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: http://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: http://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: http://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: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1558 http://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: http://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: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1203 http://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: http://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: http://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: http://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: http://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: http://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.

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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.

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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.

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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.

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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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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, FEBRUARY 2, 2016

Media Advisory: To contact Martha Clare Morris, Sc.D., call Nancy Di Fiore at 312-942-5159 or email Nancy_Difiore@rush.edu. To contact editorial co-author Edeltraut Kroger, Ph.D., call Jean-François Huppé at 418-656-7785 or email jean-francois.huppe@dc.ulaval.ca.

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In a study of deceased individuals, moderate seafood consumption was correlated with lesser Alzheimer disease neuropathology, and although seafood consumption was associated with higher brain levels of mercury, the higher mercury levels were not correlated with more Alzheimer disease neuropathology, according to a study in the February 2 issue of JAMA.

Numerous studies have found protective associations between seafood consumption and dementia. Little is known about the relationship between seafood consumption and brain neuropathology. Seafood is a source of mercury, a neurotoxin that impairs neurocognitive development. Mercury toxicity is reduced by selenium, an essential nutrient present in seafood.

Martha Clare Morris, Sc.D., of Rush University Medical Center, Chicago, and colleagues examined whether seafood consumption is correlated with increased brain mercury levels and also whether seafood consumption or brain mercury levels are correlated with brain neuropathologies. The study included analyses of deceased participants in the Memory and Aging Project clinical neuropathological cohort study, 2004-2013. The average age at death was 90 years and 67 percent were women. Seafood intake was first measured by a food frequency questionnaire at an average of 4.5 years before death.

Among the 286 autopsied brains of 544 participants, brain mercury levels were positively correlated with the number of seafood meals consumed per week. In models adjusted for age, sex, education, and total energy intake, seafood consumption (one or more meal[s]/week) was significantly correlated with less Alzheimer disease pathology, including lower density of neuritic plaques, less severe and widespread neurofibrillary tangles and lower neuropathologically defined Alzheimer disease, but only among apolipoprotein E (APOE ε4) carriers, a gene variant associated with an increased risk of developing Alzheimer disease.

Fish oil supplementation had no statistically significant correlation with any neuropathologic marker. Although seafood consumption was correlated with higher brain levels of mercury, the higher mercury levels were not significantly correlated with increased levels of brain neuropathology.

The authors note that the findings were from a very old, largely non-Hispanic white cohort and may not be generalizable to younger adults or other racial or ethnic groups.

“To our knowledge, this is the first study to report on the relationship between brain concentrations of mercury and brain neuropathology or diet. The finding of no deleterious correlations of mercury on the brain is supported by a number of case-control studies that found no difference between Alzheimer disease patients and controls in mercury concentrations in the brain, serum, or whole blood.”

(doi:10.1001/jama.2015.19451; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This study was supported by National Institutes of Health grants. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Fish Consumption, Brain Mercury, and Neuropathology in Patients With Alzheimer Disease and Dementia

“Patients and their families may be hopeful that interventions such as seafood consumption may help reduce clinical manifestations of Alzheimer disease or dementia, and the report by Morris et al provides reassurance that seafood contamination with mercury is not related to increased brain pathology,” write Edeltraut Kroger, Ph.D., and Robert Laforce Jr., M.D., Ph.D., of Universite Laval, Quebec City, Quebec, Canada, in an accompanying editorial.

“Eating fatty fish may continue to be considered potentially beneficial against cognitive decline in at least a proportion of older adults, a strategy that now generally should not be affected by concerns about mercury contamination in fish. Such a simple strategy is encouraging in the light of the lack of evidence on protection against many neurodegenerative diseases such as Alzheimer disease and Parkinson disease, another cause of dementia.”

(doi:10.1001/jama.2016.0005; Available pre-embargo to the media at htt    p:/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 2, 2016

Media Advisory: To contact Claus Bachert, M.D., Ph.D., email Claus.Bachert@UGent.be.

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Use of the medication dupilumab resulted in improvement of nasal polyps in patients with chronic sinusitis and nasal polyposis not responsive to intranasal corticosteroids alone, according to a study in the February 2 issue of JAMA.

Chronic sinusitis, an inflammatory condition of the sinuses, is common with estimates of prevalence as high as 12 percent in Western populations. Based on endoscopic findings, the condition can be divided into chronic sinusitis with or without nasal polyposis. Nasal polyps originate in the sinuses and obstruct the sinus and nasal passages. Dupilumab has demonstrated clinical efficacy for asthma and atopic dermatitis, and has also improved sino-nasal symptoms in patients with asthma.

Claus Bachert, M.D., Ph.D., of Ghent University Hospital, Ghent, Belgium, and colleagues randomly assigned 60 adults with chronic sinusitis and nasal polyposis not responsive to intranasal corticosteroids to dupilumab (by injection; n = 30) or placebo (n = 30) plus mometasone furoate nasal spray for 16 weeks. The study was conducted at 13 sites in the United States and Europe. The primary measured outcome was change in endoscopic nasal polyp score (based on polyp size).

Among the 60 patients who were randomized, 51 completed the study. The researchers found that dupilumab treatment was associated with significant improvements in endoscopic, clinical, radiographic, and pharmacodynamic end points after 16 weeks. Significant improvements in quality of life and in major symptoms, such as subjective sense of smell, nasal obstruction or congestion, and nocturnal awakenings, were reported.

Dupilumab was generally well tolerated, and no serious adverse events were considered to be related to dupilumab.

“Further studies are needed to assess longer treatment duration, larger samples, and direct comparison with other medications,” the authors write.

(doi:10.1001/jama.2015.19330; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The study was funded by Sanofi and Regeneron Pharmaceuticals Inc. 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, FEBRUARY 2, 2016

Media Advisory: To contact Kevin R. Riggs, M.D., M.P.H., email Marin Hedin at mhedin2@jhmi.edu.

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Kevin R. Riggs, M.D., M.P.H., of the Johns Hopkins University School of Medicine, Baltimore, and colleagues analyzed billing data to determine the proportion of colonoscopies for colon cancer screening and polyp surveillance that were preceded by office visits and the associated payments for those visits. The study appears in the February 2 issue of JAMA.

Widely accepted guidelines for colon cancer screening and polyp surveillance and the generally low risk of colonoscopy may obviate the need for many of the gastroenterology office visits before colonoscopy. Open-access endoscopy, which allows patients to be referred for endoscopies without a prior gastroenterology office visit, began in the United States in the 1990s, though recent estimates of the prevalence of the practice have been lacking. The researchers used a database that contains use and expenditure data for individuals with employer-sponsored private health insurance from several hundred U.S. employers and health plans and includes approximately 43 to 55 million beneficiaries each year from all 50 states. The authors included patients age 50 to 64 years with continuous insurance coverage for 12 months prior to an outpatient colonoscopy performed in the gastroenterology setting that included a diagnosis for screening or polyp surveillance, for 2010 through 2013.

Of 842,849 patients who underwent colonoscopy, 247,542 (29 percent) had a precolonoscopy office visit. Patients with office visits had a higher Charlson Comorbidity Index (CCI; a score based on health conditions of the patient). Of patients with office visits, 66 percent had a CCI of 0. Of the office visits, 77 percent were associated with a diagnosis of either screening or preoperative evaluation. Average payment for office visits was $124. Distributed across all patients, precolonoscopy office visits added an average of $36 per colonoscopy.

“Although the precolonoscopy office visits added a modest $36 per colonoscopy in this population, there are an estimated 7 million screening colonoscopies performed in the United States annually, so the cumulative costs are significant. Identifying which patients benefit from a precolonoscopy office visit and targeting those patients could increase the value of colon cancer screening,” the authors write.

(doi:10.1001/jama.2015.15278; 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 2, 2016

Media Advisory: To contact Surya P. Bhatt, M.D., call Bob Shepard at 205-934-8934 or email bshep@uab.edu.

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Among current and former smokers, the presence of excessive airway collapse (in the trachea) during expiration is associated with worse respiratory quality of life, according to a study in the February 2 issue of JAMA.

The prevalence and clinical significance of expiratory central airway collapse (ECAC) are not known. With increasing use of noninvasive imaging techniques such as computed tomography (CT), ECAC is increasingly recognized in the adult population, especially in association with cigarette smoking and chronic obstructive pulmonary disease (COPD). While the small conducting airways less than 2 mm in diameter are the major site of resistance to airflow in COPD, collapse greater than 50 percent of the larger central airway during exhalation has been hypothesized to cause additional airflow obstruction and respiratory morbidity.

Surya P. Bhatt, M.D., of the University of Alabama at Birmingham, and colleagues examined whether ECAC (>50 percent reduction) is associated with respiratory morbidity in smokers independent of underlying lung disease. The study consisted of an analysis of paired inspiratory-expiratory computed tomography images from a large multicenter study of current and former smokers from 21 clinical centers across the United States. Participants were enrolled from January 2008 to June 2011and followed up until October 2014.

The study included 8,820 participants with and without COPD (52 percent active smokers). The prevalence of ECAC was 5 percent (443 cases). Patients with ECAC compared with those without ECAC had worse scores on measures of respiratory quality of life and dyspnea (shortness of breath), but no significant difference in the distance walked in 6 minutes.

On follow-up (median, 4 years), participants with ECAC had increased frequency of total number of exacerbations and also severe exacerbations requiring hospitalization.

“Further studies are needed to assess long-term associations with clinical outcomes,” the authors write.

(doi:10.1001/jama.2015.19431; 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 2, 2016

Media Advisory: To contact Christophe Faisy, M.D., Ph.D., email christophe.faisy@egp.aphp.fr.

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Among mechanically ventilated patients with chronic obstructive pulmonary disease (COPD) and metabolic alkalosis, administration of the respiratory stimulant acetazolamide did not significantly reduce the duration of invasive mechanical ventilation, according to a study in the February 2 issue of JAMA.

Chronic obstructive pulmonary disease is a frequent cause of intensive care unit (ICU) admission. Noninvasive mechanical ventilation has altered the outcomes of patients with acute COPD exacerbation by reducing the need for intubation. Nevertheless, patients with COPD may still require invasive mechanical ventilation when noninvasive ventilation fails. Acetazolamide has been used for decades as a respiratory stimulant for patients with COPD and metabolic alkalosis (an increase in the alkalinity of body fluids due to an increase in alkali intake or a decrease in acid concentration), but no large randomized placebo-controlled trial has been available to confirm this approach.

Christophe Faisy, M.D., Ph.D., of the European Georges Pompidou Hospital, Paris, and colleagues randomly assigned 382 patients with COPD who were expected to receive mechanical ventilation for more than 24 hours to acetazolamide (500-1000 mg, twice daily) or placebo, administered intravenously in cases of pure or mixed metabolic alkalosis. Treatment was initiated within 48 hours of ICU admission and continued during the ICU stay for a maximum of 28 days; 380 patients were included in an intention-to treat analysis. The study was conducted from October 2011 through July 2014 in 15 ICUs in France. The primary outcome was the duration of invasive mechanical ventilation via endotracheal intubation or tracheotomy.

Among 382 randomized patients, 380 completed the study. For the acetazolamide group (n = 187), compared with the placebo group (n = 193), no significant between-group differences were found for median duration of mechanical ventilation (-16.0 hours), duration of weaning off mechanical ventilation (-0.9 hours), or for other respiratory parameter-values (respiratory frequency, tidal volume, and minute ventilation), although daily changes of serum bicarbonate and number of days with metabolic alkalosis decreased significantly more in the acetazolamide group.

Secondary outcomes, such as adverse events, use of noninvasive ventilation after extubation, the duration of ICU stay, and in-ICU mortality, did not differ significantly between groups.

The authors note that the primary finding of this study (duration of invasive mechanical ventilation) must be considered with prudence. “Indeed, the study may have identified a clinically important benefit of acetazolamide for the primary end point that did not demonstrate statistical significance because of a possible lack of power.”

(doi:10.1001/jama.2016.0019; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The work was supported by the French Ministry of Health and sanofi-aventis France. 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, JANUARY 26, 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 author Michael E. Thase, M.D., call Lee-Ann Donegan at 215-349-5660 or email Leeann.Donegan@uphs.upenn.edu.

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The U.S. Preventive Services Task Force (USPSTF) is recommending screening for depression in the general adult population, including pregnant and postpartum women, and that screening should be implemented with adequate systems in place to ensure accurate diagnosis, effective treatment, and appropriate follow-up. The report appears in the January 26 issue of JAMA.

This recommendation is a USPSTF grade B recommendation, meaning that there is high certainty that the net benefit is moderate, or there is moderate certainty that the net benefit is moderate to substantial.

Depression is among the leading causes of disability in persons 15 years and older. It affects individuals, families, businesses, and society and is common in patients seeking care in the primary care setting, and also common in postpartum and pregnant women. The U.S. Preventive Services Task Force (USPSTF) reviewed the evidence in the medical literature on the benefits and harms of screening for depression in adult populations, including older adults and pregnant and postpartum women; the accuracy of depression screening instruments; and the benefits and harms of depression treatment in these populations. 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. This report is an update of a 2009 USPSTF recommendation statement. The USPSTF continues to recommend that adults 18 and older be screened for depression.

Detection, and Benefits of Early Detection, Intervention and Treatment

The USPSTF found convincing evidence that screening improves the accurate identification of adult patients with depression in primary care settings, including pregnant and postpartum women, and found adequate evidence that programs combining depression screening with adequate support systems in place improve clinical outcomes (i.e., reduction or remission of depression symptoms) in adults, including pregnant and postpartum women. The USPSTF found convincing evidence that treatment of adults and older adults with depression identified through screening in primary care settings with antidepressants, psychotherapy, or both decreases clinical morbidity. The USPSTF also found adequate evidence that treatment with cognitive behavioral therapy (CBT) improves clinical outcomes in pregnant and postpartum women with depression.

Harms of Early Detection, Intervention and Treatment

The USPSTF found adequate evidence that the magnitude of harms of screening for depression in adults is small to none and that the magnitude of harms of treatment with CBT in postpartum and pregnant women is small to none. The USPSTF found that second-generation antidepressants (mostly selective serotonin reuptake inhibitors [SSRIs]) are associated with some harms, such as an increase in suicidal behaviors in adults age 18 to 29 years and an increased risk of upper gastrointestinal bleeding in adults older than 70 years, with risk increasing with age; however, the magnitude of these risks is, on average, small. The USPSTF also found evidence of potential serious fetal harms from pharmacologic treatment of depression in pregnant women, but the likelihood of these serious harms is low. Therefore, the USPSTF concludes that the overall magnitude of harms is small to moderate.

Screening

The optimal timing and interval for screening for depression is not known. A pragmatic approach might include screening all adults who have not been screened previously and using clinical judgment in consideration of risk factors, comorbid conditions, and life events to determine if additional screening of high-risk patients is warranted. Positive screening results should lead to additional assessment that considers severity of depression and comorbid psychological problems, alternate diagnoses, and medical conditions.

Treatment and Interventions

Effective treatment of depression in adults generally includes antidepressants or specific psychotherapy approaches, alone or in combination. Given the potential harms to the fetus and newborn child from certain pharmacologic agents, clinicians are encouraged to consider evidence-based counseling interventions when managing depression in pregnant or breastfeeding women.

USPSTF Assessment

The USPSTF concludes with at least moderate certainty that there is a moderate net benefit to screening for depression in adults 18 years and older, including older adults, who receive care in clinical practices that have adequate systems in place to ensure accurate diagnosis, effective treatment, and appropriate follow-up after screening. The USPSTF also concludes with at least moderate certainty that there is a moderate net benefit to screening for depression in pregnant and postpartum women who receive care in clinical practices that have CBT or other evidence-based counseling available after screening.

(doi:10.1001/jama.2015.18392; 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: Recommendations for Screening for Depression in Adults

Michael E. Thase, M.D., of the University of Pennsylvania, Philadelphia, comments on the USPSTF recommendations in an accompanying editorial.

“Until there are better methods to match patients with specific forms of treatment, the best hope to improve on a B grade for patients with depression may be to adapt care systems to respond more flexibly and decisively to key events that are associated with nonadherence or treatment failure. For example, if the clinicians working within a collaborative care model could rapidly incorporate the information that an initial prescription was not filled or was not refilled, it may be possible to diminish the chances that nonadherence will compromise treatment outcome.”

“Likewise, given evidence that nonresponse is predicted by a lack of symptom improvement during the first 14 days of therapy, web-based monitoring of symptoms early in the course of therapy may enable physicians and other mental health professionals to intervene more rapidly and reduce the chances of treatment failure. The same approach to ongoing care could be used to facilitate a more timely transition through treatment algorithms and more expeditious referral to specialty care.”

(doi:10.1001/jama.2015.18406; 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, JANUARY 26, 2016

Media Advisory: To contact Hans Bisgaard, M.D., D.M.Sc., email bisgaard@copsac.com. To contact Augusto A. Litonjua, M.D., M.P.H., call Johanna Younghans at 617- 525-6373 or email Jyounghans@partners.org. To contact editorial co-author Erika von Mutius, M.D., M.Sc., email erika.von.mutius@med.lmu.de.

To place an electronic embedded link to these articles in your story This link to the 1^st study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.18318 This link to the 2^nd study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.18589 This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.18963

Two randomized trials in the January 26 issue of JAMA examine if vitamin D supplementation during pregnancy would reduce the risk of asthma or persistent wheezing in offspring.

Asthma often begins in early childhood and is the most common chronic childhood disorder. The incidence has increased during the last half-century in westernized societies. Vitamin D deficiency has also become a common health problem in westernized societies, possibly caused by a more sedentary indoor lifestyle and decreased intake of vitamin D containing foods. Vitamin D possesses a range of immune regulatory properties, and it has been speculated that vitamin D deficiency during pregnancy may affect fetal immune programming and contribute to the development of asthma.

In one study, Hans Bisgaard, M.D., D.M.Sc., of the University of Copenhagen, Denmark and colleagues randomly assigned 623 women daily vitamin D₃ (2,400 IU/d; n = 315) or matching placebo tablets (n = 308) from pregnancy week 24 to 1 week postpartum. All women received 400 IU/d of vitamin D₃ daily as part of usual pregnancy care. Follow-up of the children (n = 581) was completed when the youngest child reached age 3 years in March 2014.

Of these children, persistent wheeze was diagnosed during the first 3 years of life in 47 children (16 percent) in the vitamin D₃ group and 57 children (20 percent) in the control group. Vitamin D₃ supplementation was not associated with the risk of persistent wheeze. The authors note that a clinically important protective effect cannot be excluded, and that analyses showed a significant reduction in number of episodes of troublesome lung symptoms. However, the development of asthma, upper and lower respiratory tract infections, allergic sensitization, and eczema was unaffected by the vitamin D₃ supplementation.

“Effective preventive strategies to alleviate the large burden of childhood wheezing and related disorders represent a major unmet clinical need. This randomized clinical trial of vitamin D₃ supplementation during pregnancy did not show a statistically significant effect on the primary end point of persistent wheeze, although a clinically important protective effect cannot be excluded, and a protective effect is suggested by the observed effect on airway immunology and symptomatic episodes. Therefore, further studies with a larger sample size, higher dose, and potentially earlier intervention during pregnancy and postnatal supplementation should be performed to establish the potential benefits of vitamin D₃ supplementation to pregnant women to reduce occurrence of wheezy disorders in the offspring,” the researches write.

(doi:10.1001/jama.2015.18318; 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.

In another study, Augusto A. Litonjua, M.D., M.P.H., of Brigham and Women’s Hospital, Boston, and colleagues randomly assigned 881 pregnant women at 10 to 18 weeks’ gestation and at high risk of having children with asthma to receive daily 4,000 IU vitamin D plus a prenatal vitamin containing 400 IU vitamin D (n = 440), or a placebo plus a prenatal vitamin containing 400 IU vitamin D (n = 436). The researchers conducted the study to determine whether prenatal vitamin D (cholecalciferol) supplementation can prevent asthma or recurrent wheeze in early childhood.

Eight hundred ten infants were born during the study period, and 806 were included in the analyses for the 3-year outcomes. Two hundred eighteen children developed asthma or recurrent wheeze: 98 of 405 (24 percent) in the 4,400-IU group vs 120 of 401 (30 percent) in the 400-IU group. The absolute reduction (6 percent) was not statistically significant; the authors note that the study may have been underpowered.

“In addition, most of the secondary outcomes were not statistically significantly different between groups, and these analyses should be considered exploratory given the null primary outcome and the absence of adjustment for multiple comparisons. Therefore, whether supplementation of pregnant women with vitamin D will reduce asthma and recurrent wheeze in their offspring at age 3 years remains unclear,” the authors write.

“Larger studies and longer follow-up of the children in this study will be needed to answer the question. If additional studies identify a significant effect, given the high prevalence of low vitamin D levels in pregnant women, the effect of this inexpensive intervention on child health could be substantial.”

(doi:10.1001/jama.2015.18589; 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: Inconclusive Results of Randomized Trials of Prenatal Vitamin D for Asthma Prevention in Offspring

It remains unclear whether the results of these studies indicate that vitamin D supplementation may have a role in asthma prevention, write Erika von Mutius, M.D., M.Sc., of Ludwig Maximilians University, Munich, Germany, and Fernando D. Martinez, M.D., of the University of Arizona, Tucson, in an accompanying editorial.

“The heterogeneous nature of wheezing illnesses during the first 3 years of life has been well established for 2 decades. Up to 60 percent of such episodes are transient and not associated with the subsequent development of asthma, and this is particularly true for incident episodes of wheezing occurring during the first 1 to 3 years of life. Therefore, it is too early to know if these findings indicate the potential for vitamin D supplementation to have any role in reducing the risk of asthma. For both trials, longer-term follow-up will be necessary to determine if maternal vitamin D supplementation in pregnancy might have any effect on risk of asthma during the early school years, if not beyond.”

(doi:10.1001/jama.2015.18963; 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, JANUARY 26, 2016

Media Advisory: To contact co-author Michael C Fiore, M.D., M.P.H., M.B.A., call Christopher Hollenback at 608-262-3902 or email ch3@ctri.wisc.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.19284

Among adults motivated to quit smoking, 12 weeks of treatment with a nicotine patch, the drug varenicline, or combination nicotine replacement therapy produced no significant differences in confirmed rates of smoking abstinence at 26 or 52 weeks, raising questions about the current relative effectiveness of intense smoking cessation pharmacotherapies, according to a study in the January 26 issue of JAMA.

Due to the profound health effects of tobacco smoking, it is important to identify treatments that increase rates of long-term smoking abstinence. Two pharmacotherapies for smoking seem particularly effective: combination nicotine replacement therapy (C-NRT) and varenicline. Because varenicline and C-NRT differ in cost, the need for a prescription, and the intensity of screening and ongoing monitoring, a comparison in a head-to-head randomized clinical trial appears warranted, as does the need to test their effectiveness relative to nicotine patch monotherapy, which might be considered a usual-care smoking cessation medication, according to background information in the article.

Timothy B. Baker, Ph.D., of the University of Wisconsin School of Medicine and Public Health, Madison, and colleagues randomly assigned smokers to one of three 12-week smoking cessation pharmacotherapy groups: nicotine patch only (n = 241); varenicline only (including 1 prequit week; n = 424); and C-NRT (nicotine patch + nicotine lozenge; n = 421). Six counseling sessions were offered. The primary measured outcome was carbon monoxide-confirmed self-reported 7-day point-prevalence abstinence (the proportion of the study population abstinent at a specific point in time) at 26 weeks.

The researchers found that the treatments did not differ significantly on any abstinence outcome measure at 26 or 52 weeks, including point-prevalence abstinence at 26 weeks (nicotine patch, 23 percent; varenicline, 24 percent; C-NRT, 27 percent) or at 52 weeks (nicotine patch, 21 percent; varenicline, 19 percent; C-NRT, 20 percent). All medications were well tolerated, but varenicline produced more frequent adverse events than did the nicotine patch for vivid dreams, insomnia, nausea, constipation, sleepiness and indigestion.

“To our knowledge, this open-label study is the first to directly contrast varenicline and C-NRT pharmacotherapies, both with one another and with the nicotine patch. Results showed no significant differences among these 3 pharmacotherapies in any of the 26- or 52-week abstinence measures,” the authors write.

(doi:10.1001/jama.2015.19284; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This research was supported by a grant from the National Heart, Lung, and Blood Institute and the National Cancer Institute to the University of Wisconsin Center for Tobacco Research and Intervention. 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, JANUARY 26, 2016

Media Advisory: To contact Sorilla Prey, M.D., email sorilla.prey@chu-bordeaux.fr.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.13969

Sorilla Prey, M.D., of the Université de Bordeaux, France and colleagues examined the safety of propranolol therapy in treating infantile hemangioma, a vascular tumor characterized by rapid growth during the first weeks of life. Severe forms require systemic therapy. Propranolol, a beta blocker, induces regression, but safety data have been lacking for children. The study appears in the January 26 issue of JAMA.

Children throughout France with proliferative infantile hemangioma requiring systemic therapy for life-threatening (i.e., potential airway obstruction) or functional risks or severe ulceration were referred to specialist centers for compassionate use of pediatric oral propranolol. Analyses involved data collected between April 2010 and April 2013. Adverse drug reactions (ADRs) were collected by questioning parents and reviewing the child health record at each monthly visit for up to 2 years.

Of 922 patients referred, 906 were treated with propranolol and had a median age of about four months. Of the 922 patients, 81 (8.8 percent) had 133 ADRs, including 24 (2.6 percent) with 36 serious ADRs. The most commonly reported ADRs were respiratory disorders (mostly infections), which were reported in 31 patients (serious ADRs related to propranolol in 6 patients). The most serious ADRs were cardiac and metabolic disorders.

“Prescribers must counsel parents at each follow-up visit to discontinue propranolol during fasting and intercurrent illness, especially in the setting of restricted oral intake and respiratory symptoms,” the authors write.

(doi:10.1001/jama.2015.13969; 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, JANUARY 19, 2016

Media Advisory: To contact Alexi A. Wright, M.D., M.P.H., call Anne Doerr at 617-632-4090 or email Anne_Doerr@dfci.harvard.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.18604

Among family members of older patients who died of advanced-stage cancer, earlier hospice enrollment, avoidance of intensive care unit (ICU) admissions within 30 days of death, and death occurring outside the hospital were associated with perceptions of better end-of-life care, according to a study in the January 19 issue of JAMA.

Patients with advanced-stage cancer receive aggressive medical care at the end of life, despite increasing evidence that high-intensity treatments may not be associated with better patient quality of life, outcomes, or caregiver bereavement. Few studies have examined whether these aggressive end-of-life care measures reflect patients’ preferences or bereaved family members’ perceptions and expectations of the quality of end-of-life care.

Alexi A. Wright, M.D., M.P.H., of the Dana-Farber Cancer Institute, Harvard Medical School, Boston, and colleagues assessed the relationship between aggressive end-of-life care and family member-reported quality ratings of end-of-life care. The researchers used information obtained from interviews with family members of Medicare patients with advanced-stage lung or colorectal cancer in the Cancer Care Outcomes Research and Surveillance study who died by the end of 2011 (median, 144.5 days after death).

Of 1,146 patients with cancer (median age, 76 years; 56 percent male), bereaved family members reported excellent end-of-life care for 51 percent. Family members reported excellent end-of-life care more often for patients who received hospice care for longer than 3 days (59 percent [352/599]) than those who did not receive hospice care or received 3 or fewer days (43 percent [236/547]). In contrast, family members of patients admitted to an ICU within 30 days of death reported excellent end-of-life care less often (45 percent) than those who were not admitted to an ICU within 30 days of death (52 percent).

Similarly, family members of patients who died in the hospital reported excellent end-of-life care less often (42 percent) than those who did not die in the hospital (57 percent). Family members of patients who did not receive hospice care or received 3 or fewer days were less likely to report that patients died in their preferred location (40 percent) than those who received hospice care for longer than 3 days (73 percent).

The authors write that, as an example, implementation of multifaceted approaches (e.g., enhanced counseling of patients and families, early palliative care referrals, and an audit and feedback system to monitor physicians’ use of aggressive end-of-life care) might result in more preference-sensitive care for patients and overall improved quality of end-of-life care.

“These findings are supportive of advance care planning consistent with the preferences of patients.”

(doi:10.1001/jama.2015.18604; 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, JANUARY 19, 2016

Media Advisory: To contact Ezekiel J. Emanuel, M.D., Ph.D., email Katie Delach at Katharine.Delach@uphs.upenn.edu.

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The first international comparative study of end-of-life care practices finds that the United States actually has the lowest proportion of deaths in the hospital and the lowest number of days in the hospital in the last 6 months of life among seven developed countries. The study appears in the January 19 issue of JAMA.

Using data from 2010-2012, Ezekiel J. Emanuel, M.D., Ph.D., of the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and colleagues examined patterns of care, health care utilization, and expenditures among patients dying in seven developed countries: Belgium, Canada, England, Germany, the Netherlands, Norway, and the United States. The researchers used administrative and registry data from 2010, and included decedents older than 65 years who died with cancer. In the U.S. 22.2 percent and in Netherlands 29.4 percent of cancer patients died in the hospital, which is in accordance with most patients’ wishes. By comparison, in Belgium and Canada over 50 percent of patients died in the hospital, while in England, Norway, and Germany over 38 percent of patients died in the hospital.

Two decades ago, the majority of deaths due to terminal illness were reported to occur in the hospital. More than a quarter of the Medicare budget is devoted to the care of beneficiaries who die in that year. Other developed nations spend less than the United States on health care, a finding some attribute to lower-intensity care at the end of life.

The United States performs poorly in other aspects of end-of-life care, especially related to high technology interventions. Over 40 percent of patients who die with cancer are admitted to the intensive care unit (ICU) in the last 6 months of life, which is more than twice any other country in the study. Similarly, 38.7 percent of American patients dying with cancer received at least one chemotherapy episode in the last 6 months of life, more than any other country in the study.

In the last 180 days of life, average per capita hospital expenditures were higher in Canada (U.S. $21,840), Norway (U.S. $19,783), and the United States (U.S. $18,500), intermediate in Germany (U.S. $16,221) and Belgium (U.S. $15,699), and lower in the Netherlands (U.S. $10,936) and England (U.S. $9,342).

Analyses that included decedents of any age, decedents older than 65 years with lung cancer, and decedents older than 65 years in the United States and Germany from 2012, showed similar results, suggesting that the differences observed were driven more by end-of-life care practices and organization rather than differences in cohort identification.

The authors write that the lower rates of acute care hospital admissions, length of stay, and in-hospital deaths in the United States and the Netherlands suggest that end-of-life care can evolve to reflect patient preferences and goals about site of death irrespective of health system. “In the early 1980s, more than 70 percent of U.S. cancer patients died in hospital. Over the last 30 years, recognition of preferences for home-based end-of-life care and patients’ rights to refuse medical interventions and economic pressures to lower end-of-life costs and expand hospice use have all played an important role in advancing end-of-life care. Yet excessive utilization of high-intensity care near the end of life, particularly in the United States relative to other developed countries, underscores the need for continued progress to improve end-of-life care practices.”

(doi:10.1001/jama.2015.18603; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This study was partially supported by the Commonwealth Fund and the National Institute on Aging and National Cancer Institute. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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