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.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.19330

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.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.15278

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.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0019

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.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.18392 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.18406

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: https://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: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.18589 This will be the link to the editorial: https://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: https://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: https://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.

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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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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 19, 2016

Media Advisory: To contact Joel S. Weissman, Ph.D., call Lori Schroth at 617-525-6374 or email Ljschroth@partners.org. To contact Saul Blecker, M.D., M.H.S., call Elaine Meyer at 646-501-2895 or email Elaine.Meyer@nyumc.org.

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Two studies in the January 19 issue of JAMA compare the intensity of end-of-life treatment and the likelihood of dying in a hospital between physicians and the general population.

In one study, Joel S. Weissman, Ph.D., of Brigham and Women’s Hospital, Boston, and colleagues examined whether physicians receive higher or lower intensity end-of-life treatments compared with nonphysicians.

Non-health maintenance organization Medicare beneficiaries age 66 years or older who died between 2004 and 2011 in Massachusetts, Michigan, Utah, and Vermont were included in this study due to availability of electronic death records and ability to link to Medicare. From Medicare records, the researchers obtained data on 5 validated measures of end-of-life care intensity during the last 6 months of life: surgery, hospice care, intensive care unit (ICU) admission; death in the hospital; and expenditures. Measures were compared between physicians and the general population (excluding other health care workers and lawyers), physicians vs lawyers, who are presumed to be socioeconomically and educationally similar, and lawyers vs the general population.

There were 2,396 deceased physicians, 2,081 lawyers, and 665,579 in the general population. In adjusted analyses, physicians were less likely to die in a hospital compared with the general population (28 percent vs 32 percent), less likely to have surgery (25 percent vs 27 percent), and less likely to be admitted to the ICU (26 percent vs 28 percent). Physicians were also less likely to die in a hospital compared with lawyers (28 percent vs 33 percent), but did not differ significantly from lawyers on other measures.

“The possible reasons physicians received less intense end-of-life care than others could be knowledge of its burdens and futility as well as the benefits and the financial resources to pay for other treatment options, such as palliative care or skilled nursing required for death at home,” the authors write.

(doi:10.1001/jama.2015.17408; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

In another study, Saul Blecker, M.D., M.H.S., of the New York University School of Medicine, New York, and colleagues compared location of death for physicians with that of other clinicians, non-health care professionals with similar education levels, and the general population.

Although most people report a preference to die at home vs at a medical facility, most deaths occur in a hospital or nursing home. Some articles have proposed that physicians die in a manner more consistent with end-of-life preferences than the general population, although studies on this topic have been lacking.

For this study, the researchers used data from the National Longitudinal Mortality Study, a random national sample of individuals based on U.S. Census Bureau surveys matched to the National Death Index, and included individuals age 30 to 98 years who died between 1979 and 2011 and excluded those missing the location of death. Decedents were categorized into 4 mutually exclusive categories based on self-report of occupation or education: physician, other health professional (dentist, veterinarian, optometrist, podiatrist, nurse, pharmacist, dietician), other higher education, and all others. Other higher education included decedents not employed in health care who completed 6 or more years of postsecondary education and were therefore comparable with physicians in this marker of socioeconomic status. Two outcomes were assessed: death in an inpatient hospital and, more broadly, death in a facility (i.e., hospital, skilled nursing facility, professional center, physician office, or clinic).

Of the 471,243 decedents in the study, 815 were physicians, 2,635 other health professionals, 15,308 other higher education, and 452,485 all others. The authors found that physicians were slightly less likely to die in a hospital than the general population (38 percent vs 40 percent), but equally as likely to die in a hospital as others in health care or with similar educational attainment. In addition, physicians were the least likely group to die at any facility: 63 percent for physicians, 65 percent for other health professionals, 66 percent for other higher education, and 72 percent for all others.

“Our results suggest that familiarity with health care (supported by the subgroup results) and educational attainment may have a small association with experience of death. These results may also be related to socioeconomic differences besides education, which we could not measure, or to differential treatment by clinicians,” the authors write.

(doi:10.1001/jama.2015.16976; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Dr. Blecker was supported by a grant from the Agency for Healthcare Research and Quality. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 12, 2016

Media Advisory: To contact Gaetan Deslee, M.D., Ph.D., email gdeslee@chu-reims.fr. To contact editorial co-author Frank C. Sciurba, M.D., call Anita Srikameswaran at 412-578-9193 or email Srikamav@upmc.edu.

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In preliminary research for patients with severe emphysema, a minimally invasive intervention involving the implantation of coils in the lungs with an endoscope resulted in improved exercise capacity at 6 months, although with high short-term costs, according to a study in the January 12 issue of JAMA.

Emphysema, a key component of chronic obstructive pulmonary disease, is characterized by lung tissue inelasticity and hyperinflation, causing dyspnea (shortness of breath), exercise limitation, and impaired quality of life. Management of severe emphysema represents a challenge because of limited efficacy of currently available treatments. Lung volume reduction surgery, which has demonstrated clinical benefit, is associated with significant illness and death. Lung volume reduction using nitinol (a metal alloy) coils is a bronchoscopic intervention (use of a thin, flexible, endoscope) inducing volume reduction and restoring lung recoil, according to background information in the article.

Gaetan Deslee, M.D., Ph.D., of the Hopital Universitaire de Reims, Reims, France and colleagues randomly assigned patients with severe emphysema to usual care (n = 50; received rehabilitation and bronchodilators with or without inhaled corticosteroids and oxygen) or bilateral coil treatment (n = 50; received usual care plus additional therapy in which approximately 10 coils per lobe were placed in 2 bilateral lobes in 2 procedures). The study was conducted at 10 university hospitals in France.

The primary measured outcome for the study, improvement of at least 54 meters (59 yards) in a 6-minute walk test at 6 months, was observed in 18 patients (36 percent) in the coil group and 9 patients (18 percent) in the usual care group. Coil treatment was associated with a significant decrease in lung hyperinflation and sustained improvement in quality of life. The average total 1-year per-patient cost difference between groups was $47,908.

The authors write that if it is assumed that the quality-adjusted life-years (QALYs) gain could be maintained over at least 3 years with identical follow-up costs in both groups, the incremental cost-effectiveness ratio would be about $270,000 per QALY, close to the incremental cost-effectiveness ratio reported for lung volume reduction surgery in the United States. “This cost-effectiveness ratio at 1 year and modeled to 3 years would not be considered efficient enough to warrant adopting the technology by most countries. Implementation of this technique in a large-scale emphysema population is likely to require this additional data given the high per-patient cost in the short run and the uncertain effect on total health care expenditures.”

“Further investigation is needed to assess durability of benefit and long-term cost implications.”

(doi:10.1001/jama.2015.17821; 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.

Images of Nitinol Coil

Editorial: Bronchoscopic Lung Volume Reduction in COPD

“As further refinements in radiologic and clinical characterization progress, clinicians could expect to be able to offer even greater clinically based ‘precision medicine’ in matching a given technologic intervention to specific patient characteristics,” write Frank C. Sciurba, M.D., of the University of Pittsburgh, and colleagues, in an accompanying editorial.

“Even though this approach may ultimately result in fewer patients eligible for treatment, those who receive treatment will be likely to have a more predictable therapeutic response. Furthermore, this improved efficiency could serve to translate into greater cost-effectiveness. Should the emerging data from larger pivotal trials support the meaningful clinical, albeit palliative, responses observed in preliminary trials, physicians caring for patients with chronic obstructive pulmonary disease (COPD) should not delay in providing evidence-based interventions that offer realistic hope to patients with few other choices to relieve their symptoms and improve their quality of life.”

(doi:10.1001/jama.2015.17714; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Sciurba reports grants from PneumRX and PulmonX. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 12, 2016

Media Advisory: To contact Aaron J. Dawes, M.D., call Enrique Rivero at 310-794-2273 or email erivero@mednet.ucla.edu.

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Mental health conditions, such as depression and binge eating disorder, are common among patients seeking and undergoing bariatric surgery, according to a study in the January 12 issue of JAMA.

Bariatric surgery is an accepted method of promoting weight loss in severely obese individuals. Mental health conditions may be common among patients seeking bariatric surgery; however, the prevalence of these conditions and whether they are associated with postoperative outcomes has not been known.

Aaron J. Dawes, M.D., of the David Geffen School of Medicine at UCLA, Los Angeles, and colleagues conducted a meta-analysis to determine the prevalence of mental health conditions among bariatric surgery candidates and recipients and the association between preoperative mental health conditions and health outcomes following bariatric surgery. The authors identified 68 publications meeting criteria for inclusion in the analysis: 59 reporting the prevalence of preoperative mental health conditions (65,363 patients) and 27 reporting associations between preoperative mental health conditions and postoperative outcomes (50,182 patients).

Results of the meta-analysis estimated that 23 percent of patients undergoing bariatric surgery reported a current mood disorder – most commonly depression (19 percent) – while 17 percent were diagnosed with an eating disorder. “Both estimates are higher than published rates for the general U.S. population, suggesting that special attention should be paid to these conditions among bariatric patients,” the researchers write. Another common mental health condition was anxiety (12 percent).

There was conflicting evidence regarding the association between preoperative mental health conditions and postoperative weight loss. Neither depression nor binge eating disorder was consistently associated with differences in weight outcomes. Bariatric surgery was, however, consistently associated with postoperative decreases in the prevalence of depression (7 studies; 8 percent-74 percent decrease) and the severity of depressive symptoms (6 studies; 40 percent-70 percent decrease).

“Previous reviews have suggested that self-esteem, mental image, cognitive function, temperament, support networks, and socioeconomic stability play major roles in determining outcomes after bariatric surgery,” the authors write. “Future studies would benefit from including these characteristics as well as having clear eligibility criteria, standardized instruments, regular measurement intervals, and transparency with respect to time-specific follow-up rates. By addressing these methodological issues, future work can help to identify the optimal strategy for evaluating patients’ mental health prior to bariatric surgery.”

(doi:10.1001/jama.2015.18118; 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 12, 2016

Media Advisory: To contact Christine H. Lee, M.D., call Veronica McGuire at 905- 525-9140, ext. 22169, or email vmcguir@mcmaster.ca. To contact editorial co-author Preeti N. Malani, M.D., M.S.J., email Shantell Kirkendoll at smkirk@med.umich.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.18098 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.18100

Among adults with Clostridium difficile infection that is recurrent or not responsive to treatment, the use of frozen compared with fresh fecal microbiota transplantation (FMT) did not result in a significantly lower rate of resolution of diarrhea, indicating that frozen FMT may be a reasonable treatment option for these patients, according to a study in the January 12 issue of JAMA.

Clostridium difficile infection (CDI; a bacterium that is one of the most common causes of infection of the colon) in health care settings and in the community has become a major clinical concern. Increases in failure rates with conventional treatment, and recurrences following initial cure, present significant challenges to health care systems: more than 60 percent of patients experience further episodes after a first recurrence. Treatment options for recurrent CDI are limited.

Restoration of protective colonic microbiota by fecal microbiota transplantation (FMT; i.e., reconstitution of normal flora [gut bacteria] by a stool transplant from a healthy individual) has shown evidence as an effective treatment for recurrent CDI. High cure rates have been achieved with FMT given by enema. However, the usefulness of this approach may be limited by logistic difficulties in preparing fresh material. By contrast, the use of frozen-and-thawed (frozen) FMT offers a number of advantages: less cost with reduction in number and frequency of donor screenings; immediate availability of FMT; and the possibility of delivering FMT at centers that do not have on-site laboratory facilities. Previous studies have supported the use of frozen FMT for management of recurrent CDI but have not directly compared frozen with fresh FMT, according to background information in the article.

Christine H. Lee, M.D., of McMaster University, Hamilton, Ontario, Canada, and colleagues randomly assigned 232 adults with recurrent or refractory CDI to receive frozen (n = 114) or fresh (n = 118) FMT via enema. The study was conducted at 6 academic medical centers in Canada.

A total of 219 patients (n = 108 in the frozen FMT group and n = 111 in the fresh FMT group) were included in the modified intention-to-treat (mITT) population and 178 (frozen FMT, n = 91; fresh FMT, n = 87) in the per-protocol population. In this group, the proportion of patients with clinical resolution of diarrhea without relapse at 13 weeks was 83.5 percent for the frozen FMT group and 85 percent for the fresh FMT group. In the mITT population the clinical resolution was 75 percent for the frozen FMT group and 70 percent for the fresh FMT group. There were no differences in the proportion of adverse or serious adverse events between the treatment groups.

“In this clinical trial, the use of frozen FMT compared with fresh FMT for the treatment of recurrent or refractory CDI was noninferior [not worse than] in terms of efficacy; findings for frozen FMT and fresh FMT were similar in terms of safety,” the authors write. “Given the potential advantages of providing frozen FMT, its use is a reasonable option in this setting.”

(doi:10.1001/jama.2015.18098; 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: Expanded Evidence for Frozen Fecal Microbiota Transplantation for Clostridium difficile Infection

“The results presented by Lee et al offer the best evidence to date supporting the use of frozen stool, with their finding that use of frozen stool for FMT resulted in a rate of clinical resolution of diarrhea that was no worse than that obtained with fresh stool for FMT and will likely expand the availability of FMT for patients with recurrent CDI,” write Preeti N. Malani, M.D., M.S.J., and Krishna Rao, M.D., M.S., of the University of Michigan Health System, Ann Arbor (Dr. Malani is also Associate Editor, JAMA), in an accompanying editorial.

“The ability to use frozen stool eliminates many of the logistical burdens inherent to FMT, because stool collection and processing need not be tied to the procedure date and time. This study also provides greater support for the practice of using centralized stool banks, which could further remove barriers to FMT by making available to clinicians safe, screened stool that can be shipped and stored frozen and thawed for use as needed. In theory, procedure costs may also be decreased, since comprehensive donor screening is expensive.”

(doi:10.1001/jama.2015.18100; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This work was supported in part by a grant from the Claude D. Pepper Older Americans Independence Center (Dr. Rao). The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JANUARY 12, 2016

Media Advisory: To contact Josef Coresh, M.D., Ph.D., call Stephanie Desmon at 410-955-7619 or email sdesmon1@jhu.edu.

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Kidney failure risk equations developed in a Canadian population showed accuracy in predicting the 2-year and 5-year probability of kidney failure in patients with chronic kidney disease from over 30 countries with a wide range of variation in age, sex and race, according to a study in the January 12 issue of JAMA.

Chronic kidney disease (CKD) is increasing in incidence and prevalence worldwide. Rates of progression to kidney failure varies among individuals with CKD. Interventions to slow CKD progression, planning for initiation of dialysis and transplant, and early creation of arteriovenous fistula (a surgically created access point for hemodialysis treatments) have been advocated, but these strategies may be expensive and are associated with risks. Treatment would ideally be recommended only for patients at high risk of progression and for whom the benefit exceeds the harm. Kidney failure risk equations were previously developed and validated in 2 Canadian cohorts. The equations include a number of variables, such as age, sex, estimated glomerular filtration rate (a measure of kidney function) and albuminuria (the presence of excessive protein in the urine), to help predict the risk of kidney failure. Validation of these equations in other regions is needed.

Josef Coresh, M.D., Ph.D., of the Johns Hopkins Bloomberg School of Public Health, Baltimore, and colleagues evaluated the accuracy of the risk equations across different geographic regions and patient populations through individual participant data meta-analysis. Thirty-one cohorts, including 721,357 participants with CKD stages 3 to 5 in more than 30 countries spanning 4 continents, were studied. These cohorts collected data from 1982 through 2014. Using the risk factors from the original risk equations, cohort-specific hazard ratios were estimated and combined in meta-analysis to form new pooled kidney failure risk equations. Original and pooled kidney failure risk equation performance was compared, and the need for regional calibration factors was assessed.

During a median follow-up of 4 years, 23,829 cases of kidney failure were observed. The original risk equations achieved excellent discrimination (ability to differentiate those who developed kidney failure from those who did not) across all cohorts; discrimination in subgroups by age, race, and diabetes status was similar. Calibration (the difference between observed and predicted risk) was adequate in North American cohorts, but the original risk equations overestimated risk in some non-North American cohorts. Addition of a calibration factor that lowered the baseline risk by 33 percent at 2 years and 16.5 percent at 5 years improved the calibration in 12 of 15 and 10 of 13 non-North American cohorts at 2 and 5 years, respectively.

“There are important clinical and research implications to this study’s findings,” the authors write. “Clinicians can now use the 4- or 8-variable kidney failure risk equations, with the recalibration factor where applicable, that can inform patient-clinician communication and treatment decisions regarding the absolute risk of kidney failure, rather than the CKD stage alone. Decisions regarding access placement or transplant referral could be made once kidney failure risk thresholds are exceeded.”

(doi:10.1001/jama.2015.18202; 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 12, 2016

Media Advisory: To contact Ayami Yoshimi, M.D., Ph.D., email ayami.yoshimi@uniklinik-freiburg.de.

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Ayami Yoshimi, M.D., Ph.D., of the University of Freiburg, Germany, and colleagues examined the use of peripheral blood stem cells and bone marrow as stem cell sources for hematopoietic stem cell transplantation in patients with bone marrow failure worldwide and factors associated with the use of each stem cell source. The study appears in the January 12 issue of JAMA.

Hematopoietic stem cell transplantation (HSCT) is a therapeutic option for many patients with bone marrow failure. Bone marrow was initially the only stem cell source available until the 1990s when peripheral blood stem cells (PBSCs) and cord blood began to be used. Currently, PBSCs are the major stem cell source, owing to faster engraftment and ease of collection despite a higher rate of graft-vs-host disease and lower survival rates in patients with nonmalignant disorders. Bone marrow is currently recommended for HSCT in patients with bone marrow failure.

For this study, the researchers used data from retrospective HSCT surveys by the Worldwide Network for Blood and Marrow Transplantation. International and regional organizations collect the numbers of transplants annually by disease, donor type, and stem cell source from countries known to perform HSCT in World Health Organization (WHO) member states. Most data are from transplant registries.

Among 194 WHO member states, 84 perform HSCT and 74 reported at least 1 HSCT during 2009 through 2010. Among 114,217 HSCTs reported by 1,482 transplant teams, 3,282 allogeneic (receipt of stem cells from another individual) HSCTs were performed for bone marrow failure. Donor type and stem cell source differed between regions. Of these HSCTs, the stem cell sources were bone marrow (54 percent), PBSC (41 percent), and cord blood (5 percent).

Bone marrow was used most commonly in the Americas (75 percent) and in Europe (60 percent), but not in the Eastern Mediterranean region and Africa (46 percent) and in the Asia Pacific region (41 percent; excluding Japan, 19 percent). The use of bone marrow increased from 20 percent in countries with low and low-middle incomes to 50 percent with high-middle incomes to 64 percent with high incomes. The gross national income per capita and stem cell source had a weak but significant association.

The authors write that PBSCs are still used, despite disadvantages in patients with bone marrow failure, most likely because centers obtain PBSCs routinely for other indications and cell separators are available at any transplant center. “These cells are associated with rapid engraftment, a cost-reducing benefit. By contrast, bone marrow harvest requires trained physicians, specific equipment, and hospitalization of the donor. The correlations with gross national income per capita support the hypothesis that short-term financial considerations are important.”

“National and international transplant organizations and authorities should foster regional-accredited bone marrow harvest centers for patients with nonmalignant disorders and provide resources to establish such infrastructures. Unrelated donor registries should provide information on the necessity of bone marrow donation for patients with bone marrow failure.”

(doi:10.1001/jama.2015.13706; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Funding for this study was indirectly provided by the funders of the Worldwide Network of Blood and Marrow Transplantation. 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 5, 2016

Media Advisory: To contact Dalane W. Kitzman, M.D., call Marguerite Beck at 336-716-2415 or email marbeck@wakehealth.edu. To contact editorial author Nanette K. Wenger, M.D., call Jennifer Johnson at 404-727-5696 or email jennifer.johnson@emory.edu.

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Among obese older patients with a common type of heart failure, calorie restriction or aerobic exercise training improved their ability to exercise without experiencing shortness of breath, although neither intervention had a significant effect on a measure of quality of life, according to a study in the January 5 issue of JAMA.

Heart failure with preserved ejection fraction (a measure of how well the left ventricle of the heart pumps with each contraction) is the most rapidly increasing form of heart failure, occurs primarily in older women, and is associated with high rates of illness, death, and health care expenditures. More than 80 percent of patients with heart failure with preserved ejection fraction (HFPEF) are overweight or obese. Exercise intolerance is the primary symptom of chronic HFPEF and a major determinant of reduced quality of life (QOL).

Dalane W. Kitzman, M.D., of the Wake Forest School of Medicine, Winston-Salem, N.C., and colleagues randomly assigned 100 older obese participants (average age, 67 years) with chronic, stable HFPEF to 20 weeks of diet, exercise, or both, or a control group. The researchers measured exercise capacity (peak oxygen consumption [Vo₂]) and QOL (with the Minnesota Living with Heart Failure Questionnaire; MLHF).

Of the study participants, 26 were assigned to exercise; 24 to diet; 25 to exercise + diet; 25 to control. Of these, 92 completed the trial. The authors found that peak Vo₂ was increased significantly by both exercise and diet, and the combination of diet with exercise produced an even greater increase in exercise capacity. The change in peak Vo₂ was positively correlated with the change in percent lean body mass. Body weight decreased by 7 percent in the diet group, 3 percent in the exercise group, 10 percent in the exercise + diet group, and 1 percent in the control group.

There was no significant change in the MLHF score with exercise or diet.

The researchers note that because of the reported “heart failure obesity paradox” (lower mortality observed in overweight or obese individuals), before diet can be recommended for obese patients with HFPEF, further studies likely are needed to determine whether these favorable changes are associated with reduced clinical events.

(doi:10.1001/jama.2015.17346; 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: Lifestyle Interventions to Improve Exercise Tolerance in Obese Older Patients With Heart Failure and Preserved Ejection Fraction

“This innovative report by Kitzman et al provides applicable evidence that dietary intervention (caloric restriction) alone or complemented by aerobic exercise training improves peak Vo₂, increasing exercise capacity,” writes Nanette K. Wenger, M.D., of the Emory University School of Medicine, Atlanta, in an accompanying editorial.

“The largest increase in exercise capacity was associated with a combination of the exercise + diet interventions. The hypothesis tested is intriguing, and worthy of further investigation in a community population, with longer follow-up, either with or without specific provision of meals to effect caloric restriction, although translation of this type of intervention to the community will be challenging. Whether nonprofessionally administered diet and nonmedically supervised exercise could safely attain similar benefit is uncertain but worthy of exploration.”

(doi:10.1001/jama.2015.17347; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: Dr. Wenger 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, JANUARY 5, 2016

Media Advisory: To contact Dan M. Roden, M.D., email Craig Boerner at craig.boerner@Vanderbilt.Edu. To contact editorial author William Gregory Feero, M.D., Ph.D., email w.gregory.feero@mainegeneral.org.

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A review of medical records of patients with genetic variations linked with cardiac disorders found that patients often did not have any symptoms or signs of the conditions, questioning the validity of some genetic variations thought to be related to serious disorders, according to a study in the January 5 issue of JAMA.

Sequencing of selected gene sets, whole exomes, and whole genomes is increasingly used for research and clinical care. These approaches also identify incidental findings (also called secondary findings) of potential clinical relevance. Driven by the prospect for preclinical diagnosis and risk factor mitigation, the American College of Medical Genetics and Genomics has supported the return of medically actionable incidental findings and generated a list of genes in which known or predicted pathogenic (pertaining to genetic cause of a disease or condition) variants should be returned to patients who undergo clinical sequencing. These recommendations have been controversial because the frequency of clinical manifestations of these variants and their implications for diagnosis and management are poorly defined. Phenotype (an appearance or characteristic of an individual, which results from the interaction of the person’s genetic makeup and his or her environment) data from electronic medical records (EMRs) may provide a resource to assess the clinical relevance of rare variants, according to background information in the article.

Dan M. Roden, M.D., and Sara Van Driest, M.D., Ph.D., of the Vanderbilt University Medical Center, Nashville, Tenn., and colleagues determined the clinical phenotypes from EMRs for individuals with variants designated as pathogenic by expert review in arrhythmia susceptibility genes. The study included 2,022 individuals recruited for nonantiarrhythmic drug exposure phenotypes for the Electronic Medical Records and Genomics Network Pharmacogenomics project from 7 U.S. academic medical centers. Variants in SCN5A and KCNH2, disease genes for long QT and Brugada syndromes (potentially fatal cardiac conditions), were assessed for potential pathogenicity by 3 laboratories and by comparison with the database ClinVar. Relevant phenotypes were determined from EMRs, with data available from 2002 (or earlier for some sites) through September 10, 2014.

Among the 2,022 study participants, a total of 122 rare variants in 2 arrhythmia susceptibility genes were identified in 223 individuals (11 percent of the study cohort). Expert laboratory review of these variants designated 42 as potentially pathogenic, and these classifications were discordant across the laboratories. Review of EMR and electrocardiographic (ECG) data revealed no difference in prevalence of arrhythmia diagnoses or ECG phenotypes among participants with the designated variants compared with those without.

After the researchers performed a manual review of EMR data and an ECG review, the majority of participants with a designated variant in either SCN5A or KCNH2 had no identifiable arrhythmia or ECG phenotype. Among patients with designated variants, 35 percent had evidence of any arrhythmia or ECG phenotype.

The authors write that there are several potential explanations for the paucity of clinical manifestations among participants with these variants, including that some participants may have clinically manifest disease that was not documented in the EMR; these variants may have low penetrance or cause subclinical disease except in the setting of additional genetic or environmental influences; this cohort may not represent individuals at risk for the phenotype; and some of these designated variants may confer little or no increased risk for either arrhythmias or ECG abnormalities.

(doi:10.1001/jama.2015.17701; 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: Establishing the Clinical Validity of Arrhythmia-Related Genetic Variations Using the Electronic Medical Record

“Establishing the clinical validity of genetic variations proposed as biomarkers for important health conditions can be technically challenging, time-consuming, and expensive. The success of precision medicine ultimately depends on the availability of biomarkers in which the clinical community has confidence,” writes William Gregory Feero, M.D., Ph.D., of Maine Dartmouth Family Medicine Residency, Fairfield, Maine, and Associate Editor, JAMA, in an accompanying editorial.

“The report by Van Driest et al provides a glimpse of a potential future in which EMR data might be used to define the clinical validity of biomarkers, genetic or otherwise, more rapidly, and at potentially lower cost, than is possible via traditional approaches. However, the study also exposes some shortcomings in the existing ability to meaningfully predict the consequences of at least some genetic variations currently thought to be causally related to serious disorders. For now, caution should be exercised when considering clinical interventions informed by the presence of ‘pathogenic’ variations in healthy individuals, families, and populations.”

(doi:10.1001/jama.2015.17702; 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, JANUARY 5, 2016

Media Advisory: To contact Ditte Molgaard-Nielsen, M.Sc., email dnl@ssi.dk.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.17844

In an analysis of approximately 1.4 million pregnancies in Denmark, use of the oral antifungal medication fluconazole during pregnancy was associated with an increased risk of spontaneous abortion compared with risk among unexposed women and women who used a topical antifungal during pregnancy, according to a study in the January 5 issue of JAMA.

Pregnant women are at increased risk of vaginal candidiasis (yeast infection); the prevalence of vaginal candidiasis among pregnant women is estimated to be 10 percent in the United States. Although intravaginal formulations of topical azole antifungals are first-line treatment for pregnant women, oral fluconazole is often used despite limited safety information. Ditte Molgaard-Nielsen, M.Sc., of the Statens Serum Institut, Copenhagen, Denmark, and colleagues evaluated the association between oral fluconazole exposure during pregnancy and the risk of spontaneous abortion and stillbirth. The study included 1,405,663 pregnancies in Denmark from 1997-2013. From this group, oral fluconazole-exposed pregnancies were compared with up to 4 unexposed pregnancies, matched on maternal age, calendar year, and gestational age. Filled prescriptions for oral fluconazole were obtained from the National Prescription Register.

Among 3,315 women exposed to oral fluconazole from 7 through 22 weeks’ gestation, 147 experienced a spontaneous abortion, compared with 563 among 13,246 unexposed matched women (women not exposed to antifungals). There was a significantly increased risk of spontaneous abortion associated with fluconazole exposure. Among 5,382 women exposed to fluconazole from gestational week 7 to birth, 21 experienced a stillbirth, compared with 77 among 21,506 unexposed matched women. There was no significant association between fluconazole exposure and stillbirth. Using topical azole exposure as a comparison, 130 of 2,823 women exposed to fluconazole vs 118 of 2,823 exposed to topical azoles had a spontaneous abortion; 20 of 4,301 women exposed to fluconazole vs 22 of 4,301 exposed to topical azoles had a stillbirth.

“In this nationwide cohort in Denmark, oral fluconazole use in pregnancy was associated with a significantly increased risk of spontaneous abortion,” the authors write. “Until more data on the association are available, cautious prescribing of fluconazole in pregnancy may be advisable. Although the risk of stillbirth was not significantly increased, this outcome should be investigated further.”

(doi:10.1001/jama.2015.17844; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This study was supported by the Danish Medical Research Council. 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, JANUARY 5, 2016

Media Advisory: To contact Lorelei A. Mucci, Sc.D., M.P.H., email lmucci@hsph.harvard.edu.

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In a long-term follow-up study among approximately 200,000 Nordic twin individuals, there was an increased cancer risk in twins whose co-twin was diagnosed with cancer, with an increased risk for cancer overall and for specific types of cancer, including prostate, melanoma, breast, ovary, and uterus, according to a study in the January 5 issue of JAMA.

The global burden of cancer is considerable, with an estimated 12 million new cases and 8 million cancer deaths each year. In 2015 in the United States, 1.7 million individuals will be diagnosed with cancer and 590,000 will die of cancer, accounting for 1 in 4 deaths. Refinement of primary and secondary prevention strategies (i.e., factors that would have the greatest influence on reducing cancer incidence and death) requires a detailed understanding of the contribution of genetic and environmental factors to disease pathogenesis (the origination and development of a disease). Large twin studies of cancer can provide insight into the relative contribution of inherited factors and characterize familial cancer risk (risk of cancer in an individual given a twin’s development of cancer) by leveraging the genetic relatedness of monozygotic (twins developed from the same fertilized egg [having the same genetic material]) and dizygotic (twins who develop from two separate fertilized eggs) twins, according to background information in the article.

Lorelei A. Mucci, Sc.D., M.P.H., of the Harvard T. H. Chan School of Public Health, Boston, and colleagues estimated familial risk and heritability (proportion of variance in cancer risk due to interindividual genetic differences) of cancer types among 80,309 monozygotic and 123,382 same-sex dizygotic twin individuals (n = 203,691) from the population-based registers of Denmark, Finland, Norway and Sweden. Twins were followed up a median of 32 years between 1943 and 2010. There were 50,990 individuals who died of any cause, and 3,804 who emigrated and were lost to follow-up.

A total of 27,156 incident cancers were diagnosed in 23,980 individuals, translating to a cumulative incidence of 32 percent. Cancer was diagnosed in both twins among 1,383 monozygotic (2,766 individuals) and 1,933 dizygotic (2,866 individuals) pairs. Of these, 38 percent of monozygotic and 26 percent of dizygotic pairs were diagnosed with the same cancer type. There was an excess cancer risk in twins whose co-twin was diagnosed with cancer, with estimated cumulative risks that were an absolute 5 percent higher in dizygotic (37 percent) and an absolute 14 percent higher in monozygotic twins (46 percent) whose twin also developed cancer compared with the cumulative risk in the overall cohort (32 percent).

For most cancer types, there were significant familial risks and the cumulative risks were higher in monozygotic than dizygotic twins. Heritability of cancer overall was 33 percent. Significant heritability was observed for the cancer types of skin melanoma (58 percent), prostate (57 percent), nonmelanoma skin (43 percent), ovary (39 percent), kidney (38 percent), breast (31 percent), and corpus uteri (a part of the uterus; 27 percent).

“The data provide strong evidence of an excess familial risk for 20 of the 23 cancer types, as shown by the comparison of familial risks for those cancers with the cumulative risk in the twin cohort overall,” the authors write.

The researchers note that dizygotic pairs of twins are as genetically similar as siblings, so that familial risk estimates among dizygotic pairs are relevant for siblings who are born at separate times.

“This information about hereditary risks of cancers may be helpful in patient education and cancer risk counseling.”

(doi:10.1001/jama.2015.17703; 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 5, 2016

Media Advisory: To contact Caroline J. Kistin, M.D., M.Sc., call Ellen Slingsby at 617-638-8489 or email ellen.slingsby@bmc.org.

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Caroline J. Kistin, M.D., M.Sc., of Boston Medical Center, and colleagues examined the incidence and timing of re-referral to child protective services, substantiated maltreatment, and foster care placement for any type of maltreatment after an initial unsubstantiated referral for neglect for children with and without disabilities. The study appears in the January 5 issue of JAMA.

According to background information in the article, children with disabilities are at increased risk for maltreatment, and neglect accounts for the majority of such cases. Although most cases of suspected neglect are unsubstantiated at the time of the initial report to child protective services (CPS), meaning there is insufficient legal evidence of maltreatment, these children are at risk for subsequent maltreatment.

For this study, the researchers analyzed data from the National Child Abuse and Neglect Data System, which collects data annually on all children reported to state-level CPS agencies in the 50 states, the District of Columbia, and Puerto Rico. Children were included if they had first-time unsubstantiated referrals for neglect in 2008; they were followed up for 4 years.

A total of 489,176 children from 33 states, Puerto Rico, and the District of Columbia were included (12,610 children with disabilities and 476,566 children without disabilities). Children with vs without disabilities were more likely to be re-referred (45 percent vs 36 percent, respectively; adjusted risk difference [ARD], 14 percent), experience substantiated maltreatment (16 percent vs 10 percent; ARD, 9 percent), and be placed in foster care (7 percent vs 3 percent; ARD, 4 percent). The median time to each outcome was shorter for children with disabilities.

“Our findings highlight the significant incidence of maltreatment experienced by children with unsubstantiated referrals for neglect, particularly children with disabilities. Such children may benefit from targeted interventions to prevent subsequent maltreatment,” the authors write.

(doi:10.1001/jama.2015.12912; 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, DECEMBER 22, 2015

Media Advisory: To contact Debbie A. Lawlor, Ph.D., email d.a.lawlor@bristol.ac.uk. To contact editorial author Evan R. Myers, M.D., M.P.H., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.17296 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.17297

Although in vitro fertilization (IVF) is often limited to 3 or 4 treatment cycles, new research shows the effectiveness of extending the number of IVF cycles beyond this number, according to a study in the December 22/29 issue of JAMA.

In vitro fertilization is commonly stopped after 3 or 4 unsuccessful embryo transfers, with 3 unsuccessful transfers labeled “repeat implantation failure.” Debbie A. Lawlor, Ph.D., of the University of Bristol, Bristol, United Kingdom, and colleagues examined the extent to which repeat IVF cycles continue to increase the likelihood of a live birth, defining an IVF cycle as the initiation of treatment with ovarian stimulation and all resulting separate fresh or frozen embryo transfers. The study included 156,947 U.K. women who received 257,398 IVF ovarian stimulation cycles between 2003 and 2010 and were followed up until June 2012. The median age at start of treatment was 35 years, and the median duration of infertility for all cycles was 4 years.

In all women, the live-birth rate for the first cycle was 29.5 percent. This remained above 20 percent up to and including the fourth cycle. The cumulative prognosis-adjusted live-birth rate across all cycles continued to increase up to the ninth cycle, with 65 percent of women achieving a live birth by the sixth cycle. In women younger than 40 years using their own oocytes (eggs), the live-birth rate for the first cycle was 32 percent and remained above 20 percent up to and including the fourth cycle. Six cycles achieved a cumulative prognosis-adjusted live-birth rate of 68 percent.

For women 40 to 42 years of age, the live-birth rate for the first cycle was 12 percent, with 6 cycles achieving a cumulative prognosis-adjusted live-birth rate of 31.5 percent. For women older than 42 years, all rates within each cycle were less than 4 percent. No age differential was observed among women using donor oocytes. Rates were lower for women with untreated male partner-related infertility compared with those with any other cause, but treatment with either intracytoplasmic sperm injection or sperm donation removed this difference.

Women younger than 40, those using donor oocytes and those with male partner-related infertility that was treated with either intracytoplasmic sperm injection or sperm donation achieved live birth rates after five or six cycles, taking a median two years of trying, which were similar to rates in couples who were trying to conceive and were not using any form of treatment after an average of one year.

The study also showed that the number of eggs retrieved after ovarian stimulation in one cycle does not influence the live birth success rate in subsequent cycles. This is important because couples are often told their chances of success with future treatments are likely to be poor in subsequent cycles, if they have had no or only a small number of eggs retrieved in a cycle.

“These findings support the efficacy of extending the number of IVF cycles beyond 3 or 4,” the authors write.

The researchers note that for some couples, the emotional stress of repeat treatments may be undesirable, and the cost of a prolonged treatment course, with several repeat oocyte stimulation cycles, may be unsustainable for health services, insurers, or couples. “However, we think the potential for success with further cycles should be discussed with couples.”

(doi:10.1001/jama.2015.17296; 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: Repeated In Vitro Fertilization Cycles for Infertility

“For clinicians, it is important that these data be shared with couples so that they can make a truly informed decision,” writes Evan R. Myers, M.D., M.P.H., of Duke University Medical Center, Durham, N.C., in an accompanying editorial.

“This will require time and expertise in communication. For policy makers, revising the National Assisted Reproductive Technology Surveillance System to allow reporting of outcomes on a per-couple basis (including oocyte donors) would provide significantly more useful information for decision-making purposes.”

(doi:10.1001/jama.2015.17297; 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, DECEMBER 22, 2015

Media Advisory: To contact Lucia Del Mastro, M.D., email lucia.delmastro@hsanmartino.it. To contact editorial author Ann H. Partridge, M.D., M.P.H., call John Noble at 617-632-4090 or email johnw_noble@dfci.harvard.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.17291 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.17299

Compared with receiving chemotherapy alone, women with breast cancer who also received the hormonal drug triptorelin to achieve ovarian suppression had a higher long-term probability of ovarian function recovery, without a statistically significant difference in pregnancy rate or disease-free survival, according to a study in the December 22/29 issue of JAMA.

The majority of young women with invasive breast cancer are candidates to receive both chemotherapy and endocrine therapy. Loss of ovarian function and impaired fertility are possible consequences of anticancer treatments. Fertility concerns can affect treatment decisions of young women with breast cancer. Whether the administration of luteinizing hormone-releasing hormone analogues (LHRHa) during chemotherapy is a reliable strategy to preserve ovarian function is controversial owing to both the lack of data on long-term ovarian function and pregnancies and the safety concerns about the potential negative interactions between endocrine therapy and chemotherapy, according to background information in the article.

Lucia Del Mastro, M.D., of the Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy and colleagues randomly assigned 281 premenopausal women (median age, 39 years) with stage I to III hormone receptor-positive or hormone receptor-negative breast cancer to receive chemotherapy alone (control group) or chemotherapy plus triptorelin (LHRHa group). The trial was conducted at 16 Italian sites. Women were enrolled between October 2003 and January 2008; last annual follow-up was June 2014. Median follow-up was 7.3 years.

The 5-year cumulative incidence estimate of menstrual resumption was 73 percent among the 148 patients in the LHRHa group and 64 percent among the 133 patients in the control group. Eight pregnancies (5-year cumulative incidence estimate of pregnancy, 2.1 percent) occurred in the LHRHa group and 3 (5-year cumulative incidence estimate of pregnancy, 1.6 percent) in the control group. Five-year disease-free survival was 80.5 percent in the LHRHa group and 84 percent in the control group. This increased but statistically nonsignificant risk appeared specific to the patients with hormone receptor-negative tumors.

The authors write that these results, together with the findings of another study (POEMS-SWOG S0230), “indicate that, in addition to fertility preservation strategies such as embryo and oocyte cryopreservation, temporary ovarian suppression with LHRHa is an option to preserve ovarian function in premenopausal women with early stage breast cancer receiving adjuvant chemotherapy.”

(doi:10.1001/jama.2015.17291; 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: Prevention of Premature Menopause and Preservation of Fertility in Young Cancer Survivors

“The report by Lambertini et al in this issue of JAMA adds long-term follow-up information to the growing literature regarding the use of LHRHa through chemotherapy for the prevention of premature menopause, a desired outcome for some patients for prevention of associated menopausal symptoms and adverse health effects,” writes Ann H. Partridge, M.D., M.P.H., of the Dana-Farber Cancer Institute, Boston, in an accompanying editorial.

“Although the findings suggest modest benefits regarding the potential prevention of treatment-associated infertility, collectively these studies reflect the emerging importance of understanding and improving such critical quality-of-life issues, offering patients new treatment and supportive care options, and ultimately providing hope regarding an issue that is highly valued by many young patients diagnosed with cancer.”

(doi:10.1001/jama.2015.17299; 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 reported serving on an advisory board for Pfizer Inc. in 2014.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, DECEMBER 22, 2015

Media Advisory: To contact Arden M. Morris, M.D., M.P.H., call Nicole Fawcett at 734-764-2220 or email nfawcett@umich.edu.

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Nearly half of working individuals with stage III colorectal cancer surveyed did not retain their jobs reportedly due to their cancer diagnosis and treatment, according to a study in the December 22/29 issue of JAMA. Paid sick leave was associated with a greater likelihood of job retention and reduced personal financial burden.

Workers who develop serious illnesses, such as colorectal cancer (CRC), can incur economic hardship, regardless of insurance coverage. Paid sick leave could reduce the need to take unpaid time off during treatment. However, 40 percent of U.S. workers have no paid sick leave. Its provision is not mandated under the Affordable Care Act or the Family Medical Leave Act, nor is it part of health insurance coverage.

Arden M. Morris, M.D., M.P.H., of the University of Michigan, Ann Arbor, and colleagues examined the association between access to paid sick leave and job retention and personal financial burden among patients with CRC. Surveys were mailed to and telephone follow-up conducted with adults with stage III CRC reported to the Surveillance, Epidemiology, and End Results cancer registries of Georgia and metropolitan Detroit between August 2011 and March 2013. Patients were contacted 4 months postoperatively and could respond up to 12 months postoperatively; only those employed at diagnosis were analyzed.

Among 567 employed respondents (68 percent response rate), 56 percent had access to paid sick leave. Fifty-five percent retained their jobs. Others were newly disabled (26 percent), retired (7 percent), or unemployed (8 percent) or had found new jobs (4 percent). Those who retained their jobs were significantly more likely to be men, white, married, without other illness, and were more highly educated and were more likely to have a higher annual income, private health insurance, and access to paid sick leave. Fifty-nine percent of respondents with paid sick leave retained their jobs vs 33 percent without paid sick leave.

(doi:10.1001/jama.2015.12383; 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, DECEMBER 22, 2015

Media Advisory: To contact Najib M. Rahman, D.Phil., email Najib.Rahman@ndm.ox.ac.uk.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.16840

Use of NSAIDs vs opiates resulted in no significant difference in measures of pain but was associated with more rescue medication (additional medicine needed due to uncontrolled pain) among patients with malignant pleural effusions (excess fluid accumulates around the lungs that is a complication of cancer) undergoing pleurodesis (a treatment for this condition that closes up the pleural space), according to a study in the December 22/29 issue of JAMA.

The incidence of malignant pleural effusion is estimated to be 150,000 new cases in the United States each year. Nonsteroidal anti-inflammatory drugs (NSAIDs) are avoided for treatment because they may reduce effectiveness of pleurodesis. Smaller chest tubes may be less painful than larger tubes during pleurodesis, but efficacy has not been proven.

Najib M. Rahman, D.Phil., of the University of Oxford, England and colleagues randomly assigned patients with malignant pleural effusion requiring pleurodesis undergoing thoracoscopy (endoscopic examination, therapy or surgery of the chest cavity) (n = 206) and who received a 24F (larger size) chest tube to receive opiates (n = 103) vs NSAIDs (n = 103). Those not undergoing thoracoscopy (n = 114) were randomized to 1 of 4 groups (24F chest tube and opioids [n = 28); 24F chest tube and NSAIDs [n = 29); 12F (smaller size) chest tube and opioids [n = 29]; or 12F chest tube and NSAIDs [n = 28]). The study was conducted at 16 UK hospitals from 2007 to 2013.

The researchers found that the use of NSAIDs, compared with opiates, resulted in no significant difference in pain scores but was associated with more use of rescue medication while the chest tube was in place; however, NSAID use also resulted in noninferior (not worse than) rates of pleurodesis efficacy at 3 months. Among patients who did not undergo thoracoscopy, placement of 12F chest tubes compared with 24F chest tubes was associated with a statistically significant but clinically modest reduction in pain scores and failed to meet noninferiority criteria for pleurodesis efficacy.

“These results challenge current guidelines that advocate avoidance of NSAIDs and use of small chest tubes,” the authors write.

(doi:10.1001/jama.2015.16840; 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, DECEMBER 22, 2015

Media Advisory: To contact Keith Van Haren, M.D., call Erin Digitale at 650-724-9175 or email digitale@stanford.edu.

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There have been nearly 60 cases identified in California from 2012 – 2015 of acute flaccid myelitis, a rare syndrome described as polio-like, with most patients being children and young adults, according to a study in the December 22/29 issue of JAMA. The cause of the condition in these cases remains unknown.

With the elimination of wild poliovirus in populations throughout most of the world, the clinical syndrome of acute flaccid paralysis (characterized by weakness or paralysis and reduced muscle tone) due to spinal motor neuron injury has largely disappeared from North America. Despite occasional case reports, the absence of centralized public health surveillance for non-polio acute flaccid paralysis in the United States has precluded accurate incidence estimates. In the fall of 2012, the California Department of Public Health (CDPH) received 3 separate reports of acute flaccid paralysis cases with evidence of spinal motor neuron injury. No such cases had been reported to the program during the preceding 14 years. In response to these unusual case reports, the CDPH implemented enhanced surveillance for similar cases with the goal of characterizing observed cases and identifying possible causes.

Keith Van Haren, M.D., of Stanford University, Palo Alto, Calif., and colleagues summarized reported cases of acute flaccid myelitis, which encompasses a subset of acute flaccid paralysis cases, in patients with radiological or neurophysiological findings suggestive of spinal motor neuron involvement reported to the CDPH with symptom onset between June 2012 and July 2015. Cerebrospinal fluid, serum samples, nasopharyngeal swab specimens, and stool specimens were submitted to the state laboratory for infectious agent testing.

Fifty-nine cases were identified. Median age was 9 years (50 of the cases were younger than 21 years). Symptoms that preceded or were concurrent included respiratory or gastrointestinal illness (n = 54), fever (n = 47), and limb myalgia (n = 41; muscle pain). Among 45 patients with follow-up data, 38 had persistent weakness at a median follow-up of 9 months. Two patients, both immunocompromised adults, died within 60 days of symptom onset. Enteroviruses were the most frequently detected pathogen in either nasopharynx swab specimens, stool specimens, serum samples (15 of 45 patients tested). No pathogens were isolated from the cerebrospinal fluid. The incidence of reported cases was significantly higher during a national enterovirus D68 outbreak occurring from August 2014 through January 2015 compared with other monitoring periods.

“The etiology of acute flaccid myelitis cases in our series remains undetermined. Although the syndrome described is largely indistinguishable from poliomyelitis on clinical grounds, epidemiological and laboratory studies have effectively excluded poliovirus as an etiology,” the authors write.

The researchers note that “ongoing surveillance efforts are required to understand the full and potentially evolving levels of infectious agent-associated morbidity and mortality.”

“To our knowledge, the California surveillance program for acute flaccid paralysis is the first to use specific case criteria and report subsequent incidence data for the subset of paralysis cases attributable solely to acute flaccid myelitis and may serve as a guide for similar surveillance efforts in the future.”

(doi:10.1001/jama.2015.17275; 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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