colleagues examined nationwide patterns of opioid prescribing following surgical tooth extraction.

Opioid abuse has reached epidemic proportions in the United States, and often begins with a prescription for a pain medication. Dentists are among the leading prescribers of opioid analgesics, and surgical tooth extraction is one of the most frequently performed dental procedures. Surveys suggest that dental practitioners commonly prescribe opioids following this procedure, despite evidence that a combination of nonsteroidal medications and acetaminophen may provide more effective treatment for postextraction pain.

The researchers collected data from a national database of health claims drawn from Medicaid transactions for the years 2000-2010. All patients who underwent surgical dental extraction were included. The frequency of opioid prescriptions filled within 7 days of extraction was determined, as was the nature and amount of opioids dispensed.

The analysis included 2,757,273 patients. Within 7 days of extraction, 42 percent of patients filled a prescription for an opioid medication. The most commonly dispensed opioid was hydrocodone (78 percent of all prescriptions), followed by oxycodone (15 percent), propoxyphene (3.5 percent), and codeine (1.6 percent). Patients age 14 to 17 years had the highest proportion who filled opioid prescriptions (61 percent), followed by patients age 18 to 24 years.

There was great variability in the amount of opioids dispensed for a given procedure, with an approximately 3-fold difference between the 10th and 90th percentile in the oral morphine equivalents prescribed. “Although a limited supply of opioids may be required for some patients following tooth extraction, these data suggest that disproportionally large amounts of opioids are frequently prescribed given the expected intensity and duration of postextraction pain, particularly as nonopioid analgesics may be more effective in this setting,” the authors write.

“This common dental procedure may represent an important area of excessive opioid prescribing in the United States. As the nation implements programs to reduce excessive prescribing of opioid medications, it will be important to include dental care in these approaches.”

(doi:10.1001/jama.2015.19058. The study is available pre-embargo at the For The Media website.)

Editor’s Note: Research reported in this publication was supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health. 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: 1:30 P.M. (ET) TUESDAY, MARCH 15, 2016

Media Advisory: To contact Hannah Wunsch, M.D., M.Sc., call Sybil Millar at 416-480-4040 or email sybil.millar@sunnybrook.ca.

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In a study published online by JAMA, Hannah Wunsch, M.D., M.Sc., of Sunnybrook Health Sciences Centre, Toronto, and colleagues assessed trends in the amount of hydrocodone/acetaminophen and oxycodone/acetaminophen prescribed from 2004-2012, two opioids commonly used for postoperative pain management.

The study included health care encounters of approximately 14 million primarily commercially insured patients, with information on pharmacy and medical claims with data on services and procedures. The sample included opioid-naive adults (n = 155,297) who underwent 1 or more of 4 low-risk surgical procedures in 2004, 2008, or 2012: carpal tunnel release, laparoscopic cholecystectomy (gallbladder removal), inguinal hernia repair, or knee arthroscopy. The researchers assessed the proportion of patients who filled any opioid prescription (and specifically hydrocodone/acetaminophen or oxycodone/acetaminophen) in the 7 days after hospital discharge (inpatients) or on the procedure date (outpatients).

Within 7 days, 80 percent filled a prescription for any opioid, and 86 percent of these prescriptions were for hydrocodone/acetaminophen or oxycodone/acetaminophen. The proportions of patients filling prescriptions for any opioid and for hydrocodone/acetaminophen and oxycodone/acetaminophen increased over time for all surgeries. The average morphine equivalent dose increased over time for all procedures examined, with an increase of 18 percent for patients undergoing knee arthroscopy, driven by a change in the average daily dose.

“Because the cohort was restricted to opioid-naive individuals, these changes are unlikely to represent an appropriate response by prescribing physicians to increasing rates of opioid tolerance over time within the population. Possible explanations include an increased focus on pain treatment or an increasing reliance on opioids for postoperative pain relief vs alternative therapies,” the authors write.

“Further research should assess the contribution of postoperative opioid prescribing practices to the epidemic of prescription opioid-related abuse.”

(doi:10.1001/jama.2016.0130. The study is available pre-embargo at the For The Media website.)

Editor’s Note: This work is supported in part by a New Investigator Award from the Canadian Institutes of Health Research and a Merit Award from the Department of Anesthesia at the University of Toronto. 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: 4 A.M. (ET) TUESDAY, MARCH 15, 2016

Media Advisory: To contact Michael C. Reade, D.Phil., F.C.I.C.M., email m.reade@uq.edu.au.

To place an electronic embedded link to this study in your story This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.2707

Michael C. Reade, D.Phil., F.C.I.C.M., of the University of Queensland, Brisbane, Australia, and colleagues evaluated the effectiveness of the drug dexmedetomidine when added to standard care in intensive care unit (ICU) patients with agitated delirium receiving mechanical ventilation. The study, published by JAMA, is being released to coincide with its presentation at the International Symposium on Intensive Care and Emergency Medicine.

The incidence of delirium in critically ill patients is high. Delirium is associated with increased mortality and decreased long-term cognitive function. Agitated delirium is particularly problematic in patients receiving mechanical ventilation because it increases the risk of self-extubation and removal of other essential medical devices. Effective therapy has not been established for patients with agitated delirium receiving mechanical ventilation.

In this study, 74 ICU patients in whom extubation was considered inappropriate because of the severity of agitation and delirium, were randomly assigned to be administered dexmedetomidine or placebo to achieve physician-prescribed sedation goals. The study drug or placebo was continued until no longer required or up to 7 days. The study was conducted at 15 ICUs in Australia and New Zealand.

The final analysis included 39 patients in the dexmedetomidine group and 32 patients in the placebo group. Dexmedetomidine increased ventilator-free hours at 7 days compared with placebo (median, 145 hours vs 128 hours, respectively). Among secondary outcomes, none were significantly worse with dexmedetomidine, and several showed statistically significant benefit, including reduced time to extubation (median, 22 hours vs 44 hours with placebo) and accelerated resolution of delirium (median, 23 hours vs 40 hours). Analysis indicated that dexmedetomidine was significantly associated with earlier extubation.

“The findings support the use of dexmedetomidine in patients such as these,” the authors write.

(doi:10.1001/jama.2016.2707; this study is available pre-embargo at the For The Media website.)

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: 4 A.M. (ET) TUESDAY, MARCH 15, 2016

Media Advisory: To contact Lonneke A. van Vught, M.D., email l.a.vanvught@amc.uva.nl.

To place an electronic embedded link to this study in your story This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.2691

Lonneke A. van Vught, M.D., of the University of Amsterdam, the Netherlands and colleagues conducted a study that included admissions in two intensive care units (ICUs) in the Netherlands stratified according to admission diagnosis (sepsis or non-infectious). The study, published by JAMA, is being released to coincide with its presentation at the International Symposium on Intensive Care and Emergency Medicine.

Sepsis is the leading cause of illness and death in hospitalized patients. It has been suggested that the immune suppression accompanying sepsis contributes to late sepsis mortality in the ICU caused by an increased occurrence of secondary infections. This study included 1,719 sepsis admissions; a comparative group included 1,921 admissions in whom infection was not present in the first 48 hours.

ICU-acquired infections occurred in 13.5 percent of sepsis admissions and 15 percent of non-sepsis ICU admissions. Patients with sepsis who developed an ICU-acquired infection had higher disease severity scores on admission than patients with sepsis who did not develop an ICU-acquired infection. The estimated difference between mortality in all patients with a sepsis admission diagnosis and mortality in those without ICU-acquired infection was 2 percent by day 60.

The authors write that a few findings from this study deserve attention. “First, the incidence of ICU-acquired infections after the first week of ICU stay was comparable in both admission groups. Second, a higher proportion of patients with a sepsis admission diagnosis acquired more than one infection in the ICU compared with patients with a non-infectious admission diagnosis. Third, patients with sepsis on admission developed more ICU-acquired infections with opportunistic pathogens like enterococci, Pseudomonas aeruginosa and viruses, hinting at possible immune suppression. Fourth, the population attributable mortality fraction of ICU-acquired infection does not seem to be higher in patients with a sepsis admission diagnosis than in patients admitted with a non-infectious condition.”

(doi:10.1001/jama.2016.2691; this study is available pre-embargo at the For The Media website.)

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

EMBARGOED FOR RELEASE: 4 A.M. (ET) TUESDAY, MARCH 15, 2016

Media Advisory: To contact Samir Jaber, M.D., Ph.D., email s-jaber@chu-montpellier.fr.

To place an electronic embedded link to this study in your story This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.2706

Samir Jaber, M.D., Ph.D., of Saint Eloi University Hospital and Montpellier School of Medicine, Montpellier, France and colleagues examined whether noninvasive ventilation vs standard oxygen therapy improves outcomes among patients developing hypoxemic (low levels of oxygen in the blood) acute respiratory failure after abdominal surgery. The study, published by JAMA, is being released to coincide with its presentation at the International Symposium on Intensive Care and Emergency Medicine.

Postoperative acute respiratory failure is a major contributor to the overall risk of surgery, leading to an increase in illness and death. Postoperative acute respiratory failure often requires tracheal reintubation and invasive mechanical ventilation. It has not been established whether noninvasive ventilation (NIV) reduces the need for invasive mechanical ventilation in patients who develop hypoxemic acute respiratory failure after abdominal surgery.

In this trial conducted at 20 French intensive care units, 293 patients who had undergone abdominal surgery and developed hypoxemic respiratory failure were randomly assigned to receive standard oxygen therapy (n = 145) or NIV delivered via facial mask (n = 148). The researchers found that reintubation occurred in 33 percent of patients in the NIV group and 46 percent of patients in the standard oxygen therapy group by 7 days after randomization. Noninvasive ventilation was associated with significantly more invasive ventilation-free days compared with standard oxygen therapy (25.4 vs 23.2 days), while fewer patients developed health care-associated infections (31 percent vs 49 percent), especially ICU acquired pneumonia. At 90 days, 15 percent of patients in the NIV group had died, compared to 22 percent in the standard oxygen therapy group.

“Among patients with hypoxemic respiratory failure following abdominal surgery, use of NIV compared with standard oxygen therapy reduced the risk of tracheal reintubation within 7 days. These findings support use of NIV in this setting,” the authors write.

(doi:10.1001/jama.2016.2706; this study is available pre-embargo at the For The Media website.)

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

EMBARGOED FOR RELEASE: 4 A.M. (ET) TUESDAY, MARCH 15, 2016

Media Advisory: To contact Gonzalo Hernandez, M.D., Ph.D., email ghernandezm@telefonica.net.

To place an electronic embedded link to this study in your story This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.2711

Gonzalo Hernandez, M.D., Ph.D., of Hospital Virgen de la Salud, Madrid, Spain and colleagues randomly assigned 527 mechanically ventilated patients at low risk for reintubation to undergo either high-flow or conventional oxygen therapy for 24 hours after extubation. The study, published by JAMA, is being released to coincide with its presentation at the International Symposium on Intensive Care and Emergency Medicine.

Studies of mechanically ventilated critically ill patients that combine populations that are at high and low risk for reintubation suggest that high-flow nasal cannula oxygen therapy after extubation improves oxygenation compared with conventional oxygen therapy. However, conclusive data about reintubation are lacking. A nasal cannula is a device for delivering oxygen by way of two small tubes that are inserted into the nostrils.

In this study 264 patients received high-flow therapy and 263 conventional oxygen therapy. Reintubation within 72 hours was less common in the high-flow group (13 patients [5 percent]) vs 32 (12 percent) in the conventional group. Postextubation respiratory failure was less common in the high-flow group (8 percent vs 14 percent in the conventional group). Time to reintubation was not significantly different between groups.

“The main finding of this study was that high-flow oxygen significantly reduced the reintubation rate in critically ill patients at low risk for extubation failure,” the authors write.

(doi:10.1001/jama.2016.2711; this study is available pre-embargo at the For The Media website.)

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

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MARCH 15, 2016

Media Advisory: To contact Saad B. Omer, M.B.B.S., M.P.H., Ph.D., email Melva Robertson at melva.robertson@emory.edu. To contact editorial author Matthew M. Davis, M.D., M.A.P.P., email Beata Mostafavi at bmostafa@med.umich.edu.

To place an electronic embedded link to this study and editorial in your story These links will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1353; https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1529

An analysis of numerous studies and reports finds that unvaccinated or undervaccinated individuals comprised substantial proportions of cases in measles and some pertussis outbreaks, and vaccine refusal was associated with an elevated risk for measles and pertussis, including among fully vaccinated individuals, according to a study appearing in the March 15 issue of JAMA.

Recent outbreaks of vaccine-preventable diseases in the United States have prompted clinicians, public health officials and the public to pay greater attention to the growing phenomenon of vaccine refusal and hesitancy. Improved understanding of the association between vaccine refusal and the epidemiology of these diseases is needed. Saad B. Omer, M.B.B.S., M.P.H., Ph.D., of Emory University, Atlanta, and colleagues examined the association between vaccine delay, refusal, or exemption and the epidemiology of measles and pertussis, two vaccine-preventable diseases with recent U.S. outbreaks. The authors searched the medical literature for reports of U.S. measles outbreaks that have occurred since measles was declared eliminated in the United States (after January 1, 2000), endemic and epidemic pertussis since the lowest point in U.S. pertussis incidence (after January 1, 1977), and for studies that assessed disease risk in the context of vaccine delay or exemption.

The researchers identified 18 published measles studies, which described 1,416 measles cases (individual age range, 2 weeks-84 years; 178 cases younger than 12 months) and more than half (57 percent) had no history of measles vaccination. Of the 970 measles cases with detailed vaccination data, 574 cases were unvaccinated despite being vaccine eligible and 71 percent of these had nonmedical exemptions (e.g., for religious or philosophical reasons, as opposed to medical contraindications; 42 percent of total).

Among 32 reports of pertussis outbreaks, which included 10,609 individuals for whom vaccination status was reported (age range, 10 days-87 years), the 5 largest statewide epidemics had substantial proportions (range, 24 percent-45 percent) of unvaccinated or undervaccinated individuals. However, several pertussis outbreaks also occurred in highly vaccinated populations, indicating waning immunity. Nine reports (describing 12 outbreaks) provided detailed vaccination data on unimmunized cases; among 8 of these outbreaks, from 59 percent through 93 percent of unvaccinated individuals were intentionally unvaccinated.

“This review has broad implications for vaccine practice and policy. For instance, fundamental to the strength and legitimacy of justifications to override parental decisions to refuse a vaccine for their child is a clear demonstration that the risks and harms to the child of remaining unimmunized are substantial. Similarly, central to any justification to restrict individual freedom by mandating vaccines to prevent harm to others is an understanding of the nature and magnitude of these risks and harms. However, the risks of vaccine refusal remain imperfectly defined, and the association between vaccine refusal and vaccine-preventable diseases may be both population- and disease-specific,” the authors write.

(doi:10.1001/jama.2016.1353; this study is available pre-embargo at the For The Media website.)

Editor’s Note: This work is supported by an award from the Emory Vaccinology Training Program of the National Institute of Allergy and Infectious Diseases. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Toward High-Reliability Vaccination Efforts in the United States

“Without a centralized infrastructure focused on the goal of maximizing community immunity, high-reliability vaccine coverage remains challenging in the United States,” writes Matthew M. Davis, M.D., M.A.P.P., of the University of Michigan, Ann Arbor, in an accompanying editorial.

“Nonetheless, if vaccines are developed for emerging diseases that threaten the U.S. population—such as Zika, Ebola, or human immunodeficiency virus—the public will likely expect the currently complex and heterogeneous vaccination system in the United States to function as a seamless organization. The U.S. population wants vaccination to be safe, effective and available in a timely manner, and for immunization to be durable. Current challenges with measles and pertussis outbreaks provide an opportunity to develop and evaluate approaches to achieve unprecedented levels of vaccination coverage, limit waning immunity, and minimize vaccine-preventable disease for children and adults alike.”

(doi:10.1001/jama.2016.1529; this editorial is available pre-embargo at the For The Media website.)

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, MARCH 15, 2016

Media Advisory: To contact Timo Laitio, M.D., Ph.D., email timo.laitio@elisanet.fi.

To place an electronic embedded link to this study in your story This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1933

Among comatose survivors of out-of-hospital cardiac arrest, treatment with inhaled xenon gas combined with hypothermia, compared with hypothermia alone, resulted in less white matter damage; however, there was no significant difference in neurological outcomes or death at 6 months, according to a study appearing in the March 15 issue of JAMA.

Survivors of out-of-hospital cardiac arrest have a poor prognosis with high rates of death and the likelihood of having severe neurological problems. Animal studies have established the neuroprotective properties of the inhaled noble gas xenon. Neuroprotection associated with xenon has been especially evident when combined with hypothermia (91.4°F to 95°F). Thus far, these neuroprotective properties have not been reported in human studies.

Timo Laitio, M.D., Ph.D., of the University of Turku, Finland, and colleagues randomly assigned 110 comatose patients who had experienced out-of-hospital cardiac arrest to receive either inhaled xenon combined with hypothermia (91.4°F) for 24 hours (n = 55) or hypothermia treatment alone (n = 55; control group). The trial was conducted at two intensive care units in Finland.

There were magnetic resonance imaging data from 97 patients a median of 53 hours after cardiac arrest. The researchers found that patients in the xenon group had less white matter damage compared to the control group. At six months, 75 patients (68 percent) were alive. There were no significant differences between the groups on measures of neurological and cognitive outcomes, or death at six months.

“These preliminary findings require further evaluation in an adequately powered clinical trial designed to assess clinical outcomes associated with inhaled xenon among survivors of out-of-hospital cardiac arrest,” the authors write.

(doi:10.1001/jama.2016.1933; this study is available pre-embargo at the For The Media website.)

Editor’s Note: The study was funded by the Academy of Finland and via clinical research funding from the Hospital District of Southwest Finland. 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, MARCH 15, 2016

Media Advisory: To contact Rachel M. Freathy, Ph.D., email r.freathy@ex.ac.uk; to contact Debbie A. Lawlor, Ph.D., email d.a.lawlor@bristol.ac.uk.

To place an electronic embedded link to this study in your story This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1975

In a study that included more than 30,000 women, genetically elevated maternal body mass index (BMI) and blood glucose levels were potentially causally associated with higher offspring birth weight, while genetically elevated maternal systolic blood pressure was potentially causally related to lower birth weight, according to a study appearing in the March 15 issue of JAMA.

Neonates born to overweight or obese women are more likely to be large for gestational age. The precise mechanisms underlying this association are poorly understood. It is important to understand which maternal traits are causally associated with birth weight because this may facilitate targeted development of interventions to be tested and enable evidence-based recommendations for pregnant women.

Rachel M. Freathy, Ph.D., of the University of Exeter, and Debbie A. Lawlor, Ph.D., of the University of Bristol, U.K., and colleagues tested for genetic evidence of causal associations of maternal BMI and related traits with birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term offspring born between 1929 and 2013 were included.

The researchers found that a genetically higher maternal BMI of 4 points was associated with a 1.9 ounces higher offspring birth weight. In addition, a genetically higher circulating maternal fasting glucose of 7.2 mg/dL was associated with a 4 ounces higher birth weight, whereas genetically higher maternal systolic blood pressure (SBP) of 10 mm Hg was associated with a 7.3 ounces lower birth weight.

“These results provide evidence that genetically elevated maternal glucose and SBP may have directionally opposite causal associations with birth weight. The estimated associations between these maternal traits and birth weight (either increased or reduced) are substantial and of clinical importance. They support efforts to maintain healthy gestational glucose and blood pressure levels to ensure healthy fetal growth,” the authors write.

“If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.”

(doi:10.1001/jama.2016.1975; this study is available pre-embargo at the For The Media website.)

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 15, 2016

Media Advisory: To contact Kathryn Rough, Sc.M., call Elaine St. Peter at 617-525-6375 or email estpeter@partners.org.

To place an electronic embedded link to this study in your story This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.18417

In a study appearing in the March 15 issue of JAMA, Kathryn Rough, Sc.M., of Brigham and Women’s Hospital, Boston, and colleagues examined the association between implementation of the Centers for Medicare & Medicaid Services (CMS) suppression policy of substance abuse-related claims and rates of diagnoses for non­substance abuse conditions in Medicaid data.

In a change from longstanding practice, the CMS recently began suppressing substance abuse-related claims in the Medicare and Medicaid Research Identifiable Files to comply with a 1987 federal regulation barring third party payers from releasing information from federally funded substance abuse treatment programs without patient consent. CMS removes any claim containing a diagnostic or procedure code related to substance abuse, meaning that the entire encounter captured by the claim is deleted (including all diagnosis and procedure codes). Therefore, important diagnoses linked to substance abuse might also be suppressed.

This study included Medicaid data for 2000-2006 prior to implementation of the suppression policy (i.e., containing substance abuse codes) and data for 2007-2010 after the policy was enacted, allowing comparison of data without vs with claim suppression. The researchers calculated annual inpatient and   outpatient rates of diagnoses for 6 conditions that commonly co-occur with substance abuse (hepatitis C, human immunodeficiency virus, cirrhosis, tobacco use, depression, and anxiety) and 4 conditions unrelated to substance abuse (type II diabetes, stroke, hypertension, and kidney disease).

The authors found that conditions unrelated to substance abuse appeared generally unassociated with the CMS suppression practices. However, implementation of the policy coincided with sudden and substantial decreases in the rates of inpatient diagnoses for conditions commonly co-occurring with substance abuse, and anxiety showed significant reductions in outpatient diagnosis rates.

“Underestimation of diagnoses has the potential to bias health services research studies and epidemiological analyses for which affected conditions are outcomes or confounders. In studies of health care utilization, the number of missing claims may vary in a nonrandom fashion between groups defined by demographics, disease, or locality. Comparisons between groups may lead to spurious conclusions—a hospital that regularly admits substance abusers will have artificially low rates of readmission, giving a false appearance of better performance.”

(doi:10.1001/jama.2015.18417; this study is available pre-embargo at the For The Media website.)

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 8, 2016

Media Advisory: To contact Steven E. Nissen, M.D., email Tora Vinci at VINCIV@ccf.org or Andrea Pacetti at PACETTA@ccf.org. To contact editorial co-author Joshua M. Sharfstein, M.D., email Stephanie Desmon at sdesmon1@jhu.edu.

To place an electronic embedded link to this study and editorial in your story These links will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1558 https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1461

The cardiovascular safety of the obesity treatment naltrexone-bupropion remains uncertain because of the unanticipated early termination of a trial to determine its safety, according to a study appearing in the March 8 issue of JAMA.

Drug treatments for obesity have yielded mixed results, with pharmacological agents achieving modest weight loss but without demonstrating a reduction in cardiovascular events. Two therapies, fenfluramine and sibutramine, were removed from the market after evidence of cardiovascular harm emerged. Accordingly, the medical community and regulatory authorities have expressed concern about the cardiovascular safety of new drugs to treat obesity. The combination of the drugs naltrexone and bupropion reduced weight during phase 3 clinical trials, but the U.S. Food and Drug Administration (FDA) deferred approval based on safety concerns related to small increases in blood pressure and heart rate in these trials.

Steven E. Nissen, M.D., of the Cleveland Clinic Center for Cardiovascular Research, Cleveland, and colleagues randomly assigned 8,910 overweight or obese patients at increased cardiovascular risk to receive placebo (n=4,454) or naltrexone and bupropion (n=4,456). An Internet-based weight management program was provided to all participants. The study was conducted at 266 U.S. centers. The researchers examined whether the combination of naltrexone and bupropion increases major adverse cardiovascular events (MACE, defined as cardiovascular death, nonfatal stroke, or nonfatal heart attack) compared with placebo.

For the 25 percent interim analysis (after approximately 87 events), MACE occurred in 59 placebo-treated patients (1.3 percent) and 35 naltrexone-bupropion–treated patients (0.8 percent). After 50 percent of planned events, outcomes were less favorable for naltrexone-bupropion patients, with MACE occurring in 102 patients (2.3 percent) in the placebo group and 90 patients (2.0 percent) in the naltrexone-bupropion group. After public release of confidential interim data (after 25 percent of planned events) by the sponsor, the academic leadership of the study recommended termination of the trial and the sponsor agreed.

The authors write that given the unplanned early termination of the trial, which directly resulted from the inappropriate release of the highly favorable 25 percent interim data, these findings do not establish the prespecified margin of noninferiority (not worse than). “Accordingly, the cardiovascular safety of this treatment remains uncertain and will require evaluation in a new adequately powered outcome trial.”

“The events leading to the termination of the study serve as a valuable reminder of the importance of maintaining confidentiality during ongoing trials. Premature release of interim data can result in inappropriate prejudgment about the benefits or risks of the studied therapy and make completion of the trial highly problematic. An FDA guidance for industry explicitly states that interim data from an ongoing clinical trial should remain confidential and warns that ‘such knowledge can bias the outcome of the study by inappropriately influencing its continuing conduct or the plan of analyses.’”

(doi:10.1001/jama.2016.1558; this study is available pre-embargo at the For The Media website.)

Editor’s Note: The study was sponsored by Orexigen Therapeutics Inc., La Jolla, Calif., and Takeda Pharmaceuticals International, Deerfield, Il. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Evaluation of the Cardiovascular Risk of Naltrexone-Bupropion

“In the shadow of [this trial, LIGHT], the FDA should review its policy of permitting approval based on interim analyses of ongoing safety studies. At a minimum, when a company violates its commitment to confidentiality and the FDA requires a new trial, the agency should delay approval at least until a viable replacement study is being conducted,” write Joshua M. Sharfstein, M.D., of the Johns Hopkins Bloomberg School of Public Health, Baltimore, and Bruce M. Psaty, M.D., Ph.D., of the University of Washington, Seattle, in an accompanying editorial.

“The FDA should pursue additional safeguards to prevent breakdowns in sponsor-investigator relationships and avoid the dissolution of future trials. For example, the agency should consider having data monitoring committees report interim results directly to the FDA, not to the sponsor.”

“The LIGHT study should serve as an important message to sponsors of clinical trials. … Repeated breaches of confidentiality may leave the FDA no alternative other than to require that full safety studies be conducted prior to product approval. The demise of the LIGHT trial is a reminder that basing approval on interim safety data is a carefully drawn compromise, not an entitlement.”

(doi:10.1001/jama.2016.1461; this editorial is available pre-embargo at the For The Media website.)

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 8, 2016

Media Advisory: To contact Changhai Ding, M.D., Ph.D., email changhai.ding@utas.edu.au.

To place an electronic embedded link to this study in your story This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1961

Vitamin D supplementation for individuals with knee osteoarthritis and low 25-hydroxyvitamin D levels did not reduce knee pain or slow cartilage loss, according to a study appearing in the March 8 issue of JAMA.

Symptomatic knee osteoarthritis occurs among 10 percent of men and 13 percent of women age 60 years or older. Currently there are no disease-modifying therapies for osteoarthritis. Vitamin D can reduce bone turnover and cartilage degradation, thus potentially preventing the development and progression of knee osteoarthritis. Observational studies suggest that vitamin D supplementation is associated with benefits for knee osteoarthritis, but current evidence from clinical trials is contradictory.

Changhai Ding, M.D., Ph.D., of the University of Tasmania, Hobart, Tasmania, Australia, and colleagues randomly assigned 413 patients with symptomatic knee osteoarthritis and low 25-hydroxyvitamin D to receive monthly treatment with oral vitamin D₃ (50,000 IU; n = 209) or an identical placebo (n = 204) for 2 years. The study was conducted in Tasmania and Melbourne, Australia.

Of 413 enrolled participants (average age, 63 years; 50 percent women), 340 (82 percent) completed the study. The researchers found that vitamin D supplementation, compared with placebo, did not result in significant differences in change in MRI-measured tibial cartilage volume or a measure of knee pain over 2 years. There were also no significant differences in change of tibiofemoral cartilage defects or change in tibiofemoral bone marrow lesions. Vitamin D levels did increase more in the vitamin D group than in the placebo group over 2 years.

“These data suggest a lack of evidence to support vitamin D supplementation for slowing disease progression or structural change in knee osteoarthritis,” the authors write.

(doi:10.1001/jama.2016.1961; this study is available pre-embargo at the For The Media website.)

Editor’s Note: This study was supported by a grant from the Australian National Health and Medical Research Council. 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, MARCH 8, 2016

Media Advisory: To contact Roger Zemek, M.D., call Adrienne Vienneau at 613-737-7600, ext. 4144 or email avienneau@cheo.on.ca. To contact editorial co-author Lynn Babcock, M.D., M.S., call Jim Feuer at 513-636-4656 or email jim.feuer@cchmc.org.

To place an electronic embedded link to this study and editorial in your story These links will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1203 https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1276

A clinical risk score developed among children presenting to an emergency department with a concussion was significantly better than physician judgment in predicting future persistent postconcussion symptoms, according to a study appearing in the March 8 issue of JAMA.

Rates of concussion have doubled during the last decade, with an estimated 750,000 pediatric acute concussion visits to emergency departments (EDs) occurring annually in the United States. Although many children experience symptom resolution within 2 weeks, approximately 33 percent experience ongoing symptoms, and those that persist beyond 28 days are referred to as persistent postconcussion symptoms (PPCS), which can have serious adverse effects, resulting in school absenteeism, impaired academic performance, depressed mood and lower quality of life. Validated and pragmatic tools to identify children at high risk of developing PPCS do not exist.

Roger Zemek, M.D., of Children’s Hospital of Eastern Ontario, University of Ottawa, Canada and colleagues conducted a study to derive and validate a clinical risk score to stratify PPCS risk occurring after acute concussion in youth using readily available clinical features. The study included children and adolescents (age 5-<18 years) who presented within 48 hours of an acute head injury to a pediatric emergency department, with follow-up 28 days after the injury. The primary outcome for the study was PPCS risk score at 28 days, which was defined as 3 or more new or worsening symptoms using the patient-reported Postconcussion Symptom Inventory compared with recalled state of being prior to the injury. The PPCS risk score incorporates 9 clinical variables containing information from demographics, history, initial symptoms, cognitive complaints, and physical examination.

In total, 3,063 patients (median age, 12 years; 39 percent girls) were enrolled (n = 2,006 in the derivation cohort; n = 1,057 in the validation cohort) and 2,584 of whom completed follow-up at 28 days after the injury. Persistent postconcussion symptoms were present in 801 patients (31 percent). The 12-point PPCS risk score model for the derivation cohort included the variables of female sex, age of 13 years or older, physician-diagnosed migraine history, prior concussion with symptoms lasting longer than 1 week, headache, sensitivity to noise, fatigue, answering questions slowly, and 4 or more errors on the Balance Error Scoring System tandem stance.

“Although the clinical utility of the PPCS risk score will need to be assessed in an externally validated implementation study prior to adoption into routine practice, the risk stratification score has the potential to individualize concussion care through optimal symptom management and appropriate follow-up. Therefore, future research needs to determine if the moderate test characteristics of the PPCS risk score allow for clinicians to confidently provide reassurance, alter management plans, or both. Future clinical benefits might include identifying high-risk individuals for further screening, prioritization for specialized concussion evaluations, and initiation of emerging treatments to prevent PPCS,” the authors write.

(doi:10.1001/jama.2016.1203; this study is available pre-embargo at the For The Media website.)

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

Editorial: Identifying Children and Adolescents at Risk for Persistent Postconcussion Symptoms

Lynn Babcock, M.D., M.S., and Brad G. Kurowski, M.D., M.S., of Cincinnati Children’s Hospital Medical Center, write in an accompanying editorial that the clinical risk score developed by Zemek et al, if validated in other settings, may facilitate selection of patients who may be at highest risk of impairments as the optimal target population for much-needed interventional trials.

“Considering the variation in individual symptom profiles and trajectories, personalized patient-oriented approaches to ongoing assessments and delivery of post-injury interventions are needed to facilitate recovery in these vulnerable children and adolescents.”

(doi:10.1001/jama.2016.1276; this editorial is available pre-embargo at the For The Media website.)

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 8, 2016

Media Advisory: To contact Ida Behrens, M.D., email idbe@ssi.dk.

To place an electronic embedded link to this study in your story This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1869

Women with a history of hypertensive disorders of pregnancy have a small but statistically significant increased risk of cardiomyopathy more than 5 months after delivery, according to a study appearing in the March 8 issue of JAMA.

Hypertensive disorders of pregnancy (HDP), which include preeclampsia and gestational hypertension, occur in up to 10 percent of pregnancies worldwide. In severe cases, preeclampsia can lead to multiple organ failure, seizures (eclampsia), and fetal and maternal death. Women with preeclampsia have a greatly increased risk of cardiomyopathy in the peripartum period (the last month of pregnancy until 5 months after delivery). Peripartum cardiomyopathy is often characterized by severely reduced myocardial contractility and symptoms of heart failure. Whether hypertensive disorders of pregnancy are also associated with cardiomyopathy later in life has not been known.

Ida Behrens, M.D., of Statens Serum Institut, Copenhagen, Denmark, and colleagues conducted a study that included 1,075,763 women with at least 1 pregnancy ending in live birth or stillbirth in Denmark, 1978-2012. These women had 2,067,633 eligible pregnancies during the study period, 76,108 of which were complicated by a hypertensive disorder of pregnancy (severe or moderate preeclampsia or gestational hypertension). During follow-up, 1,577 women (average age, 48.5 years at cardiomyopathy diagnosis) developed cardiomyopathy.

Compared with women without hypertensive disorders of pregnancy, women with a history of these disorders had significantly increased rates of cardiomyopathy, regardless of HDP severity, and these increases persisted more than 5 years after the latest pregnancy. This increase in risk appeared to be independent of ischemic heart disease, the risk of which is increased among women with a history of preeclampsia, and approximately 50 percent of the risk was not associated with postgestational hypertension. In this cohort, 11 percent of all cardiomyopathy events occurred in women with a history of hypertensive disorders of pregnancy.

The authors note that cardiomyopathy events are rare, even among women in this study with a history of HDP. “Accordingly, even though there was an association between HDP and increased risk of cardiomyopathy, the absolute risk was small.”

“Further research is necessary to understand whether there is a causal mechanism behind this association.”

(doi:10.1001/jama.2016.1869; this study is available pre-embargo at the For The Media website.)

Editor’s Note: This study was funded by the Danish Heart Association and the Danish Council for Independent Research. 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, MARCH 8, 2016

Media Advisory: To contact Sarah R. Blenner, J.D., M.P.H., email Susan O’Brien (sobrien@kentlaw.iit.edu) or Jacqueline Seaberg (jseaberg@kentlaw.iit.edu).

To place an electronic embedded link to this study in your story This link will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.19426

In a study appearing in the March 8 issue of JAMA, Sarah R. Blenner, J.D., M.P.H., of the Illinois Institute of Technology Chicago-Kent College of Law, Chicago, and colleagues examined the privacy policies of Android diabetes apps and the sharing of health information.

One-fifth of smartphone owners had health apps in 2012. Health apps can transmit sensitive medical data, including disease status and medication compliance. Privacy risks and the relationship between privacy disclosures and practices of health apps are understudied. For this study, the researchers identified all Android diabetes apps by searching Google Play using the term diabetes, and collected and analyzed privacy policies and permissions. The authors installed a random subset of apps to determine whether data were transmitted to third parties, defined as any website not directly under the developer’s control, such as data aggregators or advertising networks.

Most of the 211 diabetes apps (81 percent) in the study did not have privacy policies. Only 4 policies said they would ask users for permission to share data. In the transmission analysis that included 65 apps, sensitive health information from diabetes apps (e.g., insulin and blood glucose levels) was routinely collected and shared with third parties, with 86 percent of apps placing tracking cookies and 76 percent without privacy policies. Of the 19 apps with privacy policies that shared data with third parties, 11 apps disclosed this fact, whereas 8 apps did not.

“This study demonstrated that diabetes apps shared information with third parties, posing privacy risks because there are no federal legal protections against the sale or disclosure of data from medical apps to third parties. The sharing of sensitive health information by apps is generally not prohibited by the Health Insurance Portability and Accountability Act,” the authors write.

“Patients might mistakenly believe that health information entered into an app is private (particularly if the app has a privacy policy), but that generally is not the case. Medical professionals should consider privacy implications prior to encouraging patients to use health apps.”

(doi:10.1001/jama.2015.19426; this study is available pre-embargo at the For The Media website.)

Editor’s Note: 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, MARCH 1, 2016

Media Advisory: To contact the U.S. Preventive Services Task Force, email the Media Coordinator at Newsroom@USPSTF.net or call 202-572-2044.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0763

The U.S. Preventive Services Task Force (USPSTF) has concluded that the current evidence is insufficient to assess the balance of benefits and harms of screening for impaired visual acuity (clearness of vision) in adults age 65 years or older. The report appears in the March 1 issue of JAMA.

This is an I statement, indicating that evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined. An I statement is not a recommendation against screening but a call for more research.

Impairment of visual acuity is a serious public health problem in older adults. In 2011, about 12 percent of U.S. adults age 65 to 74 years and 15 percent of those 75 years or older reported having problems seeing, even with glasses or contact lenses. The USPSTF reviewed the evidence on screening for visual acuity impairment associated with uncorrected refractive error, cataracts, and age-related macular degeneration (AMD) among adults 65 years or older in the primary care setting who have not reported problems with their vision; the benefits and harms of screening; the accuracy of screening; and the benefits and harms of treatment of early vision impairment due to uncorrected refractive error, cataracts, and AMD. The USPSTF is an independent, volunteer panel of experts that makes recommendations about the effectiveness of specific preventive care services such as screenings, counseling services, and preventive medications.

Detection

The USPSTF found convincing evidence that screening with a visual acuity test can identify persons with a refractive error, and that screening questions are not as accurate as visual acuity testing for assessing visual acuity. The USPSTF found adequate evidence that visual acuity testing alone does not accurately identify early AMD or cataracts.

Benefits of Detection and Early Treatment

The USPSTF found inadequate overall evidence on the benefits of screening, early detection, and treatment to provide a coherent assessment of the overall benefits. Several studies evaluated the direct benefit of screening and reported no reductions in vision disorders or vision-related function in screened populations; however, these studies had limitations, including differing control interventions, high loss to follow-up, and low uptake of treatment. The USPSTF found adequate evidence that early treatment of refractive error, cataracts, and AMD improves or prevents loss of visual acuity.

Harms of Detection and Early Treatment

The USPSTF found inadequate evidence on the harms of screening, and adequate evidence that early treatment of refractive error, cataracts, and AMD may lead to harms that are small to none.

Risk Assessment

Older age is an important risk factor for most types of visual impairment. Additional risk factors for cataracts are smoking, alcohol use, ultraviolet light exposure, diabetes, corticosteroid use, and black race. Risk factors for AMD include smoking, family history, and white race.

Treatment and Interventions

Treatments include corrective lenses for refractive error; surgical removal of cataracts; laser photocoagulation, verteporfin, and intravitreal injections of vascular endothelial growth factor inhibitors for exudative (or wet) AMD; and antioxidant vitamins and minerals for dry AMD.

USPSTF Assessment

The USPSTF concludes that the evidence is insufficient to assess the balance of benefits and harms of screening for impaired visual acuity in older adults. The evidence is lacking to provide a coherent assessment, and the balance of benefits and harms cannot be determined.

(doi:10.1001/jama.2016.0763; Available pre-embargo to the media at http:/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.

Note: More information about the U.S. Preventive Services Task Force, its process, and its recommendations can be found on the newsroom page of its website.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MARCH 1, 2016

Media Advisory: To contact Ravi M. Patel, M.D., M.Sc., email Melva Robertson at melva.robertson@emory.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: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1204

Ravi M. Patel, M.D., M.Sc., of the Emory University School of Medicine & Children’s Healthcare of Atlanta, and colleagues examined whether red blood cell transfusion and severe anemia were associated with the rate of necrotizing enterocolitis (an acute, life-threatening, inflammatory disease occurring in the intestines of premature infants) among very low-birth-weight (VLBW) infants. The study appears in the March 1 issue of JAMA.

Necrotizing enterocolitis (NEC) is a leading cause of mortality among preterm infants with case-fatality rates of 20 percent to 30 percent. The origin and development of NEC remains unclear with conflicting data regarding the role of 2 risk factors, red blood cell (RBC) transfusion and anemia. Improving understanding of the role of RBC transfusion and anemia is important because more than half of VLBW (3.3 lbs. or less) infants receive 1 or more transfusions during hospitalization. This study included VLBW infants enrolled at 3 neonatal intensive care units in Atlanta within 5 days of birth. Infants received follow-up until 90 days, hospital discharge, transfer to a non-study-affiliated hospital, or death (whichever came first).

Of 600 VLBW infants enrolled, 598 were evaluated. Forty-four (7.4 percent) infants developed NEC. Thirty-two (5.4 percent) infants died (all cause). Fifty-three percent of infants (319) received a total of 1,430 RBC transfusion exposures. Analyses indicated that RBC transfusion was not significantly related to the development of NEC, although the rate of NEC was significantly increased among VLBW infants with severe anemia compared with those who did not have severe anemia.

“Because severe anemia, but not RBC transfusion, was a risk factor for NEC in this study, preventing severe anemia may be more clinically important than minimizing RBC transfusion exposure as a strategy to decrease the risk of NEC. However, the effect of such a strategy on other important neonatal outcomes is unclear, and further study is needed. Ongoing clinical trials comparing liberal vs conservative transfusion practices may provide additional experimental data regarding the risks of both severe anemia and RBC transfusion to NEC,” the authors write.

(doi:10.1001/jama.2016.1204; the study is available pre-embargo at the For The Media website.)

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 1, 2016

Media Advisory: To contact John B. Buse, M.D., Ph.D., call Mark Derewicz at 984-974-1915 or email mark.derewicz@unch.unc.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: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1252

In a study appearing in the March 1 issue of JAMA, John B. Buse, M.D., Ph.D., of the University of North Carolina School of Medicine, Chapel Hill, and colleagues compared the outcomes of once-daily injection of basal insulin (glargine) vs a once-daily injection of the combination of basal insulin degludec and the glucagon-like peptide-1 receptor agonist liraglutide in patients with uncontrolled type 2 diabetes.

Achieving optimal glucose control is a challenge for the majority of patients with type 2 diabetes, with less than one-third of patients treated with basal insulin reaching a glycated hemoglobin (HbA_1c) level of less than 7 percent. In this trial, 557 patients with uncontrolled diabetes were randomly assigned to degludec/liraglutide (n = 278) or glargine (n = 279). The 26-week trial was conducted at 75 centers in 10 countries.

The researchers found that HbA_1c level reduction was greater with degludec/liraglutide vs glargine, and met criteria for noninferiority (not worse than). Secondary analysis indicated a greater HbA_1c level reduction with degludec/liraglutide. Analyses also indicated that degludec/liraglutide was associated with weight loss compared with weight gain with glargine, and a lower rate of hypoglycemia. Overall and serious adverse event rates were similar in the 2 groups, except for more nonserious gastrointestinal adverse events reported with degludec/liraglutide.

“Further research is indicated to evaluate the durability of the effects of degludec/liraglutide in longer-term studies, in clinical practice, and to assess whether patients and physicians consider degludec/liraglutide a suitable treatment option to overcome barriers to treatment intensification,” the authors write.

(doi:10.1001/jama.2016.1252; the study is available pre-embargo at the For The Media website.)

Editor’s Note: This study was funded by Novo Nordisk. 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, MARCH 1, 2016

Media Advisory: To contact Douglas O. Staiger, Ph.D., call Amy Olson at 603-646-3274 or email Amy.D.Olson@dartmouth.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: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.16972

In a study appearing in the March 1 issue of JAMA, Douglas O. Staiger, Ph.D., of Dartmouth College, Hanover, N.H., and colleagues examined the prevalence of physicians with highly educated spouses and whether having such a spouse was associated with working in rural underserved areas.

An undersupply of physicians in rural areas remains a problem. Rural origin, age, and sex have been linked to physician choice of rural settings. An additional factor may be that many physicians have highly educated spouses with independent careers, which may constrain their ability to locate in rural areas. For this analysis, the researchers studied a 1 percent sample of all employed physicians age 25 to 70 years working in the United States every 10 years from 1960 to 2000 (n = 19,668) and every year from 2005 to 2011 (n = 55,381). The authors identified spouses reporting 6 or more years of college (before 1990) or a master’s degree or higher (1990 and later).

Overall, 5.3 percent of physicians worked in a rural Health Professional Shortage Area (HPSA) between 2005 and 2011, whereas 10.9 percent of the U.S. population lived in these areas. Compared with other married physicians, physicians with a highly educated spouse were significantly less likely to work in a rural HPSA (4.2 percent for married physicians with highly educated spouses vs 7.2 percent for married physicians without highly educated spouses). Single physicians were also less likely to work in a rural HPSA, as were physicians who were young, women, black, or Hispanic.

The authors note that the absolute difference between those with and without highly educated spouses was only 2.9 percent, and the proportion of both groups locating in rural underserved areas was small relative to the population. “Other approaches, such as allowing provision of health care without requiring physicians to locate in rural areas (i.e., through telemedicine), should be investigated.”

(doi:10.1001/jama.2015.16972; the study is available pre-embargo at the For The Media website.)

Editor’s Note: The Gordon and Betty Moore Foundation provided grant support. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 3:15 P.M. (ET) MONDAY, FEBRUARY 22, 2016

Media Advisory: To contact corresponding author Clifford S. Deutschman, M.D., M.S., call Adrienne Stoller at 516-463-7585 or email adrienne.m.stoller@hofstra.edu. To contact editorial author Edward Abraham, M.D., call Marguerite Beck at 336-716-2415 or email marbeck@wakehealth.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: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0287 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0290

Updated definitions and clinical criteria for sepsis should facilitate earlier recognition and more timely management of patients with or at risk of developing sepsis. The report, which appears in the February 23 issue of JAMA, is being released to coincide with its presentation at the Society of Critical Care Medicine’s 45th Critical Care Congress.

Sepsis, a syndrome of physiologic, pathologic, and biochemical abnormalities induced by infection, is a major public health concern, accounting for more than $20 billion (5.2 percent) of total U.S. hospital costs in 2011. The reported incidence is increasing. Although the true incidence of sepsis is unknown, conservative estimates indicate that sepsis is a leading cause of mortality and critical illness worldwide. In addition, there is increasing awareness that patients who survive sepsis often have long-term physical, psychological, and cognitive disabilities with significant health care and social implications.

Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathophysiology, management, and epidemiology of sepsis, suggesting the need for reexamination. In January 2014, a task force (n = 19) with expertise in sepsis pathophysiology, clinical trials, and epidemiology was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine to evaluate and, as needed, update definitions for sepsis and septic shock. Definitions and clinical criteria were generated through meetings, Delphi processes, analysis of electronic health record databases, and voting, followed by circulation to international professional societies, requesting peer review and endorsement.

Among the Recommendations

• Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.

• Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone.

• In out-of-hospital, emergency department, or general hospital ward settings, adult patients with suspected infection can be rapidly identified as being more likely to have poor outcomes typical of sepsis if they have at least 2 of the following clinical criteria that together constitute a new bedside clinical score termed quick Sequential (Sepsis-related) Organ Failure Assessment (qSOFA): respiratory rate of 22/min or greater, altered mentation (mental activity), or systolic blood pressure of 100 mm Hg or less.

“The debate and discussion that this work will inevitably generate are encouraged. Aspects of the new definitions do indeed rely on expert opinion; further understanding of the biology of sepsis, the availability of new diagnostic approaches, and enhanced collection of data will fuel their continued reevaluation and revision,” the authors write.

The full report is available at the For The Media website.

(doi:10.1001/jama.2016.0287)

Editor’s Note: This work was supported in part by a grant from the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: New Definitions for Sepsis and Septic Shock

“Although the present definition for sepsis provides needed evolution in categorization of this syndrome, incorporation of more information about the molecular and cellular characterization of sepsis may have been helpful,” writes Edward Abraham, M.D., of the Wake Forest School of Medicine, Winston-Salem, N.C., in an accompanying editorial.

“Hopefully, the next iteration of this consensus process will take full advantage of the rapidly advancing understanding of molecular processes that lead from infection to organ failure and death so that sepsis and septic shock will no longer need to be defined as a syndrome but rather as a group of identifiable diseases, each characterized by specific cellular alterations and linked biomarkers. Such evolution will be required to truly transform care for the millions of patients worldwide who develop these life-threatening conditions.”

(doi:10.1001/jama.2016.0290; Available pre-embargo to the media at http:/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: 3:15 P.M. (ET) MONDAY, FEBRUARY 22, 2016

Media Advisory: To contact John G. Laffey, M.D., M.A., email Leslie Shepherd at ShepherdL@smh.ca.

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Among nearly 460 intensive care units (ICUs) in 50 countries, acute respiratory distress syndrome (ARDS) appeared to be underrecognized, undertreated, and associated with a high mortality rate, according to a study that appears in the February 23 issue of JAMA, which is being released to coincide with the Society of Critical Care Medicine’s 45th Critical Care Congress.

Acute respiratory distress syndrome is an acute inflammatory lung injury. Limited information exists about its epidemiology, recognition, management, and outcomes for patients. John G. Laffey, M.D., M.A., of St. Michael’s Hospital, University of Toronto, and colleagues at the European Society of Intensive Care Medicine conducted a study of patients undergoing invasive or noninvasive ventilation during 4 consecutive weeks in the winter of 2014 in 459 ICUs from 50 countries across 5 continents.

Of 29,144 patients admitted to participating ICUs, 3,022 (10.4 percent) fulfilled ARDS criteria. Of these, 2,377 patients developed ARDS in the first 48 hours and received invasive mechanical ventilation. Clinical recognition of ARDS ranged from 51 percent in mild to 78.5 percent in severe ARDS. Hospital mortality was 35 percent for those with mild, 40 percent for those with moderate, and 46 percent for those with severe ARDS.

The authors write that the major findings in this study were the underrecognition of ARDS by clinicians, the low use of contemporary ventilatory and adjunctive treatment strategies, and the limited effect of physician diagnosis of ARDS on treatment decisions. “These findings indicate the potential for improvement in management of patients with ARDS.”

To read the full article and an accompanying editorial by Brendan J. Clark, M.D., and Marc Moss, M.D., of the University of Colorado School of Medicine, Aurora, please visit the For The Media website.

(doi:10.1001/jama.2016.0291)

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: 3:15 P.M. (ET) MONDAY, FEBRUARY 22, 2016

Media Advisory: To contact Cheng-Hock Toh, M.D., email Toh@Liverpool.ac.uk.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0136

Cheng-Hock Toh, M.D., of the University of Liverpool, United Kingdom, and colleagues examined the association between circulating histones and thrombocytopenia in patients in the intensive care unit. Histones are proteins associated with DNA; thrombocytopenia a blood disease characterized by an abnormally low number of platelets in the blood. The study appears in the February 23 issue of JAMA, which is being released to coincide with the Society of Critical Care Medicine’s 45th Critical Care Congress.

Thrombocytopenia is observed in approximately 30 percent to 40 percent of patients in the intensive care unit (ICU) and associated with poor outcomes. Histones induce profound thrombocytopenia in mice and are associated with organ injury when released following extensive cell damage in patients who are critically ill. This study included 56 patients with thrombocytopenia and 56 controls with normal platelet counts who were admitted to the ICU at Royal Liverpool University Hospital between June 2013 and January 2014.

The researchers found that histones circulated in the majority of thrombocytopenic patients and the histone levels were 2.5- to 5.5-fold higher than in nonthrombocytopenic controls. There was a significant association between high levels of histones at admission and subsequent decline in platelet counts among thrombocytopenic patients. High admission histone levels were associated with moderate to severe thrombocytopenia and development of clinically important thrombocytopenia.

“Circulating histones are potential markers of disease severity, and the association with thrombocytopenia may reflect this. Nevertheless, the novel associations reported in this study extend previous reports demonstrating profound thrombocytopenia following histone infusion into mice and suggest that, if confirmed, circulating histones may be valuable in predicting or monitoring thrombocytopenia in patients who are critically ill,” the authors write.

(doi:10.1001/jama.2016.0136; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This work was funded by the National Institute of Health Research, British Heart Foundation, and the Royal Liverpool & Broadgreen University Hospitals NHS Trust. 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: 4:30 P.M. (ET) TUESDAY, FEBRUARY 23, 2016

Media Advisory: To contact Frederic T. Billings IV, M.D., M.Sc., email Craig Boerner at craig.boerner@Vanderbilt.Edu. To contact editorial author Rinaldo Bellomo, M.B.B.S. (Hons), M.D., F.R.A.C.P., F.C.I.C.M., email Rinaldo.BELLOMO@austin.org.au.

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: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0548 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0245

Among patients undergoing cardiac surgery, high-dose treatment with atorvastatin before and after surgery did not reduce the overall risk of acute kidney injury compared with placebo, according to study published by JAMA. The study is being released to coincide with its presentation at the Society of Critical Care Medicine’s 45th Critical Care Congress.

Acute kidney injury (AKI) complicates recovery from cardiac surgery in up to 30 percent of patients. Statins affect several mechanisms underlying postoperative AKI. Previous studies have found mixed results regarding the effect of statins to reduce AKI in cardiac surgery patients.

Frederic T. Billings IV, M.D., M.Sc., of the Vanderbilt University School of Medicine, Nashville, Tenn., and colleagues randomly assigned cardiac surgery patients naive to statin treatment (n = 199) to 80 mg of atorvastatin the day before surgery, 40 mg of atorvastatin the morning of surgery, and 40 mg of atorvastatin daily following surgery (n = 102) or matching placebo (n = 97). Patients already taking a statin prior to study enrollment (n = 416) continued taking the pre-enrollment statin until the day of surgery, were randomly assigned 80 mg of atorvastatin the morning of surgery and 40 mg of atorvastatin the morning after (n = 206) or matching placebo (n = 210), and resumed taking the previously prescribed statin on postoperative day 2.

Among all participants (n = 615), AKI occurred in 64 of 308 (21 percent) in the atorvastatin group vs 60 of 307 (19.5 percent) in the placebo group. Among patients naive to statin treatment (n = 199), AKI occurred in 22 of l02 (22 percent) in the atorvastatin group vs 13 of 97 (13 percent) in the placebo group and there was a greater increase in serum creatinine concentration in the atorvastatin group compared to the placebo group. Among patients already taking a statin (n = 416), AKI occurred in 20 percent of the patients in the atorvastatin group vs 22 percent in the placebo group.

“This double-blinded, placebo-controlled randomized clinical trial found no evidence that high-dose perioperative atorvastatin reduces the incidence or severity of AKI following cardiac surgery. Among patients naïve to statin treatment, high-dose perioperative atorvastatin increased serum concentrations of creatinine, and there was some evidence that statin treatment may increase AKI among patients naive to statin treatment with preexisting chronic kidney disease. Among patients already taking a statin, there was no evidence that perioperative statin continuation or withdrawal affected postoperative AKI,” the authors write.

“These results do not support the initiation of statin therapy to prevent AKI following cardiac surgery.”

(doi:10.1001/jama.2016.0548; Available pre-embargo to the media at http:/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: Perioperative Statins in Cardiac Surgery and Acute Kidney Injury

“Even though the use of statins in cardiac surgery is likely to continue to generate interest and trials in an attempt to demonstrate other so-far unproven benefits, any use as [kidney] protective agents in patients naive to statin treatment undergoing cardiac surgery should now be abandoned,” writes Rinaldo Bellomo, M.B.B.S. (Hons), M.D., F.R.A.C.P., F.C.I.C.M., of the University of Melbourne, Australia, in an accompanying editorial.

“The challenge of finding an adjuvant intervention capable of attenuating AKI during cardiac surgery, however, remains unmet and further exploration of promising or novel interventions and more studies aimed at understanding the pathogenesis of AKI following cardiac surgery remain a clinical priority and are certain to follow.”

(doi:10.1001/jama.2016.0245; Available pre-embargo to the media at http:/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, FEBRUARY 16, 2016

Media Advisory: To contact Yongning Wu, Ph.D., email wuyongning@cfsa.net.cn.

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Yongning Wu, Ph.D., of the China National Centre for Food Safety Risk Assessment, Beijing, China, and colleagues compared salt and sodium consumption in China in 2000 with 2009-2012. The study appears in the February 16 issue of JAMA.

Noncommunicable diseases are increasing globally, with major socioeconomic implications. The World Health Organization proposed noncommunicable disease-related targets, including 30 percent reduction in salt/sodium intake to reduce risk of hypertension. In China, hypertension prevalence is rising and salt intake is high (12 g/person/d). However, this estimate derives from 2002, and China’s dietary habits are changing.

Total diet studies were undertaken in 2000 and 2009-2011 in 12 of China’s 31 mainland provinces; eight additional provinces were studied in 2009-2012, expanding geographic coverage; only China’s far west region was not studied. Total diet studies include weighed food intake and laboratory analysis of prepared foods representing dietary intake. In 2000, 1,080 households participated (n = 3,725); from 2009 through 2012, 1,800 households participated (n = 6,072).

The researchers found that all provinces exceeded the recommended daily maximum intake of salt (5 g/d) and sodium (2 g/d). “Although salt added during food preparation has decreased over time, total sodium intake has not. These findings update studies using different methodologies in the 1990s and 2002 and confirm that simply weighing dietary salt intake underestimates sodium consumption in China.”

“China’s diet is changing and refrigeration is replacing salt for food preservation. High sodium intake persists due to addition of salt and other seasonings during food preparation, and increasing consumption of processed food. Further efforts are needed to limit salt/sodium intake, and regular monitoring is needed to assess progress.”

(doi:10.1001/jama.2015.15816; Available pre-embargo to the media at http:/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, FEBRUARY 16, 2016

Media Advisory: To contact Philip J. Peters, M.D., call the NCHHSTP Media Team at 404-639-8895 or email NCHHSTPMediaTeam@cdc.gov.

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In a study appearing in the February 16 issue of JAMA, Philip J. Peters, M.D., of the Centers for Disease Control and Prevention, Atlanta, and colleagues evaluated the performance of an HIV antigen/antibody (Ag/Ab) combination assay to detect acute HIV infection (early infection) compared with pooled HIV RNA testing, the reference standard. The study included 86,836 participants in a high-prevalence population from 7 sexually transmitted infection clinics and 5 community-based programs in New York, California, and North Carolina. Although acute HIV infection contributes disproportionately to onward HIV transmission, HIV testing has not routinely included screening for acute infection.

The researchers found that the HIV Ag/Ab combination assay in place of rapid HIV testing increased the absolute HIV diagnostic yield by 0.15 percent and diagnosed 82 percent of the acute HIV infections detectable by pooled RNA testing. Compared with rapid HIV testing alone, HIV Ag/Ab combination testing increased the relative HIV diagnostic yield (both established and acute HIV infections) by 10.4 percent and pooled HIV RNA testing increased the relative HIV diagnostic yield by 12.4 percent. “Alternative strategies such as using a laboratory-based HIV Ag/Ab combination assay that can detect acute infection should be considered in high-prevalence populations in the United States.”

To read the full article, please visit the For The Media website.

(doi:10.1001/jama.2016.0286)

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, FEBRUARY 16, 2016

Media Advisory: To contact Ivan O. Rosas, M.D., call Elaine St. Peter at 617-525-6375 or email estpeter@partners.org.

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The presence of interstitial lung abnormalities are associated with a greater risk of all-cause mortality, according to a study in the February 16 issue of JAMA.

Interstitial lung abnormalities are defined as specific patterns of increased lung density noted on chest computed tomography (CT) scans identified in participants with no prior history of interstitial lung disease (a large group of disorders characterized by progressive scarring of the lung tissue between and supporting the air sacs). In studies of adults, interstitial lung abnormalities are present in approximately 2 percent to 10 percent of research participants (and 7 percent of a general population sample) and are associated with reductions in lung capacity and exercise capacity.

Ivan O. Rosas, M.D., of Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues examined whether interstitial lung abnormalities are associated with increased mortality. The study included 2,633 participants from the FHS (Framingham Heart Study), 5,320 from the AGES-Reykjavik Study (Age Gene/Environment Susceptibility), 2,068 from the COPDGene Study (Chronic Obstructive Pulmonary Disease), and 1,670 from ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints).

Interstitial lung abnormalities were present in 7 percent of the FHS participants, 7 percent from AGES-Reykjavik, 8 percent from COPDGene, and 9 percent from ECLIPSE. Over median follow-up times of approximately 3 to 9 years, there were more deaths (and a greater absolute rate of mortality) among participants with interstitial lung abnormalities when compared with those who did not have interstitial lung abnormalities: 7 percent vs 1 percent in FHS, 56 percent vs 33 percent in AGES-Reykjavik, and 11 percent vs 5 percent in ECLIPSE. Interstitial lung abnormalities were associated with a higher risk of death in all groups. In the AGES-Reykjavik cohort, the higher rate of mortality could be explained by a higher rate of death due to respiratory disease, specifically pulmonary fibrosis. The associations between interstitial lung abnormalities and mortality were not lessened after adjustment for smoking, cancer, COPD, or coronary artery disease.

“These findings, in conjunction with those previously published, demonstrate that despite often being undiagnosed and asymptomatic, interstitial lung abnormalities may be associated with lower survival rates among older persons,” the authors write. “The clinical implications of this association require further investigation.”

“Follow-up studies should determine the risk factors for and the events that lead to death among persons with interstitial lung abnormalities. Given the ability to treat more advanced stages of pulmonary fibrosis, future clinical trials attempting to reduce the overall mortality associated with pulmonary fibrosis should consider including early stages of the disease.”

(doi:10.1001/jama.2016.0518; Available pre-embargo to the media at http:/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, FEBRUARY 16, 2016

Media Advisory: To contact Amber K. Sabbatini, M.D., M.P.H., call Brian  Donohue at 206-543-7856 or email bdonohue@uw.edu. To contact James G. Adams, M.D., call Marla Paul at 312-503-8928 or email marla-paul@northwestern.edu.

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Hospital admissions associated with return visits to the emergency department (ED) may not adequately capture deficits in the quality of care delivered during an ED visit, according to a study in the February 16 issue of JAMA.

All-cause hospital readmissions are considered to capture deficits in transitions of care from the hospital setting and are now a reportable measure of hospital quality tied to financial penalties for poor-performing hospitals. Similar to the rationale for monitoring performance using hospital readmissions, unscheduled return visits after ED discharge may also reflect inadequate ED discharge practices or follow-up procedures. Short-term unscheduled return visits to the ED are increasingly monitored as an administrative performance measure and have been considered for wider adoption as a measure of the quality of emergency care, particularly if the patient requires hospitalization during the return ED visit. However, the ramifications of using return visits to the ED as a measure of quality are uncertain.

Amber K. Sabbatini, M.D., M.P.H., of the University of Washington, Seattle, and colleagues examined in-hospital clinical outcomes and resource use among patients who had a return visit to the ED and subsequent hospital admission compared with patients who were hospitalized and did not experience a return visit to the ED. The authors analyzed adult ED visits to acute care hospitals in Florida and New York in 2013 using data from the Healthcare Cost and Utilization Project. Patients with index ED visits were identified and followed up for return visits to the ED within 7, 14, and 30 days.

The study included 9,036,483 index ED visits to 424 hospitals. The authors found that patients who experienced an ED return visit that resulted in admission shortly after an earlier ED discharge had significantly lower rates of in-hospital mortality, intensive care unit (ICU) admission, and costs, but somewhat longer lengths of hospital stay compared with admissions among patients without a return visit to the ED. In contrast, patients who returned to the ED after hospital discharge and were readmitted had higher mortality and ICU admission rates during the repeat hospitalization along with longer lengths of stay and higher costs. Results were consistent for patients returning to the ED within 7, 14, or 30 days of their initial ED visit.

“These findings suggest that ED return admissions may not adequately capture deficits in the quality of care delivered during an ED visit based on information from administrative data sets,” the authors write.

“How rates of return visits to the ED are interpreted—as reflecting medical error or as a failure of an appropriate trial of outpatient management—has important policy implications for a value-driven health care system. Recent changes in health care financing, such as payer scrutiny over short-stay hospitalizations, physician profiling with pay-for-performance incentives or penalties, and expansion of risk-sharing agreements have placed increased pressure on hospitals and physicians to reduce unnecessary admissions.”

(doi:10.1001/jama.2016.0649; Available pre-embargo to the media at http:/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: Ensuring the Quality of Quality Metrics for Emergency Care

These findings provide a definitive argument that the overall ED revisit rate should not be used as a quality metric, writes James G. Adams, M.D., of Northwestern University and Northwestern Memorial HealthCare, Chicago, in an accompanying editorial. “Although potentially sensitive, this measure is recognized as too nonspecific. To identify misdiagnoses and inadequate treatment, a more precise approach is warranted.”

“The journey toward better, meaningful quality measures continues with the realization that there is no easily accessible measure for overall ED diagnostic and therapeutic quality. The fact that this key question is answered serves as a good reminder that much detailed, difficult, and diligent work lies ahead.”

(doi:10.1001/jama.2016.19484; Available pre-embargo to the media at http:/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, FEBRUARY 16, 2016

Media Advisory: To contact the U.S. Preventive Services Task Force, email the Media Coordinator at Newsroom@USPSTF.net or call 202-572-2044. To contact editorial co-author Michael Silverstein, M.D., M.P.H., call Gina DiGravio-Wilczewski at 617-638-8480 or email ginad@bu.edu.

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The U.S. Preventive Services Task Force (USPSTF) has concluded that the current evidence is insufficient to assess the balance of benefits and harms of screening for autism spectrum disorder (ASD) in children 18 to 30 months of age for whom no concerns of ASD have been raised by their parents or a clinician. The report appears in the February 16 issue of JAMA.

This is an I statement, indicating that evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined. An I statement is not a recommendation against screening but a call for more research.

Autism spectrum disorder is a developmental disorder characterized by persistent and significant impairments in social interaction and communication and restrictive and repetitive behaviors and activities, when these symptoms cannot be accounted for by another condition. In 2010, the prevalence of ASD in the United States was estimated at 14.7 cases per 1,000 children, or 1 in 68 children, with substantial variability in estimates by region, sex, and race/ethnicity.

The USPSTF reviewed the evidence on the accuracy, benefits, and potential harms of brief, formal screening instruments for ASD administered during routine primary care visits and the benefits and potential harms of early behavioral treatment for young children identified with ASD through screening. The USPSTF is an independent, volunteer panel of experts that makes recommendations about the effectiveness of specific preventive care services such as screenings, counseling services, and preventive medications.

Detection, and Benefits of Early Detection and Intervention or Treatment

The USPSTF found adequate evidence that currently available screening tests can detect ASD among children age 18 to 30 months, but found inadequate direct evidence on the benefits of screening for ASD in toddlers and preschool-age children for whom no concerns of ASD have been raised by family members, other caregivers, or health care professionals. There are no studies that focus on the clinical outcomes of children identified with ASD through screening. Although there are studies suggesting treatment benefit in older children identified through family, clinician, or teacher concerns, the USPSTF found inadequate evidence on the efficacy of treatment of cases of ASD detected through screening or among very young children. Treatment studies were generally very small, few were randomized trials, most included children who were older than would be identified through screening, and all were in clinically referred rather than screen-detected patients.

Harms of Early Detection and Intervention or Treatment

The USPSTF found that the harms of screening for ASD and subsequent interventions are likely to be small based on evidence about the prevalence, accuracy of screening, and likelihood of minimal harms from behavioral interventions.

Risk Assessment

Although a number of potential risk factors for ASD have been identified, there is insufficient evidence to determine if certain risk factors modify the performance characteristics of ASD screening tests, such as the age at which screening is performed or other characteristics of the child or family.

Treatment and Interventions

Treatments for ASD include behavioral, medical, educational, speech/language, and occupational therapy and complementary and alternative medicine approaches. Treatments for young children are primarily behavioral interventions, particularly early intensive behavioral and developmental interventions.

USPSTF Assessment

The USPSTF concludes that there is insufficient evidence to assess the balance of benefits and harms of screening for ASD in children age 18 to 30 months for whom no concerns of ASD have been raised. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined.

(doi:10.1001/jama.2016.0018; Available pre-embargo to the media at http:/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.

Note: More information about the U.S. Preventive Services Task Force, its process, and its recommendations can be found on the newsroom page of its website.

Editorial: Embrace the Complexity

“In rendering its determination of insufficient evidence for ASD screening, the USPSTF demonstrated its understanding of the real-world complexities of primary care and its commitment to be a rigorous, transparent arbiter of best available evidence,” write Michael Silverstein, M.D., M.P.H., of the Boston University School of Medicine, Boston Medical Center, Boston, and Jenny Radesky, M.D., of the University of Michigan School of Medicine, Ann Arbor, in an accompanying editorial.

“The ensuing debate around the findings of the USPSTF with respect to screening for ASD has thrown into relief the importance of this circumscribed but critical role. The USPSTF has delivered an important message, which should spur more research and enhance the knowledge base around universal ASD screening. The USPSTF embraced this issue in all its complexity. Physicians, other health professionals, policy makers, insurers, and other stakeholders should do the same.”

(doi:10.1001/jama.2016.0051; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Both 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, FEBRUARY 9, 2016

Media Advisory: To contact Harlan M. Krumholz, M.D., S.M., call Mark Dantonio at 203-688-2493 or email Mark.Dantonio@ynhh.org. To contact Ashish K. Jha, M.D., M.P.H., call Todd Datz at 617-432-8413 or email tdatz@hsph.harvard.edu.

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Among older men with heart attack, heart failure or pneumonia, hospitalization at Veterans Affairs (VA) hospitals, compared with hospitalization at non-VA hospitals, was associated with lower 30-day all-cause mortality rates for heart attack and heart failure, and higher 30-day all-cause readmission rates for all 3 conditions, both nationally and within similar geographic areas, although absolute differences between these outcomes were small, according to a study in the February 9 issue of JAMA.

Little contemporary information is available about comparative performance between VA and non-VA hospitals, particularly related to mortality and readmission rates, important outcomes of care. Harlan M. Krumholz, M.D., S.M., of Yale-New Haven Hospital, New Haven, Conn., and colleagues conducted an analysis that included male Medicare fee-for-service beneficiaries age 65 years or older hospitalized between 2010 and 2013 in VA (n = 104) and non-VA (1,513) acute care hospitals for acute myocardial infarction (AMI; heart attack), heart failure (HF), or pneumonia, using Medicare and VA data. Each condition-outcome analysis cohort for VA and non-VA hospitals contained at least 7,900 patients, in 92 metropolitan statistical areas (MSAs).

The researchers found that mortality rates were lower in VA hospitals than non-VA hospitals for AMI (13.5 percent vs 13.7 percent) and HF (11.4 percent vs 11.9 percent), but higher for pneumonia (12.6 percent vs 12.2 percent). Hospital readmission rates were higher in VA hospitals for all 3 conditions (AMI, 17.8 percent vs 17.2 percent; HF, 24.7 percent vs 23.5 percent,; pneumonia, 19.4 percent vs 18.7 percent). In within-MSA comparisons, VA hospitals had lower mortality rates for AMI (percentage-point difference, -0.22) and HF (-0.63), and mortality rates for pneumonia were not significantly different (-0.03); however, VA hospitals had higher readmission rates for AMI (0.62), HF (0.97), or pneumonia (0.66).

The authors write that the differences in mortality and readmission rates persisted after accounting for geographic variation in hospital location by limiting comparisons of VA and non-VA hospitals to those within the same metropolitan statistical area. “In general, however, the magnitudes of differences were small for both measures across all 3 conditions.”

(doi:10.1001/jama.2016.0278; Available pre-embargo to the media at http:/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: Learning From the Past to Improve VA Health Care

Ashish K. Jha, M.D., M.P.H., of the Harvard T. H. Chan School of Public Health, Boston, writes in an accompanying editorial that the study by Nuti et al begins to answer the question of whether the VA is meeting its obligations to adequately care for veterans.

“The authors focus on a narrow set of questions: how does the VA compare with the rest of the health care system on care for a common set of medical conditions? The findings are reassuring and make plain that even though the VA has much work to do, it is starting off from a substantially better place than it was in 2 decades ago.”

“These findings are important because they suggest that despite all of the challenges that VA hospitals have faced, they are still able to deliver high-quality care for some of the sickest, most complicated patients. In addition, although there are large variations in outcomes among VA hospitals, on average, the system seems to be performing reasonably well.”

(doi:10.1001/jama.2016.0243; Available pre-embargo to the media at http:/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, FEBRUARY 9, 2016

Media Advisory: To contact Jason N. Doctor, Ph.D., call Emily Gersema at 213-740-0252 or email gersema@usc.edu. To contact Jeffrey S. Gerber, M.D., Ph.D., call Natalie Virgilio at 267-426-6246 or email virgilion@email.chop.edu.

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Among primary care practices, the use of two socially motivated behavioral interventions – accountable justification and peer comparison – resulted in significant reductions in inappropriate antibiotic prescribing for acute respiratory tract infections, while an intervention that lacked a social component, suggested alternatives, had no significant effect, according to a study in the February 9 issue of JAMA.

Most antibiotics prescribed in the United States are for acute respiratory tract infections, and roughly half of these prescriptions are intended to treat diagnoses for which antibiotics have no benefit. Despite published clinical guidelines and decades of efforts to change prescribing patterns, antibiotic overuse persists. Interventions based on behavioral science might reduce inappropriate antibiotic prescribing. Researchers are beginning to apply models from psychology and behavioral economics to identify new social and cognitive devices to gently nudge clinician decision making while preserving freedom of choice.

Jason N. Doctor, Ph.D., of the University of Southern California, Los Angeles, and colleagues randomly assigned 248 clinicians from 47 primary care practices in Boston and Los Angeles to receive 0, 1, 2, or 3 interventions for 18 months. The three behavioral interventions, implemented alone or in combination, were: suggested alternatives, which presented electronic order sets suggesting nonantibiotic treatments; accountable justification, which prompted clinicians to enter free-text justifications for prescribing antibiotics into patients’ electronic health records; and peer comparison, which sent emails to clinicians that compared their antibiotic prescribing rates with those of “top performers” (those with the lowest inappropriate prescribing rates). All clinicians received education on antibiotic prescribing guidelines on enrollment.

There were 14,753 visits (average patient age, 47 years) for antibiotic-inappropriate acute respiratory tract infections during the baseline period and 16,959 visits (average patient age, 48 years) during the intervention period. Average antibiotic prescribing rates decreased from 24 percent at intervention start to 13 percent at intervention month 18 for control practices; from 22 percent to 6 percent for suggested alternatives; from 23 percent to 5 percent for accountable justification; and from 20 percent to 4 percent for peer comparison. Analysis indicated that accountable justification and peer comparison resulted in statistically significant reductions in inappropriate antibiotic prescribing, while suggested alternatives had no statistically significant effect.

All 3 interventions involved modest changes to the practice environment; none restricted clinicians’ choice of treatment or changed how clinicians were paid.

The authors note that there were no statistically significant interactions between interventions; therefore, applying these interventions simultaneously might have additive effects on antibiotic prescribing.

(doi:10.1001/jama.2016.0275; Available pre-embargo to the media at http:/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: Improving Outpatient Antibiotic Prescribing

“This report highlights the promise of various types of immediate feedback to improve antibiotic prescribing and justifies further investigation to devise the most effective, generalizable, and sustainable interventions,” writes Jeffrey S. Gerber, M.D., Ph.D., of the Children’s Hospital of Philadelphia, in an accompanying editorial.

“This might require tailoring the intervention to specific practice, practitioner, or patient characteristics. Future work should also expand to focus on the most common infections for which antibiotics are sometimes (but often not) indicated, such as acute pharyngitis and sinusitis (although these conditions triggered the nudge in this intervention, prescribing rates for pharyngitis and sinusitis were not measured), and to optimize guideline-concordant antibiotic choice (narrower) and duration of therapy (shorter) for common bacterial infections.”

(doi:10.1001/jama.2016.0430; Available pre-embargo to the media at http:/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, FEBRUARY 9, 2016

Media Advisory: To contact Carolee J. Winstein, Ph.D., call Zen Vuong at 213-740-5277 or email zvuong@usc.edu.

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The use of a structured, task-oriented rehabilitation program, compared with usual rehabilitation, did not result in better motor function or recovery after 12 months for patients with moderate upper extremity impairment following a stroke, according to a study in the February 9 issue of JAMA.

Clinicians providing care for patients with stroke lack evidence for determining the best type and amount of motor therapy during outpatient rehabilitation. Clinical trials suggest that higher doses of task-oriented training are superior to current clinical practice for patients with stroke with upper extremity motor deficits.

Carolee J. Winstein, Ph.D., of the University of Southern California, Los Angeles, and colleagues randomly assigned 361 participants with moderate motor impairment following a stroke to structured, task-oriented upper extremity training (n = 119); dose-equivalent occupational therapy (DEUCC; n = 120); or monitoring-only occupational therapy (UCC; n = 122). The DEUCC group was prescribed 30 one-hour sessions over 10 weeks; the UCC group was only monitored, without specification of dose. Participants were recruited from 7 U.S. hospitals, treated in the outpatient setting, and tested at 12 months on various measures of motor function and recovery.

Among the 361 patients (average age, 61 years), 304 (84 percent) completed the 12-month primary outcome assessment. The researchers found there were no group differences in upper extremity motor performance; specifically, the structured, task-oriented motor therapy was not superior to usual outpatient occupational therapy for the same number of hours, showing no additional benefit for an evidence-based, intensive, restorative therapy program. In addition, there was no advantage to providing more than twice the average dose (average, 27 hours) of therapy compared with the average 11 hours received by the observation-only group, showing that substantially more therapy time was not associated with additional motor restoration.

“These findings do not support superiority of this task-oriented rehabilitation program for patients with motor stroke and moderate upper extremity impairment,” the authors write.

“With payer pressures on reducing inpatient rehabilitation, outpatient rehabilitation may be of greater importance for patients with stroke. The findings from this study provide important new guidance to clinicians who must choose the best treatment for patients with stroke,” the researchers write. “The results suggest that usual and customary community-based therapy, provided during the typical outpatient rehabilitation time window by licensed therapists, improves upper extremity motor function and that more than doubling the dose of therapy does not lead to meaningful differences in motor outcomes.”

“The data pertaining to dose of rehabilitation therapy may be important to policy makers and may be useful to estimate the cost and expected effect of aftercare in the outpatient setting.”

(doi:10.1001/jama.2016.0276; Available pre-embargo to the media at http:/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, FEBRUARY 9, 2016

Media Advisory: To contact Andrew Fenelon, Ph.D., call the NCHS Press Office at 301-458-4800 or email paoquery@cdc.gov.

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Andrew Fenelon, Ph.D., of the National Center for Health Statistics, Hyattsville, Md., and colleagues estimated the contribution of 3 causes of injury death to the gap in life expectancy between the United States and 12 comparable countries in 2012. The researchers focused on motor vehicle traffic (MVT) crashes, firearm-related injuries, and drug poisonings, the 3 largest causes of U.S. injury death, responsible for more than 100,000 deaths per year. The study appears in the February 9 issue of JAMA.

The United States experiences lower life expectancy at birth than many other high-income countries. Although research has focused on mortality of the population older than 50 years, much of this life expectancy gap reflects mortality at younger ages, when mortality is dominated by injury deaths, and many decades of expected life are lost. For this study, the researchers used data from the U.S. National Vital Statistics System and the World Health Organization Mortality Database and calculated death rates by age, sex, and cause for the United States and 12 high-income countries that had similar levels of development and quality of vital registration: Austria, Denmark, Finland, Germany, Italy, Japan, the Netherlands, Norway, Portugal, Spain, Sweden, and the United Kingdom.

The researchers found that men in the comparison countries had a life expectancy advantage of 2.2 years over U.S. men (78.6 years vs 76.4 years), as did women (83.4 years vs 81.2 years). The injury causes of death accounted for 48 percent (1.02 years) of the life expectancy gap among men. Firearm-related injuries accounted for 21 percent of the gap, drug poisonings 14 percent, and MVT crashes 13 percent. Among women, these causes accounted for 19 percent (0.42 years) of the gap, with 4 percent from firearm-related injuries, 9 percent from drug poisonings, and 6 percent from MVT crashes. The 3 injury causes accounted for 6 percent of deaths among U.S. men and 3 percent among U.S. women. The U.S. death rates from injuries exceeded those in each comparison country.

“Although the reasons for the gap in life expectancy at birth between the United States and comparable countries are complex, a substantial portion of this gap reflects just 3 causes of injury,” the authors write.

(doi:10.1001/jama.2015.15564; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This study was supported by the U.S. Centers for Disease Control and Prevention. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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