EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, AUGUST 26, 2014
Media Advisory: To contact Laura P. Richardson, M.D., M.P.H., email Rose Ibarra at rose.ibarra@seattlechildrens.org. To contact editorial co-author Mark A. Riddle, M.D., email Ekaterina Pesheva at epeshev1@jhmi.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.9259. This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.9258.

Collaborative Care Intervention Improves Depression Among Teens

Among adolescents with depression seen in primary care, a collaborative care intervention that included patient and parent engagement and education resulted in greater improvement in depressive symptoms at 12 months than usual care, according to a study in the August 27 issue of JAMA.

Depressed youth are at greater risk of suicide, substance abuse, early pregnancy, low educational attainment, recurrent depression and poor long-term health. Fourteen percent of adolescents between the ages of 13-18 years have major depression yet few receive evidence-based treatments for their depression. The failure to accurately diagnose and treat adolescents and an inadequate supply of child mental health specialists have led to increasing focus on improving the quality of depression treatment in pediatric primary care, according to background information in the article.

Laura P. Richardson, M.D., M.P.H., of Seattle Children’s Research Institute and the University of Washington School of Medicine, Seattle, and colleagues randomly assigned 101 adolescents (ages 13-17 years) at Group Health Cooperative who had screened positive for depression to a 12-month collaborative care intervention or usual care. The intervention included an education and engagement session, during which perspectives on symptoms were elicited, depression education was provided, and active treatment participation of adolescents and parents was encouraged. During the session, a depression care manager helped the youth and parent choose and initiate treatment with antidepressant medication, brief cognitive behavioral therapy, or both. The intervention youth then received ongoing follow-up with care provided in the primary care clinic. In the usual care group, youth received depression screening results and could access mental health services through Group Health.

Intervention youth (n = 50), compared with those who received usual care (n = 51), had greater decreases in depressive symptoms by 12 months. Sixty-eight percent of intervention youth had a 50 percent or greater reduction in depressive symptoms compared to 39 percent among control youth. The overall rate of depression remission at 12 months was 50.4 percent for intervention youth and 20.7 percent for control youth.

These findings suggest that mental health services for adolescents with depression can be effectively integrated into primary care, the authors conclude.
(doi:10.1001/jama.2014.9259; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: A Practical and Effective Primary Care Intervention for Treating Adolescent Depression

Gloria M. Reeves, M.D., of the University of Maryland School of Medicine, Baltimore, and Mark A. Riddle, M.D., of the Johns Hopkins University School of Medicine, Baltimore, comment on this study in an accompanying editorial.

“Pediatric primary care clinicians have substantial potential to improve identification and treatment of adolescent depression. This study suggests that collaborative care treatment of adolescent depression can be structured to promote care that is evidence­based, personalized, and effective. Further research on this type of model has tremendous potential to benefit both families and clinicians.”
(doi:10.1001/jama.2014.9258; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Riddle receives salary support from the Center for Mental Health Services in Pediatric Primary Care. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, AUGUST 26, 2014
Media Advisory: To contact Richard J. McManus, F.R.C.G.P., email richard.mcmanus@phc.ox.ac.uk. To contact editorial co-author Peter M. Nilsson, M.D., Ph.D., email Peter.Nilsson@med.lu.se.

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Hypertension Self-Management Program Helps Reduce Blood Pressure For High-Risk Patients

Among patients with hypertension at high risk of cardiovascular disease, a program that consisted of patients measuring their blood pressure and adjusting their antihypertensive medication accordingly resulted in lower systolic blood pressure at 12 months compared to patients who received usual care, according to a study in the August 27 issue of JAMA.

Data from national and international surveys suggest that despite improvements over the last decade, significant proportions of patients have poor control of their elevated blood pressure. Self-monitoring of blood pressure with self-titration (adjusting) of antihypertensives results in lower blood pressure in patients with hypertension, but there are no data about patients in high-risk groups, according to background information in the article.

Richard J. McManus, F.R.C.G.P., of the University of Oxford, and colleagues randomly assigned 552 patients with hypertension and a history of stroke, coronary heart disease, diabetes, or chronic kidney disease to self-monitoring of blood pressure combined with an individualized self-titration algorithm or a control group (patients received usual care consisting of seeing their health care clinician for routine blood pressure measurement and adjustment of medication if necessary).

After 12 months, the average systolic blood pressure decreased in both groups, but was lower in the intervention group (128.2/73.8 mm Hg vs 137.8/76.3 mm Hg). Imputation for missing values showed a marginally lower average difference in systolic blood pressure of 8.8 mm Hg. The reduction in diastolic blood pressure was also greater in the self-monitoring group. The results were comparable in all subgroups, without excessive adverse events.

“This trial has shown for the first time, to our knowledge, that a group of high-risk individuals, with hypertension and significant cardiovascular comorbidity, are able to self-monitor and self-titrate antihypertensive treatment following a pre­specified algorithm developed with their family physician and that in doing so, they achieved a clinically significant reduction in systolic and diastolic blood pressure without an increase in adverse events,” the authors write. “This is a population with the most to gain in terms of reducing future cardiovascular events from optimized blood pressure control.”
(doi:10.1001/jama.2014.10057; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Self-titration of Antihypertensive Therapy in High-Risk Patients
Bring It Home

“Although the trial by McManus et al does not settle all questions regarding self-titration based on self-measurement, it is an important step toward adaptation of treatment for patients who want to actively take part in their own risk-factor control,” write Peter M. Nilsson, M.D., Ph.D., of Skane University Hospital, Malmo, Sweden, and Fredrik H. Nystrom, M.D., Ph.D., of Linkoping University, Linkoping, Sweden, in an accompanying editorial.

“Future trials studying the effects of self-titration on cardiovascular events are needed. With the gain in knowledge from [this trial], it may be possible to make the recruitment of patients less restricted, to incorporate education about self-measurement as a standard procedure and focus on which scheme for titration to use, or to study the timing of the home blood pressure recordings. In many countries antihypertensive drugs are now available as inexpensive generic drugs. The time has come to fully use these noncostly medications and to design optimal individualized care of patients.”

“Based on these findings, a ‘bring it home’ blood pressure-lowering strategy appears suitable for patients with hypertension and comorbidities.”
(doi:10.1001/jama.2014.10058; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, AUGUST 19, 2014
Media Advisory: To contact Shani Delaney, M.D., email Susan Gregg at sghanson@uw.edu.

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Prevalence of Herpes Simplex Virus Type 2 Decreases Among Pregnant Women in the Pacific Northwest

In a study that included approximately 15,000 pregnant women, seroprevalence of herpes simplex virus (HSV) type 2 decreased substantially between 1989 and 2010 while there was no overall decrease for HSV type 1, but a slight increase among black women, according to a study in the August 20 issue of JAMA.

Shani Delaney, M.D., and Anna Wald, M.D., M.P.H., of the University of Washington, Seattle, and colleagues examined trends in the seroprevalence of HSV-1 and HSV-2 among pregnant women who delivered newborns at the University of Washington Medical Center between January 1989 and May 2010. The researchers identified 15,738 women with 18,993 pregnancies who had prenatal HSV serological results.

HSV-1 seroprevalence decreased from 69.1 percent during the first decade (1989-1999) to 65.5 percent during 2000-2010, whereas HSV-2 seroprevalence decreased from 30.1 percent to 16.3 percent. After adjusting for various factors, the researchers found no significant annual trend in HSV-1 seroprevalence; however, rates of HSV-2 seroprevalence decreased significantly by 4.8 percent/year. Seroprevalence of HSV-1 increased slightly among black women (0.9 percent/year). Seroprevalence of HSV-2 decreased significantly over time among women of all races; however, rates per year decreased substantially less for black women relative to white women.

The authors note that the decline in HSV-2 seroprevalence does not necessarily avert the potential for neonatal herpes, a rare but serious complication. “Women who are seronegative entering pregnancy and acquire HSV during late pregnancy are at higher risk for transmission of HSV to their infants than seropositive women.”
(doi:10.1001/jama.2014.9237; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, AUGUST 19, 2014
Media Advisory: To contact corresponding author Jennifer M. Puck, M.D., email Juliana Bunim at juliana.bunim@ucsf.edu. To contact editorial author Neil A. Holtzman, M.D., M.P.H., call Ekaterina Pesheva at 410-502-9433 or email epeshev1@jhmi.edu.

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Study Examines Incidence, Survival Rate of Severe Immunodeficiency Disorder in Newborns

Newborn screening performed in numerous states indicates that the incidence of the potentially life-threatening disorder, severe combined immunodeficiency, is higher than previously believed, at 1 in 58,000 births, although there is a high rate of survival, according to a study in the August 20 issue of JAMA.

The purpose of newborn screening is early detection of inborn conditions for which prompt treatments can reduce the risk of death or irreversible damage. The first heritable immune disorders to which newborn screening has been applied are those that together comprise severe combined immunodeficiency (SCID), a disorder that can result in life-threatening infections, making early detection and treatment critical. Population-based screening is the only means to detect SCID prior to the onset of infections in most cases. The incidence of SCID has been estimated to be 1 in 100,000 births. SCID was added to the national recommended uniform panel for newborn screened disorders in 2010, and currently 23 states, the District of Columbia, and the Navajo Nation screen approximately two-thirds of all infants born in the United States for SCID, according to background information in the article.

Antonia Kwan, Ph.D., M.R.C.P.C.H., of the University of California, San Francisco, and colleagues conducted the first combined analysis of more than 3 million infants screened for SCID in 10 states and the Navajo Nation. Infants born from the start of each participating program from January 2008 through the most recent evaluable date prior to July 2013 were included.

There were 52 SCID cases identified during the study period, an overall incidence of 1 in 58,000 births. The incidence was not significantly different in any state program but was higher in the Navajo Nation (1/3,500), attributed to a genetic mutation found in this population. Survival of SCID-affected infants through their diagnosis and immune reconstitution was 87 percent, 92 percent for infants who received transplantation, enzyme replacement, and/or gene therapy. Additional interventions for SCID and non-SCID T-cell lymphopenia (abnormally low level of certain white blood cells) included immunoglobulin infusions, preventive antibiotics, and avoidance of live vaccines.

“These findings support the view that SCID has previously been underdiagnosed in infants with fatal infections,” the authors write.

“Now that infants with SCID are being detected at a very young age in diverse medical settings, it is imperative to tailor protocols for their treatment, including choice and pharmacokinetic monitoring of drugs administered to facilitate hematopoietic cell engraftment.”
(doi:10.1001/jama.2014.9132; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Newborn Screening for Severe Combined Immunodeficiency
Progress and Challenges

“Infants born with SCID in the 27 states that do not screen for SCID have a greater chance of not being detected promptly, or at all, and are at increased risk of dying, compared with those born in the 23 states that do screen for SCID,” writes Neil A. Holtzman, M.D., M.P.H., of the Johns Hopkins Medical Institutions, Baltimore, in an accompanying editorial.

“Although many states require their own pilot programs before a new screening test is added to their battery of tests, no state could amass as much data in a reasonable time frame as have Kwan et al. Before screening becomes universal in the United States, agreement is needed on what constitutes a positive T-cell receptor excision circle [a biomarker used to help identify SCID] screening test, on ensuring referrals to physicians competent to make a diagnosis, and on providing definitive therapy to every infant detected with SCID in every state.”
(doi:10.1001/jama.2014. 9133; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, AUGUST 19, 2014
Media Advisory: To contact Suzanne Schuh, M.D., F.R.C.P.C., call Matet Nebres at 416-813-6380 or email matet.nebres@sickkids.ca. To contact editorial co-author Robert Vinci, M.D., email Jenny Eriksen Leary at Jenny.Eriksen@bmc.org.

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Findings Suggest Over-Reliance on Pulse Oximetry for Determining Whether Children With Respiratory Infection Should Be Hospitalized

Among infants presenting to a pediatric emergency department with mild to moderate bronchiolitis, those with an artificially elevated oxygen saturation reading were less likely to be hospitalized or receive hospital care for more than 6 hours than those with unaltered readings, suggesting that these readings should not be the only factor in the decision to admit or discharge, according to a study in the August 20 issue of JAMA.

Bronchiolitis, a viral lower respiratory tract infection, is the leading cause of infant hospitalizations in the United States, with annual costs in excess of $1 billion. Between 1980 and 2000, the rate of hospitalizations for bronchiolitis more than doubled. Pulse oximetry, which involves an instrument usually attached on the finger or ear lobe, is a noninvasive method of measuring oxygen saturation, and its routine use has been associated with changes in the management of bronchiolitis. There is no evidence that certain cutoff measurements predict progression from relatively mild to severe bronchiolitis, according to background information in the article. “If well-appearing children with mild to moderate bronchiolitis can be sent home, fewer hospitalizations and lower health care costs could result.”

Suzanne Schuh, M.D., F.R.C.P.C., of The Hospital for Sick Children, Toronto, and colleagues conducted a randomized clinical trial to determine if increasing the displayed oximetry reading three percentage points above the true values would decrease the probability of hospitalization within 72 hours or hospital care for greater than 6 hours. The study included 213 otherwise healthy infants 4 weeks to 12 months of age with mild to moderate bronchiolitis in a tertiary-care pediatric emergency department in Toronto.

The researchers found that 41 percent (44/108) of children in the true oximetry group were hospitalized within 72 hours, compared with 25 percent (26/105) in the altered oximetry group. There were 23 of 108 (21.3 percent) subsequent unscheduled medical visits for bronchiolitis in the true oximetry group and 15 of 105 (14.3 percent) in the altered oximetry group.

“Artificially increasing the oximetry display in emergency department patients with mild to moderate bronchiolitis by a physiologically small amount significantly reduced hospitalizations within 72 hours or active hospital care for more than 6 hours compared with infants with unaltered oximetry readings. This conclusion also held true after adjustment for other variables significantly associated with this outcome. Because the groups had similar severity and the adjustment for the experimental saturation resulted in lack of primary treatment effect, the difference in displayed saturations was likely the primary reason for the observed reduction in hospitalizations,” the authors write.

The researchers add that these findings suggest “that oxygen saturation should not be the only factor in the decision to admit, and its use may need to be re-evaluated.”
(doi:10.1001/jama.2014.8637; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Bronchiolitis, Deception in Research, and Clinical Decision Making

In an accompanying editorial, Robert Vinci, M.D., of the Boston University School of Medicine, and Howard Bauchner, M.D., Editor in Chief, JAMA, comment on the findings of this study.

“… it is now clear that the oxygen saturation reading can influence decision making in ways that many clinicians have thought likely—overreliance on physiologic information of uncertain importance derived from a medical device. While physicians seek to improve the science of clinical decision making, the art of medicine and clinical assessment should not be trumped by overreliance on a single physiologic parameter. The care of patients with bronchiolitis will continue to improve as experienced physicians emphasize and continue to use a complete clinical evaluation and assessment as the most important element in the care of these infants and children.”
(doi:10.1001/jama.2014.8638; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, AUGUST 19, 2014
Media Advisory: To contact Nancy A. Rigotti, M.D., call Terri Ogan at 617-726-0954 or email togan@partners.org.

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Intervention Helps Smokers Quit Following Hospital Stay

Among hospitalized adult smokers who wanted to quit, a postdischarge intervention that included automated telephone calls and free medication resulted in higher sustained smoking cessation rates at six months than standard postdischarge advice to use smoking cessation medication and counseling, according to a study in the August 20 issue of JAMA.

Cigarette smoking is the leading preventable cause of death in the United States. For the nearly 4 million smokers hospitalized each year, a hospital stay offers a good opportunity to quit smoking because all hospitals are now smoke-free, requiring patients to abstain temporarily from tobacco use. The major challenge for hospitals in providing evidence­based care is identifying how to sustain tobacco treatment after discharge, according to background information in the article.

Nancy A. Rigotti, M.D., of Massachusetts General Hospital, Boston, and colleagues randomly assigned 397 hospitalized daily smokers (average age, 53 years) who wanted to quit smoking after discharge to sustained or standard tobacco treatment care. Sustained care participants (n = 198) received automated interactive voice response telephone calls and their choice of free smoking cessation medication (any type approved by the U.S. Food and Drug Administration) for up to 90 days. The automated telephone calls promoted cessation, provided medication management, and triaged smokers for additional counseling. Standard care participants (n = 199) received recommendations for postdischarge pharmacotherapy and counseling.

The researchers found that more participants in the sustained care group than in the standard care group achieved the primary outcome of biochemically confirmed past 7-day tobacco abstinence (using saliva samples to measure a nicotine metabolite) at 6-month follow-up (26 percent vs 15 percent, respectively). Sustained care also resulted in higher self-reported continuous abstinence rates for 6 months after discharge (27 percent vs 16 percent for standard care).

“[This] trial demonstrated the effectiveness of a program to promote long-term tobacco cessation among hospitalized cigarette smokers who received an inpatient tobacco dependence intervention and expressed an interest in cessation treatment after discharge. The intervention aimed to sustain the tobacco cessation treatment that had begun in the hospital. It succeeded in improving the use of both counseling and pharmacotherapy by smokers after discharge, and it increased by 71 percent the proportion of patients with biochemically confirmed tobacco abstinence 6 months after discharge, which is a standard measure of long-term smoking cessation. The intervention appeared to be effective across abroad range of smokers and provided high-value care at a relatively low cost,” the authors write.

“These findings, if replicated, suggest a translatable, low-cost approach to achieving sustained smoking cessation after a hospital stay.”
(doi:10.1001/jama.2014.9237; Available pre-embargo to the media at https://media.jamanetwork.com)

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

For related articles on this subject, please see our tobacco control theme issue from earlier this year, available at this link.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, AUGUST 12, 2014
Media Advisory: To contact Agnes Dechartres, M.D., Ph.D., email agnes.dechartres@htd.aphp.fr. To contact editorial co-author Robert M. Golub, M.D., call Jim Michalski at 312-464-5785 or email jim.michalski@jamanetwork.org.

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Approach Used to Conduct Meta-Analyses May Affect Outcomes

Depending on the analysis strategy used, estimating treatment outcomes in meta­analyses may differ and may result in major alterations in the conclusions derived from the analysis, according to a study in the August 13 issue of JAMA.

Meta-analyses of randomized clinical trials (RCTs) are generally considered to provide among the best evidence of efficacy of medical interventions. They should be conducted as part of a systematic review, a scientifically rigorous approach that identifies, selects, and appraises all relevant studies. Which trials to combine in a meta­analysis remains a persistent dilemma. Meta-analysis of all trials may produce a precise but biased estimate, according to background information in the article.

Agnes Dechartres, M.D., Ph.D., of the Centre de Recherche Epidemiologie et Statistique, INSERM U1153, Paris, and colleagues compared treatment outcomes estimated by meta-analysis of all trials and several alternative strategies for analysis: single most precise trial (i.e., trial with the narrowest confidence interval), meta-analysis restricted to the 25 percent largest trials, limit meta-analysis (a meta-analysis model adjusted for small-study effect), and meta-analysis restricted to trials at low overall risk of bias. The researchers included 163 meta-analyses published between 2008 and 2010 in high-impact-factor journals and between 2011 and 2013 in the Cochrane Database of Systematic Reviews: 92 (705 RCTs) with subjective outcomes and 71 (535 RCTs) with objective outcomes.

The researchers found that treatment outcome estimates differed depending on the analytic strategy used, with treatment outcomes frequently being larger with meta-analysis of all trials than with the single most precise trial, meta-analysis of the largest trials, and limit meta­analysis. The difference in treatment outcomes between these strategies was substantial in 47 of 92 (51 percent) meta-analyses of subjective outcomes and in 28 of 71 (39 percent) meta-analyses of objective outcomes. The authors did not find any difference in treatment outcomes by overall risk of bias.

“In this study, we compared meta-analysis of all trials with several ‘best­evidence’ alternative strategies and found that estimated treatment outcomes differed depending on the strategy used. We cannot say which strategy is the best because … we cannot know with 100 percent certainty the truth in any research question. Nevertheless, our results raise important questions about meta-analyses and outline the need to re­think certain principles,” the researchers write.

“We recommend that authors of meta-analyses systematically assess the robustness of their results by performing sensitivity analyses. We suggest the comparison of the meta-analysis result to the result for the single most precise trial or meta­analysis of the largest trials and careful interpretation of the meta-analysis result if they disagree.”
(doi:10.1001/jama.2014.8166; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Meta-analysis as Evidence – Building a Better Pyramid

Jesse A. Berlin, Sc.D., of Johnson & Johnson, Titusville, N.J., and Robert M. Golub, M.D., Deputy Editor, JAMA, write in an accompanying editorial that “findings such as those in the study by Dechartres et al reinforce concerns that journals and readers have about meta­analysis as a study design. Those findings deserve consideration not only in the planning of the studies but in the journal peer review and evaluation. They also reinforce the need for circumspection in study interpretation.”

“Meta-analysis has the potential to be the best source of evidence to inform decision making. The underlying methods have become much more sophisticated in the last few decades, but achieving this potential will require continued advances in the underlying science, parallel to the advances that have occurred with other biomedical research design and statistics. Until that occurs, an informed reader must approach these studies, as with all other literature, as imperfect information that requires critical appraisal and assessment of applicability of the findings to individual patients. This is not easy, and it requires skill and intelligence. Whatever clinical evidence looks like, and wherever it is placed on a pyramid, there are no shortcuts to truth.”
(doi:10.1001/jama.2014.8167; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, AUGUST 12, 2014
Media Advisory: To contact corresponding author K. E. Juhani Airaksinen, M.D., Ph.D., email juhani.airaksinen@tyks.fi.

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Delay in Correcting Irregular Cardiac Rhythm From Atrial Fibrillation Associated With Increased Risk of Complications

A delay of 12 hours or longer to correct an abnormal cardiac rhythm from atrial fibrillation was associated with a greater risk of thromboembolic complications such as stroke, according to a study in the August 13 issue of JAMA.

In 1995, practice guidelines recommended a limit of 48 hours after the onset of atrial fibrillation (AF) for cardioversion (the conversion of a cardiac rhythm from abnormal to normal) without anticoagulation. Whether the risk of thromboembolic complications is increased when cardioversion without anticoagulation is performed in less than 48 hours is unknown, according to background information in the article.

Ilpo Nuotio, M.D., Ph.D., of Turku University Hospital, Turku, Finland and colleagues conducted a study that included patients with a successful cardioversion in the emergency department within the first 48 hours of AF. The primary outcome, a thromboembolic event, was defined as a clinical stroke or systemic embolism (blood clot) within 30 days after cardioversion. Procedures were divided into groups according to the time to cardioversion: less than 12 hours (group 1), 12 hours to less than 24 hours (group 2), and 24 hours to less than 48 hours (group 3).

Of 2,481 patients with acute AF, 5,116 successful cardioversions were performed without anticoagulation. Thirty­eight thromboembolic events occurred in 38 patients (0.7 percent); 31were strokes. The incidence of thromboembolic complications increased from 0.3 percent in group 1 to 1.1 percent in group 3. In analysis, time to cardioversion longer than 12 hours was an independent predictor for thromboembolic complications.
(doi:10.1001/jama.2014.3824; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, AUGUST 12, 2014
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Experiencing Atrial Fibrillation While Hospitalized For Surgery Associated With Increased Long-Term Risk of Stroke

In a study that included 1.7 million patients undergoing inpatient surgery, experiencing atrial fibrillation while hospitalized was associated with an increased long-term risk of ischemic stroke, especially following noncardiac surgery, according to a study in the August 13 issue of JAMA.

Atrial fibrillation (AF) and flutter affect more than 33 million people worldwide. The presence of chronic AF confers a 3-fold increased risk of stroke. Perioperative (around the time of surgery) atrial fibrillation may be viewed as a transient response to physiological stress, and the long-term risk of stroke after perioperative atrial fibrillation is unclear, according to background information in the article.

Gino Gialdini, M.D., of Weill Cornell Medical College, New York, and colleagues conducted a study to determine the long-term risk of ischemic stroke after perioperative AF of patients undergoing surgery, using administrative claims data from California acute care hospitals between 2007 and 2011. For this study, perioperative was defined as AF newly diagnosed during the hospitalization for surgery.

The study included 1,729,360 eligible patients with an average follow-up time of 2.1 years. Among these patients, perioperative AF was documented in 24,711 cases (1.43 percent). After discharge from the index hospitalization for surgery, 13,952 patients (0.81 percent) went on to experience an ischemic stroke. At 1 year after hospitalization for noncardiac surgery, cumulative rates of stroke were 1.47 percent in those with perioperative AF and 0.36 percent in those without AF. At 1 year after cardiac surgery, cumulative rates of stroke were 0.99 percent in those with perioperative AF and 0.83 percent in those without AF.

Analyses indicated that perioperative AF after noncardiac surgery was associated with twice the risk of stroke and a 30 percent greater risk after cardiac surgery.

“Our results may have significant implications for the care of perioperative patients. The associations we found suggest that while many cases of perioperative AF after cardiac surgery may be an isolated response to the stress of surgery, perioperative AF after noncardiac surgery may be similar to other etiologies of AF in regard to future thromboembolic risk. Our results suggest the need for future studies involving long-term ambulatory cardiac monitoring to better delineate the risk associated with transient vs persistent perioperative AF, as well as randomized clinical trials to determine optimal strategies for antithrombotic therapy in patients with perioperative AF and a significant burden of other risk factors for stroke,” the authors write.
(doi:10.1001/jama.2014.9143; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, AUGUST 12, 2014
Media Advisory: To contact Øyvind Holme, M.D., email oyvind.holme@sshf.no. To contact editorial author Allan S. Brett, M.D., email Matt Splett at matt.splett@uscmed.sc.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.8266. This will be the link to the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.8613.

Flexible Sigmoidoscopy Screening Reduces Colorectal Cancer Incidence, Rate of Death

Among about 100,000 study participants, screening with flexible sigmoidoscopy resulted in a reduced incidence and rate of death of colorectal cancer, compared to no screening, according to a study in the August 13 issue of JAMA.

Colorectal cancer is the third most commonly occurring cancer worldwide. Most colorectal cancer cases develop from adenomas (benign tumors). Removal of adenomas by colonoscopy or flexible sigmoidoscopy (a thin flexible lighted tube used for inspection of the inside of the rectum and lower part of the colon) has been endorsed as a primary prevention tool for colorectal cancer, according to background information in the article.

Øyvind Holme, M.D., of the Sorlandet Hospital Kristiansand, Kristiansand, Norway and colleagues randomly assigned study participants in Norway to receive once-only flexible sigmoidoscopy (n=10, 283); a combination of once-only flexible sigmoidoscopy and fecal occult blood testing (FOBT; n=10,289), or no intervention (control group; n=78,220). Screening was performed in 1999-2000 (55-64-year age group) and in 2001 (50-54-year age group), with follow-up ending December 2011. Participants with positive screening test results were offered colonoscopy.

After a median of 11 years, 71 participants died of colorectal cancer in the screening groups vs 330 in the control group. Colorectal cancer was diagnosed in 253 participants in the screening groups vs 1,086 in the control group. Analysis of the data indicated that compared to no screening, flexible sigmoidoscopy screening reduced colorectal cancer incidence by 20 percent (absolute difference, 28.4 cases/100,000 person years) and colorectal cancer mortality by 27 percent (absolute difference, 11.7 deaths/100,000 person years). There was no significant difference in these outcomes between the flexible sigmoidoscopy only vs the flexible sigmoidoscopy and FOBT screening groups.

Younger participants 50 to 54 years of age seemed to benefit at least as much from the screening interventions as older participants ages 55 to 64 years.
(doi:10.1001/jama.2014.8266; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Flexible Sigmoidoscopy for Colorectal Cancer Screening
More Evidence, Persistent Ironies

In an accompanying editorial, Allan S. Brett, M.D., of the University of South Carolina School of Medicine, Columbia, S.C., writes that while there may be debate over the use of flexible sigmoidoscopy or colonoscopy for colorectal cancer screening, another screening technique, stool DNA testing, might render this debate moot in the not-too­distant future.

“A large, recently published study examined the performance of a multitarget stool test that identifies several DNA abnormalities associated with colorectal cancer or precancerous adenomas. With colonoscopy as the reference standard, the sensitivity of the stool DNA test was 92 percent for detecting cancer and 42 percent for detecting advanced precancerous lesions; specificity was 90 percent. Notably, the stool DNA test was much more sensitive than a separate fecal immunochemical test for hemoglobin performed for each participant. Repeated at some defined interval, stool DNA testing has potential to reduce colorectal cancer mortality substantially while sharply reducing the number of routine colonoscopies. For now, however, the muddled landscape of colorectal cancer screening in the United States continues, and the place of flexible sigmoidoscopy among screening tools remains unsettled.”
(doi:10.1001/jama.2014.8613; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, AUGUST 5, 2014
Media Advisory: To contact corresponding author Wen-Hung Chung, M.D., Ph.D., email chung1@cgmh.org.tw; to contact Shuen-Iu Hung, Ph.D., email sihung@ym.edu.tw.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.7859.

Study Identifies Genetic Variants Associated with Severe Skin Reactions to Commonly Used Antiepileptic Drug

Researchers have identified genetic variants that are associated with severe adverse skin reactions to the antiepileptic drug phenytoin, according to a study in the August 6 issue of JAMA.

Phenytoin is a widely prescribed antiepileptic drug and remains the most frequently used first-line antiepileptic drug in hospitalized patients. Although effective for treating neurological diseases, phenytoin can cause cutaneous (skin) adverse reactions ranging from mild to severe. The pharmacogenomic basis of phenytoin-related severe cutaneous adverse reactions has not been known, according to background information in the article.

Wen-Hung Chung, M.D., Ph.D., of Chang Gung Memorial Hospital, Keelung, Taiwan, and colleagues investigated the genetic factors associated with phenytoin-related severe cutaneous adverse reactions. The case-control study was conducted in 2002-2014 among 105 cases with phenytoin-related severe cutaneous adverse reactions (n=61 Stevens-Johnson syndrome/toxic epidermal necrolysis and n=44 drug reactions with eosinophilia and systemic symptoms), 78 cases with maculopapular exanthema (a less severe type of rash), 130 phenytoin-tolerant control participants, and 3,655 population controls from Taiwan, Japan, and Malaysia. A genome-wide association study (GWAS) was conducted using the samples from Taiwan. The initial GWAS included samples of 60 cases with phenytoin-related severe cutaneous adverse reactions and 412 population controls from Taiwan.

Analysis of the data indicated that variants of the gene CYP2C, including CYP2C9*3, were associated with phenytoin-related severe cutaneous adverse reactions. The statistically significant association between CYP2C9*3, known to reduce drug clearance (the elimination of a drug from the body), and phenytoin-related severe cutaneous adverse reactions was replicated by the samples from Taiwan, Japan, and Malaysia, with a meta-analysis showing an 11 times higher odds of experiencing this reaction with this variant. Delayed clearance of plasma phenytoin was detected in patients with severe cutaneous adverse reactions, especially CYP2C9*3 carriers, providing a clinical link of the associated variants to the disease.

Delayed clearance was also noted in patients with severe cutaneous adverse reactions without CYP2C9*3, suggesting that nongenetic factors such as renal insufficiency, hepatic dysfunction, and concurrent use of substances that compete or inhibit the enzymes may also affect phenytoin metabolism and contribute to severe cutaneous adverse reactions.

“This study identified CYP2C variants, including CYP2C9*3, known to reduce drug clearance, as important genetic factors associated with phenytoin-related severe cutaneous adverse reactions. These findings may have potential to improve the safety profile of phenytoin in clinical practice and offer the possibility of prospective testing for preventing phenytoin-related severe cutaneous adverse reactions. More research is required to replicate the genetic association in different populations and to determine the test characteristics and clinical utility,” the authors conclude.
(doi:10.1001/jama.2014.7859; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, AUGUST 5, 2014
Media Advisory: To contact corresponding author Maurizio Gasparini, M.D., email maurizio.gasparini@humanitas.it.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.4783.

Using Long-Detection Interval for ICDs Associated With Reduction in Hospitalizations, Costs

Use of implantable cardioverter-defibrillators (ICDs) programmed with long-detection intervals for ventricular arrhythmias was associated with an increase in the time to first hospitalization and reductions in hospitalization rate, length of stay and costs, compared with standard interval programming, according to a study in the August 6 issue of JAMA.

An ICD programming strategy that allows delayed detection of arrhythmias has been shown to reduce unnecessary and inappropriate therapies. Alessandro Proclemer, M.D., of the Azienda Ospedaliera Universitaria S. Maria della Misericordia, Udine, Italy, and colleagues assessed the association of programming a long-detection interval on hospitalizations, length of stay (LOS) in the hospital and costs. The researchers analyzed data from the ADVANCE III study, a trial conducted at 94 international centers between 2008 and 2010 in which 1,902 patients receiving their first ICD were randomized to a long-detection interval group (n = 948; the number of intervals to detect arrhythmias was programmed at 30 of 40) or a standard interval group (n = 954; 18 of 24 intervals).

During 12 months of follow-up, 546 patients reported 865 overall hospitalizations (473 hospitalizations in 302 patients in the standard interval group and 392 hospitalizations in 244 patients in the long-detection interval group). The long-detection interval group was associated with a longer time to the first overall hospitalization and cardiovascular hospitalization compared with the standard interval group, and reductions in overall hospitalization rate and LOS, without difference in the rate of death.

Similar results were found for cardiovascular hospitalization rates and LOS. The long-detection interval group was also associated with an average reduction of $299 per patient-year for overall hospitalizations and $329 per patient-year for cardiovascular hospitalizations, compared with the standard interval group.

“These favorable results for resource use complement the demonstrated clinical effectiveness of the long-detection interval strategy and come without additional costs for the hospitals or patients,” the authors write.
(doi:10.1001/jama.2014.4783; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The ADVANCE III study was supported by Medtronic 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: 3 P.M. (CT) TUESDAY, AUGUST 5, 2014
Media Advisory: To contact Arthur R. H. van Zanten, M.D., Ph.D., email zantena@zgv.nl. To contact editorial author Todd W. Rice, M.D., M.Sc., email Craig Boerner at craig.boerner@Vanderbilt.Edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.7698. This will be the link for the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.7699.

Enriching Feeding Tube Nutrition With Immune-Modulating Nutrients Does Not Reduce Risk of Infection Among ICU Patients

Among mechanically ventilated intensive care unit (ICU) patients, receipt of high-protein nutrition via a feeding tube enriched with immune-modulating nutrients (such as glutamine, omega-3 fatty acids, and antioxidants) vs standard high-protein nutrition did not result in a significant difference in the incidence of new complications and may be harmful, as suggested by an increased risk of death at 6 months, according to a study in the August 6 issue of JAMA.

Several meta-analyses have reported that use of immune-modulating nutrients in enteral (via feeding tube) nutrition is associated with reductions in illness from infections and improved recovery from critical illness compared with standard enteral nutrition. However, there is a lack of consensus in guidelines regarding enteral administration of immune-modulating nutrients, according to background information in the article.

Arthur R. H. van Zanten, M.D., Ph.D., of the Gelderse Vallei Hospital, Ede, the Netherlands, and colleagues randomly assigned 301 adult ICU patients who were expected to be ventilated and to require enteral nutrition for more than 72 hours to either immune-modulating nutrients (IMHP) (n = 152) or high-protein enteral nutrition (HP) (n = 149). The patients were from 14 ICUs in the Netherlands, Germany, France, and Belgium. Patients were followed for up to six months.

The researchers found that there were no significant differences in the incidence of new infections between groups. Overall, 53 percent of those in the IMHP group vs 52 percent in the HP group had new infections. No significant differences were observed in outcomes such as mechanical ventilation duration, ICU and hospital lengths of stay, and a measure of organ failure. The 6-month mortality rate was higher in the medical subgroup: 54 percent in the IMHP group vs 35 percent in the HP group.

“These findings do not support the use of high-protein enteral nutrition enriched with immune-modulating nutrients in these patients,” the authors conclude.
(doi:10.1001/jama.2014.7698; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Nutricia Advanced Medical Nutrition, Nutricia Research, Utrecht, the Netherlands was the study sponsor. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Immunonutrition in Critical Illness – Limited Benefit, Potential Harm

Todd W. Rice, M.D., M.Sc., of the Vanderbilt University School of Medicine, Nashville, Tenn., writes in an accompanying editorial that many questions surrounding immunonutrition remain unanswered.

“Are there specific critically ill populations that may benefit from some immunomodulation or supplementation of individual immunomodulating agents, such as glutamine supplementation in burns or vitamin D replacement in severe sepsis? Does administration of multiple potential immunologic modulating agents together alter the individual effects of each agent? Combined administration in a single formula or supplement in all of these trials prevents implicating any single component (i.e., omega-3 fatty acids, glutamine, or antioxidants). In addition, enteral and parenteral [intravenous] administration may result in differential effects. Although these uses of immunomodulating nutrition still need to be explored, the similarity of the results and the suggestion of harm from recently published, large, randomized trials of immunonutrition should strongly discourage intensivists from its routine prescription for critically ill patients in clinical practice outside the scope of well-designed randomized clinical trials.”
(doi:10.1001/jama.2014.7699; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, AUGUST 5, 2014
Media Advisory: To contact Peter Roy-Byrne, M.D., call 206-386-3103. To contact Richard Saitz, M.D., email Lisa Chedekel at chedekel@bu.edu. To contact editorial co-author Ralph Hingson, Sc.D., M.P.H., call the NIAAA Press Office at 301-443-3860 or email NIAAAPressOffice@mail.nih.gov.

To place an electronic embedded link to these studies in your story This link for the first study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.7860. This will be the link for the 2nd study: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.7862. This will be the link for the editorial: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.7863.

Studies Find Brief Interventions Ineffective for Reducing Unhealthy, Problem Drug Use

Two studies in the August 6 issue of JAMA examine the effectiveness of using brief interventions in primary care settings to reduce drug use.

In one study, Peter Roy-Byrne, M.D., formerly of the University of Washington, Seattle, and colleagues write that few data exist on the effectiveness of brief (1-2 sessions) interventions for reducing problem drug use, a common issue in disadvantaged populations seeking care in safety-net medical settings (hospitals and community health clinics serving low-income patients with limited or no insurance). Based on the established efficacy of brief interventions for hazardous alcohol use among patients seen in medical settings, national dissemination programs of screening, brief intervention, and referral to treatment for “alcohol and drugs” have been implemented on a widespread scale, according to background information in the article.

The researchers randomly assigned 868 patients from 7 safety-net primary care clinics in Washington State who had reported problem drug use in the past 90 days to a single brief intervention (n = 435) or enhanced care as usual, which included a handout and list of substance abuse resources (n = 433). The single brief intervention included a handout and list of substance abuse resources along with giving participants feedback about their drug use screening results, exploring the pros and cons of drug use, increasing participant confidence in being able to change, and discussing options for change. In addition, attempts were made for a 10-minute follow-up session by telephone within 2 weeks of the initial intervention. The patients were assessed for drug use at the beginning of the study, and at 3, 6, 9, and 12 months.

Average days used of the most common problem drug at baseline were 14.40 (brief intervention) and 13.25 (enhanced care as usual); at 3 months postintervention, averages were 11.87 (brief intervention) and 9.84 (enhanced care as usual) and not significantly different. During the 12 months following intervention, no significant treatment differences were found between the two groups for drug use or for secondary outcomes, which included admission to substance abuse treatment, emergency department and inpatient hospital admissions, arrests, death and behavior that increases risk of human immunodeficiency virus transmission.

The authors write that these “finding suggests a need for caution in promoting widespread adoption of this intervention for drug use in primary care.”

“… further research to identify subgroups responsive to this intervention, as well as the role of more intensive interventions, appears to be warranted. For example, targeting intervention efforts toward individuals with severe drug abuse, many of whom use stimulants and opiates and may be at higher risk of overdose and other harmful consequences, might increase the uptake of specialty treatment and reduce emergency department utilization.”
(doi:10.1001/jama.2014.7860; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by a grant from the National Institute on Drug Abuse. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

In another study, Richard Saitz, M.D., of the Boston University School of Public Health, and colleagues tested the effectiveness of two brief counseling interventions for unhealthy drug use (any illicit drug use or prescription drug misuse) among primary care patients identified by screening.

The United States has invested substantially in screening and brief intervention for illicit drug use and prescription drug misuse, based in part on evidence of efficacy for unhealthy alcohol use. However, it is not a recommended universal preventive service in primary care because of lack of evidence of efficacy, according to background information in the article.

The researchers randomly assigned 528 adult primary care patients with unhealthy drug use to one of three groups: to receive a brief negotiated interview (BNI), which was a 10- to 15-minute structured interview conducted by health educators; an adaptation of motivational interviewing (MOTIV), which was a 30- to 45-minute intervention based on motivational interviewing with a 20- to 30-minute booster conducted by masters-level counselors; or no brief intervention. All study participants received a written list of substance use disorder treatment and mutual help resources. At the beginning of the study, 63 percent of participants reported their main drug was marijuana, 19 percent cocaine, and 17 percent opioids.

For the primary outcome (number of days of use in the past 30 days of the self-identified main drug), there were no significant differences between the BNI, MOTIV or control groups (adjusted average days using the main drug at 6 months, 11, 12 and 12 days, respectively). In addition, there were no significant between-group differences overall or in stratified analyses at 6 weeks or 6 months in drug use consequences, injection drug use, unsafe sex, health care utilization (hospitalizations and emergency department visits, overall or for addiction or mental health reasons), or mutual help group attendance.

The authors write that despite the potential for benefit with a brief intervention, drug use differs from unhealthy alcohol use in that it is often illegal and socially unacceptable, and is diverse—from occasional marijuana use, which was illegal during this study, to numerous daily heroin injections. “Prescription drug misuse is particularly complex, with diagnostic confusion between misuse for symptoms (e.g., pain, anxiety), euphoria-seeking, and drug diversion. Brief counseling may simply be inadequate to address these complexities, even as an initial strategy.”

“These results do not support widespread implementation of illicit drug use and prescription drug misuse screening and brief intervention.”
(doi:10.1001/jama.2014.7862; Available pre-embargo to the media at https://media.jamanetwork.com)

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

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, August 5 at this link.

Editorial: Screening and Brief Intervention and Referral to Treatment for Drug Use in Primary Care – Back to the Drawing Board

In an accompanying editorial, Ralph Hingson, Sc.D., M.P.H., of the National Institute on Alcohol Abuse and Alcoholism, Bethesda, Md., and Wilson M. Compton, M.D., M.P.E., of the National Institute on Drug Abuse, Rockville, Md., comment on the findings of these studies.

“Although these studies offer no direct evidence of effectiveness for universal drug screening, brief intervention, and referral to treatment in primary care settings, exploring drug use with patients should remain a priority in primary care. The goal for clinical research is to develop and test new interventions with potential for benefiting patients. Drug screening and brief intervention research that focuses on adolescents and young adults is especially needed because rates of marijuana use among young people and the potency of marijuana have increased at the same time that recognition among youth of the health risks of marijuana use have declined.”

“If brief interventions are insufficient, then easily accessible treatment services with long-term follow-up may be needed, as will development of efficient primary care referral approaches to address risky substance use and related physical and mental comorbidities.”
(doi:10.1001/jama.2014.7863; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 10 A.M. (CT) TUESDAY, JULY 22, 2014
Media Advisory: To contact Jason D. Wright, M.D., email Lucky Tran at cumcnews@columbia.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.9005

Among women undergoing a minimally invasive hysterectomy using electric power morcellation, uterine cancers were present in 27 per 10,000 women at the time of the procedure, according to a study published by JAMA. There has been concern that this procedure, in which the uterus is fragmented into smaller pieces, may result in the spread of undetected malignancies.

Despite the commercial availability of electric power morcellators for 2 decades, accurate estimates of the prevalence of malignancy at the time of electric power morcellation (in this study referred to as morcellation) have been lacking, according to background information in the article.

Jason D. Wright, M.D., of the Columbia University College of Physicians and Surgeons, New York, and colleagues used a large insurance database to investigate the prevalence of underlying cancer in women who underwent uterine morcellation. The database includes more than 500 hospitals capturing 15 percent of hospitalizations.

The researchers identified 232,882 women who underwent minimally invasive hysterectomy from 2006-2012; morcellation was performed in 36,470 (15.7 percent). Among those who underwent morcellation, 99 cases of uterine cancer were identified at the time of the procedure, a prevalence of 27/10,000. Other malignancies and precancerous abnormalities were also detected. Among women who underwent morcellation, advanced age was associated with underlying cancer and endometrial hyperplasia (a condition characterized by overgrowth of the lining of the uterus).

“Although morcellators have been in use since 1993, few studies have described the prevalence of unexpected pathology at the time of hysterectomy. Prevalence information is the first step in determining the risk of spreading cancer with morcellation,” the authors write. “Patients considering morcellation should be adequately counseled about the prevalence of cancerous and precancerous conditions prior to undergoing the procedure.”
(doi:10.1001/jama.2014.9005; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 10 P.M. (CT) SUNDAY, JULY 20, 2014
Media Advisory: To contact Harsha Thirumurthy, Ph.D., call David Pesci at 919-962-2600 or email dpesci@email.unc.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.9087

Among uncircumcised men in Kenya, compensation in the form of food vouchers worth approximately U.S. $9 or $15, compared with lesser or no compensation, resulted in a modest increase in the prevalence of circumcision after 2 months, according to a study published by JAMA. The study is being released to coincide with its presentation at the International AIDS Conference.

Following randomized trials that demonstrated that medical male circumcision reduces men’s risk of HIV acquisition by 50 percent to 60 percent, UNAIDS and the World Health Organization recommended the scale-up of voluntary medical male circumcision (VMMC) in 14 countries in eastern and southern Africa. Despite considerable scale-up efforts, most countries are far short of target goals. Novel strategies are needed to increase VMMC uptake. Potential barriers include concerns about lost wages during and after the procedure, according to background information in the article.

Harsha Thirumurthy, Ph.D., of the University of North Carolina at Chapel Hill, and colleagues studied 1,504 uncircumcised men (25 to 49 years of age) in Nyanza region, Kenya, who were randomly assigned to 1 of 3 intervention groups or a control group. Participants in the intervention groups received varying amounts of compensation conditional on VMMC uptake at 1 of 9 study clinics within 2 months of enrollment. Compensation took the form of food vouchers worth approximately U.S. $2.50, $8.75, or $15, which reflected a portion of transportation costs and lost wages associated with getting circumcised. The control group received no compensation.

The researchers found VMMC uptake within 2 months was higher in the $8.75 group (6.6 percent [25 of 381]) and the $15 group (9.0 percent [34 of 377]) than in the $2.50 group (1.9 percent [7 of 374]) and the control group (1.6 percent [6 of 370]). Further analysis indicated that compared with participants in the control group, those in the $15 and $8.75 groups were significantly more likely to get circumcised; those enrolled in the $2.50 group were not. The difference in VMMC uptake between the $8.75 and $15 groups was not significant.

“There was also a significant increase in VMMC uptake among married and older participants, groups that have been harder to reach previously. The interventions also significantly increased the likelihood of circumcision uptake among participants at higher risk of acquiring HIV. This latter result is especially promising from an HIV prevention standpoint,” the authors write.

“The overall increase in VMMC uptake within 2 months, as a result of providing compensation, was modest, with an increase of at most 7.4 percent in the U.S. $15.00 group. This increased uptake was in a population with an estimated circumcision prevalence of 35.6 percent. Evaluation of scaled-up implementation of the intervention is needed to determine whether it will help achieve higher circumcision coverage over longer periods of time.”
(doi:10.1001/jama.2014.9087; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 10 A.M. (CT) SATURDAY, JULY 19, 2014
Media Advisory: To contact corresponding author Steven K. Grinspoon, M.D., call Cassandra Aviles at 617-724-6433 or email cmaviles@partners.org.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.8334

In a preliminary study, HIV-infected patients with excess abdominal fat who received the growth hormone-releasing hormone analog tesamorelin for 6 months experienced modest reductions in liver fat, according to a study in the July 23/30 issue of JAMA, a theme issue on HIV/AIDS. Patients infected with HIV demonstrate a high prevalence of nonalcoholic fatty liver disease, estimated at 30 percent to 40 percent. The issue is being released early to coincide with the International AIDS Conference.

In human immunodeficiency virus (HIV) infection, abdominal fat accumulation is associated with ectopic (out of place) fat accumulation in the liver. Nonalcoholic fatty liver disease (NAFLD) may progress to end-stage liver disease and liver cancer. To date, there are no approved pharmacologic strategies to reduce liver fat. Tesamorelin specifically targets abdominal fat reduction but its effects on liver fat are unknown, according to background information in the article.

Takara L. Stanley, M.D., of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues randomly assigned 50 antiretroviral-treated HIV-infected men and women with abdominal fat accumulation to receive tesamorelin (n=28), or placebo (n=22), subcutaneously daily for 6 months.

The researchers found a modest but statistically significant decrease in liver fat with tesamorelin. Hepatic lipid to water percentage (a measure of liver fat), decreased in the tesamorelin group (median, -2.0 percent) compared with placebo (median, 0.9 percent). In addition, there was a significant reduction in abdominal fat: the average change was -9.9 percent with tesamorelin vs 6.6 percent with placebo.

“The decrease in liver fat in this study suggests that strategies to reduce visceral adiposity merit further investigation in HIV-infected patients with NAFLD, a condition for which there are no approved treatments. Importantly, NAFLD is associated with visceral adiposity and other metabolic abnormalities in HIV,” the authors write.

“Further studies are needed to determine the clinical importance and long-term consequences of these findings.”
(doi:10.1001/jama.2014.8334; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 10 A.M. (CT) SATURDAY, JULY 19, 2014
Media Advisory: To contact corresponding author Jared M. Baeten, M.D., Ph.D., call Bobbi Nodell at 206-543-7129 or email bnodell@uw.edu. To contact editorial co-author David A. Cooper, M.D., D.Sc., email dcooper@kirby.unsw.edu.au.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.8735

Among heterosexual African couples in which the male was HIV positive and the female was not, receipt of antiretroviral pre-exposure preventive (PrEP) therapy did not result in significant differences in pregnancy incidence, birth outcomes, and infant growth compared to females who received placebo, according to a study in the July 23/30 issue of JAMA, a theme issue on HIV/AIDS. The authors note that these findings do not provide a definitive conclusion regarding the safety of PrEP therapy prior to pregnancy. The issue is being released early to coincide with the International AIDS Conference.

Antiretroviral pre-exposure prophylaxis as daily oral tenofovir disoproxil fumarate (TDF) and co-formulated emtricitabine/tenofovir disoproxil fumarate (FTC+TDF) has been demonstrated to be efficacious for the prevention of human immunodeficiency virus (HIV) acquisition in diverse populations. PrEP could be an important component of safer conception strategies for women at risk for HIV infection, including those in HIV-serodiscordant couples (i.e., in which only one member is HIV infected), but the effect on pregnancy outcomes is not well defined, according to background information in the article.

Nelly R. Mugo, M.B.Ch.B., M.P.H., of the Kenya Medical Research Institute, Nairobi, Kenya, and University of Washington, Seattle, and colleagues conducted further follow-up of the Partners PrEP Study, a randomized, placebo-controlled trial of PrEP for HIV prevention among HIV-serodiscordant couples conducted between July 2008 and June 2013. For this analysis, which included 1,785 couples in Kenya and Uganda, the researchers assessed pregnancy incidence and outcomes among women using PrEP during the periconception period. Females had been randomized to daily oral TDF (n = 598), combination FTC+TDF (n = 566), or placebo (n = 621) through July 2011, when PrEP demonstrated efficacy for HIV prevention. Thereafter, participants continued receiving active PrEP without placebo.

A total of 431 pregnancies occurred. The researchers found that pregnancy incidence did not differ significantly by study group, and that there was no statistically significant association between women receiving PrEP and those receiving placebo and the occurrence of pregnancy losses, which was 42.5 percent for women receiving FTC+TDF, 32.3 percent for those receiving placebo, and 27.7 percent for those receiving TDF alone. After July 2011 (when the placebo group was discontinued), the frequency of pregnancy loss was 37.5 percent for FTC+TDF and 36.7 percent for TDF alone.

Occurrence of preterm birth, congenital anomalies, kidney function and growth throughout the first year of life did not differ significantly for infants born to women who received PrEP vs placebo.

The authors write that for some outcomes, including pregnancy loss, preterm birth, congenital anomalies, and infant mortality, confidence intervals were wide (suggesting uncertainty in the result and the need for more data), including both a null effect and potential harm, and thus definitive statements about safety of PrEP in the periconception period cannot be made.

“These results should be discussed with HIV-uninfected women receiving PrEP who are considering becoming pregnant.”
(doi:10.1001/jama.2014.8735; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Integrating HIV Prevention Into Practice

Bradley M. Mathers, M.B.Ch.B., M.D., and David A. Cooper, M.D., D.Sc., of the University of New South Wales, Sydney, Australia, comment on the findings of this study in an accompanying editorial.

“… it appears (from the magnitude and asymmetry of the confidence intervals) that there may be a signal suggesting potential harm as pregnancy loss based on the emtricitabine/tenofovir vs placebo comparison (absolute difference ending in pregnancy loss of 10.2 percent) and on the post hoc emtricitabine/tenofovir vs tenofovir alone comparison (absolute difference ending in pregnancy loss of 9.2 percent).”

“These intriguing findings reported by Mugo et al provide important information from one of the largest studies of exposure to these nucleoside analogues in HIV-negative persons and therefore must be considered carefully. Tenofovir and emtricitabine are both category B drugs, but this signal suggesting a possible association with pregnancy loss has not to date appeared in studies of HIV-infected persons, suggesting that this observation deserves evaluation in future studies. Moreover, the nucleosides were stopped according to the trial protocol no later than 6 weeks into the pregnancy, albeit this period is highly sensitive to subsequent adverse pregnancy outcomes, but exposure to these drugs may be longer in the real-world setting.”
(doi:10.1001/jama.2014.8606; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 10 A.M. (CT) SATURDAY, JULY 19, 2014
Media Advisory: To contact Peter MacPherson, Ph.D., email petermacp@gmail.com.

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Among adults in the African country of Malawi offered HIV self-testing, optional home initiation of care compared with standard HIV care resulted in a significant increase in the proportion of adults initiating antiretroviral therapy, according to a study in the July 23/30 issue of JAMA, a theme issue on HIV/AIDS. The issue is being released early to coincide with the International AIDS Conference.

In 2012, an estimated 35 million individuals were infected with the human immunodeficiency virus (HIV) worldwide. Antiretroviral therapy (ART) substantially reduces the risk of HIV transmission as well as greatly reducing illness and death, raising hopes that high uptake of annual HIV testing and early initiation of ART could improve HIV prevention as well as care. Achieving high coverage of HIV testing in sub-Saharan African countries is a major challenge, with low rates of HIV testing, according to background information in the article.

Self-testing for HIV infection (defined as individuals performing and interpreting their HIV test in private) is a novel approach that has seen high acceptance in Malawi and the United States, and is a process that could overcome barriers to conventional facility-based and community-based HIV testing, which lack privacy and convenience. However, no studies in high HIV prevalence settings have investigated linkage into HIV care after HIV self-testing, the authors write.

Peter MacPherson, Ph.D., of the Liverpool School of Tropical Medicine, Liverpool, U.K., and colleagues randomly assigned 16,660 adult residents of Blantyre, Malawi, who received access to home HIV self-testing, to facility-based care or optional home initiation of HIV care, for those reporting positive HIV self-test results.

During 6 months of availability, 58 percent of the adult residents took an HIV self-test kit. Participants in the home group (6.0 percent) were significantly more likely to report a positive HIV self-test result than facility group participants (3.3 percent). A significantly greater proportion of adults in the home group initiated ART (181/8,194; 2.2 percent) compared with the facility group (63/8,466; 0.7 percent).

“The main finding of this cluster randomized trial was that population-level ART initiations were significantly increased by availability of home initiation of care,” the authors write.

“At a time when universal test and treat approaches to controlling the HIV epidemic are being considered, home initiation of HIV care shows high promise as a simple strategy to improve uptake of ART when HIV self-testing is carried out at home.”
(doi:10.1001/jama.2014.6493; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR EARLY RELEASE: 10 A.M. (CT) SATURDAY, JULY 19, 2014
Media Advisory: To contact Mark S. Sulkowski, M.D., call Lauren Nelson at 410-955-8725 or email lnelso35@jhmi.edu. To contact editorial co-author Michael S. Saag, M.D., email Nicole Wyatt at nwyatt@uab.edu.

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HIV-infected patients also infected with hepatitis C virus (HCV) who received a combination of the medications sofosbuvir plus ribavirin had high rates of sustained HCV virologic response 12 weeks after cessation of therapy, according to a study in the July 23/30 issue of JAMA, a theme issue on HIV/AIDS. The issue is being released early to coincide with the International AIDS Conference.

Up to 7 million persons worldwide are infected with both human immunodeficiency virus (HIV) and hepatitis C virus. Treatment of this coinfection has been limited due to the need to use interferon (an antiviral protein used to treat HCV) and drug interactions with antiretroviral therapies (ARTs), according to background information in the article.

Mark S. Sulkowski, M.D., of Johns Hopkins University, Baltimore, and colleagues evaluated the rates of sustained virologic response (SVR) (what is clinically considered “cure”) and adverse events in 223 patients infected with HIV and HCV (genotypes 1, 2, or 3) who were treated with an interferon-free combination of the drugs sofosbuvir and ribavirin for 12 or 24 weeks. The trial was conducted at 34 treatment centers in the United States and Puerto Rico from August 2012 to November 2013.

Among participants with no prior treatment for HCV, 76 percent with genotype 1, 88 percent with genotype 2, and 67 percent with genotype 3 achieved SVR12 (serum HCV <25 copies/mL 12 weeks after cessation of HCV therapy). Among patients who had previously received treatment, 92 percent with genotype 2 and 94 percent with genotype 3 achieved SVR12. Seven patients (3 percent) discontinued HCV treatment due to adverse events, of which the most common were fatigue, insomnia, headache, and nausea. No adverse effect on HIV disease or its treatment was observed. “In this open-label, nonrandomized, uncontrolled study, HIV-infected patients with HCV genotypes 1, 2, or 3 coinfection who received an oral combination of sofosbuvir plus ribavirin for 12 or 24 weeks had high rates of sustained HCV virologic response 12 weeks after cessation of therapy,” the authors write. “Further studies of this regimen in more diverse populations of coinfected patients are needed.” (doi:10.1001/jama.2014.7734; Available pre-embargo to the media at https://media.jamanetwork.com) Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc. There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 10 a.m. CT Saturday, July 19 at this link. [ama_toc_item id="24027"] Editorial: Quantum Leaps, Microeconomics, and the Treatment of Patients With Hepatitis C and HIV Coinfection Michael S. Saag, M.D., of the University of Alabama School of Medicine, Birmingham, writes in an accompanying editorial that although this study (PHOTON-l) represents a quantum leap forward in the treatment of patients coinfected with HIV and HCV, the current cost of the regimen makes wide-spread use unaffordable. “When combined with ribavirin, the average wholesale price of a 12- week course of treatment is $94,500 and $189,000 for a 24-week course, as used in the PHOTON-l study. Industry analysts indicate that the pricing of the drug is not based on the cost of ingredients or the duration of therapy, but rather the ‘cost per cure.’ With more than 185 million HCV seropositive people worldwide with HCV infection and with 4.4 million HCV seropositive persons in the United States, the world simply cannot afford to pay on a ‘cost per cure’ basis, especially when the majority of persons with chronic infection, an estimated 75 percent, do not progress to cirrhosis or end-stage liver disease over 20 to 30 years.” “Hopefully, competition among the new products coming to market in the next 18 months will result in substantially lower pricing for the drugs. Indeed, the release of the new products will be, perhaps for the first time, a genuine test of whether there is a free market, microeconomic system in the pharmaceutical industry.” (doi:10.1001/jama.2014.7734; Available pre-embargo to the media at https://media.jamanetwork.com) Editor’s Note: Please see the article for additional information, including financial disclosures, funding and support, etc. # # #

EMBARGOED FOR EARLY RELEASE: 10 A.M. (CT) SATURDAY, JULY 19, 2014
Media Advisory: To contact Anna Satcher Johnson, M.P.H., call the CDC’s news media line at 404-639-8895 or email NCHHSTPMediaTeam@cdc.gov.

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The annual HIV diagnosis rate in the U.S. decreased more than 30 percent from 2002-2011, with declines observed in several key populations, although increases were found among certain age groups of men who have sex with men, especially young men, according to a study in the July 23/30 issue of JAMA, a theme issue on HIV/AIDS. The issue is being released early to coincide with the International AIDS Conference.

“There has been increasing emphasis on care and treatment for persons with human immunodeficiency virus (HIV) in the United States during the past decade, including the use of antiretroviral therapy for increasing survival and decreasing transmission. Accurate HIV diagnosis data recently became available for all states, allowing for the first time an examination of long-term national trends. These data can be used to monitor awareness of serostatus among persons living with HIV, primary prevention efforts, and testing initiatives,” according to background information in the article.

Anna Satcher Johnson, M.P.H., of the Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention (CDC), Atlanta, and colleagues examined trends in HIV diagnoses from 2002-2011 among persons ages 13 years or older in the United States, using data from the National HIV Surveillance System of the CDC. All data were collected through routine HIV surveillance mandated by laws or regulations in the 50 states and the District of Columbia.

During 2002-2011, 493,372 persons were diagnosed with HIV in the United States. The annual diagnosis rate decreased by 33.2 percent, from 24.1 per 100,000 population in 2002 to 16.1 in 2011. Statistically significant decreases in diagnosis rates over time were found in nearly every demographic population with the largest changes observed in women, persons 35-44 years of age, and persons of multiple races. Changes were not evident for Asians or Native Hawaiians/other Pacific Islanders. The annual number of HIV diagnoses decreased in persons with infection attributed to injection drug use or to heterosexual contact.

From 2002-2011, diagnoses attributed to male-to-male sexual contact remained stable overall, increasing among males 13-24, 45-54, and 55 years or older, and decreasing among males 35-44 years of age. The largest change (132.5 percent increase) was observed among males 13-24 years of age.

The authors note that because of delays in diagnosis, trends in diagnoses and variations among groups may reflect earlier changes in HIV infection rates. They add that this study is limited in that trends in diagnoses can be influenced by changes in testing patterns. “The HIV testing services were expanded during the analysis period and early outcomes of testing initiatives often indicate increases in diagnoses until some level of testing saturation occurs. Our study found overall decreases in annual diagnosis rates despite the implementation of testing initiatives during the period of analysis.”

“Among men who have sex with men, unprotected risk behaviors in the presence of high prevalence and unsuppressed viral load may continue to drive HIV transmission. Disparities in rates of HIV among young men who have sex with men present prevention challenges and warrant expanded efforts.”
(doi:10.1001/jama.2014.8534; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The CDC provides funds to all states and the District of Columbia to conduct the HIV surveillance data used in this study. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 15, 2014

Media Advisory: To contact corresponding author Jacques-Eric Gottenberg, M.D., Ph.D., email jacques-eric.gottenberg@chru-strasbourg.fr; to contact Xavier Mariette, M.D., Ph.D., email xavier.mariette@bct.aphp.fr.

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Among patients with the systemic autoimmune disease primary Sjögren syndrome, use of hydroxychloroquine, the most frequently prescribed treatment for the disorder, did not improve symptoms during 24 weeks of treatment compared with placebo, according to a study in the July 16 issue of JAMA.

Primary Sjögren syndrome is characterized by mouth and eye dryness, pain, and fatigue, with systemic manifestations occurring in approximately one-third of patients. Despite the wide use of hydroxychloroquine in clinical practice, evidence regarding its efficacy is limited, according to background information in the article.

Jacques-Eric Gottenberg, M.D., Ph.D., of the Universite de Strasbourg, Strasbourg, France, and colleagues randomly assigned 120 patients with primary Sjögren syndrome to receive hydroxychloroquine or placebo for 24 weeks. All patients (treatment and placebo) were prescribed hydroxychloroquine between weeks 24 and 48.  The study was conducted at 15 university hospitals in France.

At 24 weeks, the proportion of patients meeting the primary end point (30 percent or greater reduction in 2 of 3 scores evaluating dryness, pain, and fatigue) was 17.9 percent (10/56) in the hydroxychloroquine group and 17.2 percent (11/64) in the placebo group. Use of hydroxychloroquine was also not associated with improvement in certain lab tests used to monitor the activity of Sjögren (anti-SSA antibodies, IgG levels).  During the first 24 weeks, there were 2 serious adverse events in the hydroxychloroquine group and 3 in the placebo group. In the last 24 weeks, there were 3 in the hydroxychloroquine group and 4 in the placebo group.

“In the present study, hydroxychloroquine did not demonstrate efficacy for the main disabling symptoms—dryness, pain, and fatigue—of primary Sjögren syndrome compared with placebo. [This trial] extends the negative results of the only previous controlled crossover trial, which included 19 patients and confirms that previous open trials might have overestimated the therapeutic efficacy of hydroxychloroquine in primary Sjögren syndrome,” the authors write.

“Further studies are needed to evaluate longer-term outcomes.”

(doi:10.1001/jama.2014.7682; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 15, 2014

Media Advisory: To contact co-author Amit X. Garg, M.D., Ph.D., email Julia Capaldi at Julia.Capaldi@LawsonResearch.com.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.2934

A study that included about 15,000 physicians found that they were more likely to be registered as an organ donor compared to the general public, according to a study in the July 16 issue of JAMA.

A shortage of organs for transplant has prompted many countries to encourage citizens to register (“opt in”) to donate their organs and tissues when they die. However, less than 40 percent of the public is registered for organ donation in most countries with a registry. “One common fear is that physicians will not take all measures to save the life of a registered citizen at a time of illness. Showing that many physicians are registered for organ donation themselves could help dispel this myth. Although most physicians in surveys support organ donation, whether they are actually registered remains unknown,” according to background information in the article.

Alvin Ho-ting Li, B.H.Sc., of Western University, London, Ontario, Canada, and colleagues used various databases to determine the proportion of physicians (n = 15,233), the general public (n = 10,866,752) or matched citizens (n = 60,932) of Ontario, Canada who were registered for deceased organ donation.  Matched citizens were a comparison group with similar backgrounds as physicians and matched to each physician by age, sex, income, and neighborhood.

A total of 6,596 physicians (43.3 percent) were registered, a significantly higher proportion than matched citizens (29.5 percent) or the general public (23.9 percent). Physicians were 47 percent more likely to be registered for organ and tissue donation than matched citizens. Similar to factors associated with registration in nonphysicians, younger physicians and women were more likely to register.

Among those registered for organ donation, 11.7 percent of physicians, 14.3 percent of matched citizens, and 16.8 percent of the general public excluded at least 1 organ or tissue from donation.

The authors note that future research should determine if these findings are generalizable to other countries.

(doi:10.1001/jama.2014.2934; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 15, 2014

Media Advisory: To contact Mads E. Jørgensen, M.B., email mads.emil.joergensen@regionh.dk.

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In an analysis that included more than 480,000 patients who underwent elective noncardiac surgery, a history of stroke was associated with an increased risk of major adverse cardiovascular events and death, particularly if time elapsed between stroke and surgery was less than 9 months, according to a study in the July 16 issue of JAMA.

Noncardiac surgeries performed in patients with a recent heart attack or stent implantation have been associated with increased risk of perioperative cardiac events, as well as stent thrombosis (blood clot), and bleeding compared with patients with more distant heart attack or stent placement. Whether a similar time-dependent relationship exists for stroke has not been known, and recommendations on timing of surgery in patients with prior stroke in current perioperative guidelines are sparse, according to background information in the article.

Mads E. Jørgensen, M.B., of the University of Copenhagen, Denmark, and colleagues investigated the association between prior stroke (including time elapsed between stroke and surgery) and the risk of major adverse cardiovascular events (MACE, including ischemic stroke, heart attack, and cardiovascular death) and all-cause death up to 30 days after surgery in a group of Danish patients who underwent noncardiac elective surgery (n = 481,183 surgeries) from 2005-2011.

Crude incidence rates of MACE among patients with (n = 7,137) and without (n = 474,046) prior stroke were 54.4 vs 4.1 respectively, per 1,000 patients. Further analysis indicated:

• Prior ischemic stroke, irrespective of time between ischemic stroke and surgery, was associated with an adjusted 1.8- and 4.8-fold increased relative risk of 30-day mortality and 30-day MACE, respectively, compared with patients without prior stroke.

• A strong time-dependent relationship between prior stroke and adverse postoperative outcome, with patients experiencing a stroke less than 3 months prior to surgery at particularly high risk. After 9 months, the associated risk appeared stable yet still increased compared with patients with no stroke.

• Low- and intermediate-risk surgeries seemed to pose at least the same relative risk of MACE in patients with recent stroke compared with high-risk surgery.

“Our findings need to be confirmed but may warrant consideration in future perioperative guidelines,” the authors conclude.

(doi:10.1001/jama.2014.8165; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 15, 2014

Media Advisory: To contact Kurt Kroenke, M.D., email Lisa Welch at llwelch@regenstrief.org. To contact editorial co-author Gary E. Rosenthal, M.D., email Tom Moore at thomas-moore@uiowa.edu.

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A telephone-delivered intervention, which included automated symptom monitoring, produced clinically meaningful improvements in chronic musculoskeletal pain compared to usual care, according to a study in the July 16 issue of JAMA.

Pain is the most common symptom reported both in the general population and patients seen in primary care, the leading cause of work disability, and a condition that costs the United States more than $600 billion each year in health care and lost productivity. Musculoskeletal pain accounts for nearly 70 million outpatient visits annually in the United States each year. Telemedicine strategies for pain care have been proposed but not rigorously tested to date, according to background information in the article.

Kurt Kroenke, M.D., of Roudebush VA Medical Center, Indiana University School of Medicine, and the Regenstrief Institute, Indianapolis, and colleagues randomly assigned 250 patients with chronic musculoskeletal pain to an intervention group (n = 124) or to a usual care group whose members received all pain care as usual from their primary care physicians (n = 126). The intervention group received 12 months of telecare management that included automated symptom monitoring with an algorithm-guided approach to optimizing pain medications.

Among the key results of the trial:

• Patients in the intervention group were nearly twice as likely to report at least a 30 percent improvement in their pain score by 12 months (51.7 percent vs 27.1 percent);

• The intervention was associated with clinically meaningful improvements in pain and a greater rate of improvement (56 percent vs 31 percent);

• Patients in the usual care group were almost twice as likely to experience worsening of pain by 6 months compared with those in the intervention group (36 percent vs 19 percent);

• Few patients in either group were started on opioids or had escalations in their opioid dose during the study period;

• Patients in the intervention group were also more likely to rate as good to excellent the medication prescribed for their pain (73.9 percent vs 50.9 percent) as well as the overall treatment of their pain (76.7 percent vs 51.6 percent).

“The intervention was effective, even though most trial participants reported pain that had been present for many years, that involved multiple sites, and that had been unsuccessfully treated with numerous analgesics,” the authors write. “The improvement in pain with minimal opioid initiation or dose escalation is noteworthy, given increasing concerns about the consequences of long-term opioid use.”

The researchers add that the results of this trial, along with findings from a previous trial conducted among patients with cancer, show that algorithm-guided optimization of pain medication can be efficiently delivered through a predominantly telephone and Internet-based approach.

(doi:10.1001/jama.2014.7689; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial – Advancing Telecare for Pain Treatment in Primary Care

Michael E. Ohl, M.D., M.S.P.H., and Gary E. Rosenthal, M.D., of the University of Iowa Carver College of Medicine, Iowa City, comment on this study in an accompanying editorial.

“Historically, implementation of collaborative care innovations—such as collaborative care for depression—has been slow. However, there is reason to believe that telecare for chronic pain can be more rapidly implemented into routine practice. Adoption of collaborative care for depression was hindered by the fee-for-service payment system, which favors procedures and in-person physician visits over team-based and between-visit care. Recent movement toward reimbursement for telehealth and between-visit care may make telecare for pain management more attractive to primary care practices.”

“In summary, Kroenke et al describe a promising telecare strategy that may enhance the ability of primary care practices to effectively treat patients with chronic pain. Additional studies are required to determine the generalizability, sustainability, and cost-effectiveness of this strategy and to assess how it may best be incorporated within primary care practices.”

(doi:10.1001/jama.2014.7690; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 15, 2014

Media Advisory: To contact corresponding author Josef Coresh, M.D., Ph.D., call Stephanie Desmon at 410-955-7619 or email sdesmon1@jhu.edu. To contact editorial co-author Ralph L. Sacco, M.D., call Lisa Worley at 305-243-5184 or email lworley2@med.miami.edu.

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In a study that included a large sample of black and white U.S. adults from several communities, rates of stroke incidence and subsequent death decreased from 1987 to 2011, with decreases varying across age-groups, according to a study in the July 16 issue of JAMA.

Stroke ranks fourth among all causes of death in the U.S. and is recognized as a leading cause of serious physical and cognitive long-term disability in adults. Almost 800,000 Americans suffer a stroke each year, and over 600,000 of them are first-ever events. Stroke incidence varies by gender and ethnic group, according to background information in article.

Silvia Koton, Ph.D., of Johns Hopkins University School of Public Health, Baltimore, and colleagues examined trends in stroke incidence and subsequent death among black and white adults in the Atherosclerosis Risk in Communities (ARIC) cohort, a study of 15,792 residents in four communities in the U.S., ages 45 to 64 years at baseline (1987-1989). The communities were Minneapolis, Washington County, Md., Forsyth County, N.C., and Jackson, Mississippi. For this analysis, the researchers followed-up on 14,357 participants free of stroke at baseline for all stroke hospitalizations and deaths from 1987 to 2011.

During the study period, there were 1,051 (7 percent) participants with incident stroke. The researchers found a significant decrease in stroke incidence from 1987 to 2011 in both whites and blacks as well as men and women, but this decrease was seen only above age 65 years, with younger participants experiencing stable stroke incidence rates.

Of participants with incident stroke, 614 (58 percent) died through 2011, with analysis indicating a decrease in mortality during the last two decades, mostly due to a decrease among participants younger than 65 years. This decrease was generally similar in men and women and by race.

The authors speculate that “more successful control of risk-factors in the last decades, mainly hypertension control starting in the 1970s, and later, hypertension treatment combined with smoking cessation, control of diabetes and dyslipidemia, and treatment of atrial fibrillation may have resulted in lower stroke incidence and less severe strokes, which may account for the observed lower case-fatality rates.”

(doi:10.1001/jama.2014.7692; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial – Declining Stroke Incidence and Improving Survival in U.S. Communities

Evidence for Success and Future Challenges

“Whether the decline in stroke incidence and mortality will continue in older age groups is still speculative, and the absence of a decline in younger age groups could be an early warning sign,” write Ralph L. Sacco, M.D., and Chuanhui Dong, M.D., Ph.D., of the University of Miami, in an accompanying editorial.

“Although there has been significant progress in reducing smoking and lowering blood pressure and cholesterol, formidable challenges to address stroke disparities and successfully control risk factors and lifestyle behaviors across race, ethnicity, and regions persist. Unless health disparities are addressed and innovative strategies to change behavior are developed and adopted, the cerebrovascular health of the population will be unlikely to improve. Greater improvements in brain health, especially with controllable risk factors such as diet, exercise, smoking, and obesity, among younger segments of the population are required to reduce the risk of stroke and enhance the chance of successful cognitive aging for all adults.”

(doi:10.1001/jama.2014.7693; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 8, 2014

Media Advisory: To contact Danny Dvir, M.D., call Dave Lefebvre at 604-682-2344, ext. 66987; or email Dlefebvre@providencehealth.bc.ca.

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In an analysis of about 460 patients with failed bioprosthetic aortic valves who underwent transcatheter valve-in-valve implantation, overall survival at one year was 83 percent, with survival associated with surgical valve size and mechanism of failure, according to a study in the July 9 issue of JAMA.

Surgical aortic valve replacements increasingly use bioprosthesis (composed of biological tissue) implants rather than mechanical valves. Owing to a considerable shift toward bioprosthesis implantation, it is expected that there will be an increase in the number of patients with degeneration of these types of valves. Treatment of patients with failed bioprostheses is a clinical challenge; although reoperation is considered the standard of care, these patients are frequently elderly and have other medical conditions, and repeat cardiac surgery can pose significant illness and risk of death. Transcatheter aortic valve-in-valve implantation is a less invasive approach, however a comprehensive evaluation of survival after the procedure has not previously been performed, according to background information in the article.

Danny Dvir, M.D., of St. Paul’s Hospital, Vancouver, Canada, and colleagues evaluated survival of 459 patients after transcatheter valve-in-valve implantation inside failed surgical bioprosthetic valves using a multinational registry. The patients (average age, 78 years) underwent implantation between 2007 and May 2013 at 55 centers.

Reasons for bioprosthesis failure were stenosis (narrowing of the valve opening; 39.4 percent), regurgitation (backflow of blood through the orifice of the valve due to imperfect closing; 30.3 percent), and combined stenosis and regurgitation (30.3 percent). The overall 1-year survival rate was 83.2 percent.

Patients in the stenosis group had worse 1-year survival (76.6 percent) in comparison with the regurgitation group (91.2 percent) and the combined group (83.9 percent). Similarly, patients with small valves (≤ 21 mm) had worse 1-year survival (74.8 percent) compared with larger valves.

“Thorough assessment of candidates for valve-in-valve implantation is a key step to obtain optimal results. The current analysis highlights the need for meticulous evaluation of bioprosthesis mechanism of failure before attempting a valve-in-valve procedure,” the authors write.

(doi:10.1001/jama.2014.7246; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 8, 2014

Media Advisory: To contact Pouya Iranmanesh, M.D., email pouya.iranmanesh@hcuge.ch.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.7587

Among patients with possible common duct stones, removal of the gall bladder, compared with endoscopic assessment of the common duct followed by gall bladder removal, resulted in a shorter length of hospital stay without increased illness and fewer common duct examinations, according to a study in the July 9 issue of JAMA.

Many common duct stones eventually pass into the duodenum (a section of the small intestine just below the stomach), making preoperative common duct investigations unnecessary. Conversely, a strategy of gall bladder removal first can lead to the discovery of a retained common duct stone during surgery. It is uncertain what is the best initial strategy for treating this condition, according to background information in the article.

Pouya Iranmanesh, M.D., of Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland, and colleagues randomly assigned 100 patients with possible common duct stones to undergo immediate laparoscopic cholecystectomy (gall bladder removal) with intraoperative cholangiogram (an imaging technique using a dye injection to evaluate the common duct) or endoscopic common duct evaluation followed by cholecystectomy, with patient follow-up of 6 months.

Patients who underwent cholecystectomy as a first step (study group) had a significantly shorter median length of hospital stay (5 days vs 8 days) compared to patients in the control group. In addition, the total number of common duct investigations (various procedures to look for stones in the common duct) performed in the study group was smaller (25 vs 71). Overall, complications were observed in 8 percent of patients in the study group and 14 percent in the control group. There was no significant difference in illness or quality of life measures between groups.

The authors note that overall, 60 percent of patients in the study group did not need any common duct investigation after the intraoperative cholangiogram. “Thus, many intermediate-risk patients undergo unnecessary preoperative common duct procedures.”

The researchers add that although a thorough cost analysis was beyond the scope of this study, the significantly shorter length of hospital stay and fewer common duct investigations in the study group, coupled with the similar complication rates between the 2 groups, predicts substantial savings when using a cholecystectomy-first strategy.

“If these findings are confirmed, initial cholecystectomy with intraoperative cholangiogram may be a preferred approach,” the authors conclude.

(doi:10.1001/jama.2014.7587; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 8, 2014

Media Advisory: To contact Nikolai Madrid Scheller, M.B., email nmscheller@gmail.com.

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Although some data has suggested a potential association between receipt of the quadrivalent human papillomavirus (HPV) vaccination and subsequent venous thromboembolism (VTE; blood clot), an analysis that included more than 500,000 women who received the vaccine did not find an increased risk of VTE, according to a study in the July 9 issue of JAMA.

“Safety concerns can compromise immunization programs to the detriment of public health, and timely evaluations of such concerns are essential,” the authors write.

Nikolai Madrid Scheller, M.B., of Statens Serum Institut, Copenhagen, Denmark, and colleagues used data from Danish national registers to evaluate the potential link between quadrivalent HPV vaccination and VTE. Information on vaccination, use of oral contraceptives, use of anticoagulants (blood thinners), and the outcome of a first hospital diagnosis of VTE not related to pregnancy, surgery, or cancer was obtained from Danish registers.

The study included all Danish women, ages 10 through 44 years, from October 2006 through July 2013 (n = 1,613,798), including 500,345 (31 percent) who received the quadrivalent HPV vaccine; there were 4,375 incident cases of VTE. Of these, 889 women (20 percent) were vaccinated during the study period. Analysis of the data did not find an association between the quadrivalent HPV vaccine and VTE during the 42 days following vaccination (defined as the main risk period).

“Our results, which were consistent after adjustment for oral contraceptive use and in girls and young women as well as mid-adult women, do not provide support for an increased risk of VTE following quadrivalent HPV vaccination,” the researchers write.

(doi:10.1001/jama.2014.2198; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 8, 2014

Media Advisory: To contact Jean Marc Regimbeau, M.D., Ph.D., email regimbeau.jean-marc@chu-amiens.fr. To contact editorial author Joseph S. Solomkin, M.D., call Katy Cosse at 513-558-0207 or email kathryn.cosse@uc.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.7586

Among patients who underwent gall bladder removal for acute calculous cholecystitis, lack of postoperative antibiotic treatment did not result in a greater incidence of infections, according to a study in the July 9 issue of JAMA.

Acute calculous cholecystitis (inflamed and enlarged gall bladder along with abdominal pain) is the third most frequent cause of emergency admissions to surgical wards. In the United States, approximately 750,000 cholecystectomies (surgical removal of the gall bladder) are performed each year and about 20 percent of these operations are due to acute calculous cholecystitis. Many patients receive postoperative antibiotics with the intent to reduce subsequent infections, although there is limited information from controlled studies demonstrating benefit, according to background information in the article.

Jean Marc Regimbeau, M.D., Ph.D., of the Amiens University Medical Center, Amiens, France, and colleagues randomly assigned 414 patients with mild or moderate acute calculous cholecystitis to continue with a preoperative antibiotic regimen (amoxicillin plus clavulanic acid) or receive no antibiotics after cholecystectomy. The study was conducted at 17 medical centers between May 2010 and August 2012.

The researchers found that the postoperative infection rates were 17 percent in the nontreatment group and 15 percent in the antibiotic group. In a per protocol analysis involving 338 patients, the corresponding rates were both 13 percent. Based on a noninferiority (not worse than) margin of 11 percent established for this trial, the lack of postoperative antibiotic treatment was not associated with worse outcomes than antibiotic treatment. The two groups of patients had similar length of hospital stay and readmission rates.

The authors note that guidelines published by the Infectious Diseases Society of America and the World Society of Emergency Surgery recommend treatment with amoxicillin plus clavulanic acid or sulbactam after cholecystectomy for noncomplicated acute calculous cholecystitis. “In the present series, we did not observe a benefit of postoperative antibiotic treatment on infections for patients with [mild or moderate] acute calculous cholecystitis.”

“It is well known that continuation of antibiotic treatment increases costs and promotes the selection of multiresistant bacteria. In 2010, 37,499 cholecystectomies for acute calculous cholecystitis were performed in France, and 90 percent of these were for grades I and II [mild or moderate] acute calculous cholecystitis. Supposing that these patients did not really need postoperative antibiotics (which are generally prescribed for 5 days), we estimate that many days of antibiotic treatment could be avoided each year. Reduction of the use of unnecessary antibiotics is important given that there is an increasing antibiotic resistance and a higher incidence of antibiotic complications such as Clostridium difficile infection. Our study demonstrates that postoperative antibiotics following acute calculous cholecystitis are not necessary.”

(doi:10.1001/jama.2014.7586; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Clinical Trial Evidence to Advance the Science of Cholecystectomy

 Joseph S. Solomkin, M.D., of the University of Cincinnati College of Medicine, Cincinnati, writes in an accompanying editorial that the two cholecystectomy-related trials in this issue provide important new evidence to better inform surgeons performing this procedure; “however, both studies have a frequently encountered limitation of surgical trials—lack of blinding. In many surgical trials, blinding is not possible, or in some cases, as with sham procedures, blinding may raise important ethical considerations.”

“Blinding in randomized trials avoids physician and patient perceptions of efficacy from influencing protocol adherence or outcome assessment. Blinding is usually associated with random treatment assignment, and the treating physician, the patient, and the outcome assessor do not know what intervention the patient received. Blinding and randomization minimize the risk of conscious and unconscious bias in clinical trials (performance bias) and interpretation of outcomes (ascertainment bias).”

Dr. Solomkin notes that randomized trials, even if blinding is not possible, contribute greatly to evidence-based recommendations for clinical practice guidelines. “The clinical trials by Regimbeau et al and Iranmanesh et al provide useful data that help answer important questions about the management of patients undergoing cholecystectomy.”

(doi:10.1001/jama.2014.7588; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 8, 2014

Media Advisory: To contact Coenraad F. N. Koegelenberg, M.D., Ph.D., email coeniefn@sun.ac.za.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.7195.

Combining the smoking cessation medication varenicline with nicotine replacement therapy was more effective than varenicline alone at achieving tobacco abstinence at 6 months, according to a study in the July 9 issue of JAMA.

The combination of behavioral approaches and pharmacotherapy are of proven benefit in assisting smokers to quit. Combining nicotine replacement therapy (NRT) with varenicline has been a suggested treatment to improve smoking abstinence, but its effectiveness is uncertain, according to background information in the article.

Coenraad F. N. Koegelenberg, M.D., Ph.D., of Stellenbosch University, Cape Town, South Africa, and colleagues randomly assigned 446 generally healthy smokers to nicotine or placebo patch treatment 2 weeks before a target quit date (TQD) and continued for an additional 12 weeks. Varenicline was begun 1 week prior to TQD, continued for a further 12 weeks, and tapered off during week 13. The study was conducted in 7 centers in South Africa from April 2011 to October 2012; 435 participants were included in the efficacy and safety analyses.

The researchers found that participants who received active NRT and varenicline were more likely to achieve continuous abstinence from smoking (confirmed by exhaled carbon monoxide measurements) at 12 weeks (55.4 percent vs 40.9 percent) and 24 weeks (49.0 percent vs 32.6 percent) and point prevalence abstinence (a measure of abstinence based on behavior at a particular point in time) at six months (65.1 percent vs 46.7 percent) than those receiving placebo NRT and varenicline.

In the combination treatment group, there was more nausea, sleep disturbance, skin reactions, constipation, and depression reported, with only skin reactions reaching statistical significance (14.4 percent vs 7.8 percent); the varenicline-alone group experienced more abnormal dreams and headaches.

“In this study, to our knowledge the largest study to date examining the efficacy and safety of supplementing varenicline treatment with NRT, we have found the combination treatment to be associated with a statistically significant and clinically important higher continuous abstinence rate at 12 and 24 weeks, as well as a higher point prevalence abstinence rate at 6 months,” the authors write.

They add that further studies are needed to assess long-term efficacy and safety.

(doi:10.1001/jama.2014.7195; Available pre-embargo to the media at https://media.jamanetwork.com)

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

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 1, 2014

Media Advisory: To contact corresponding author Patrick F. Chinnery, Ph.D., F.R.C.P., F.Med.Sci., email patrick.chinnery@ncl.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: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.7184

Use of exome sequencing improved the ability to identify the underlying gene mutations in patients with biochemically defined defects affecting multiple mitochondrial respiratory chain complexes (enzymes that are involved in basic energy production), according to a study in the July 2 issue of JAMA.

Defects of the mitochondrial respiratory chain have emerged as the most common cause of childhood and adult neurometabolic disease, with an estimated prevalence of l in 5,000 live births. Clinically these disorders can present at any time of life, are often seen in association with neurological impairment, and cause chronic disability and premature death. The diagnosis of mitochondrial disorders remains challenging, according to background information in the article. Examples of problems caused by mitochondrial diseases include a type of epilepsy; mitochondrial encephalopathy; lactic acidosis; and a syndrome that includes stroke-like episodes.

Robert W. Taylor, Ph.D., F.R.C.Path., of Newcastle University, Newcastle upon Tyne, U.K., and colleagues studied whether a whole-exome sequencing approach could help define the molecular basis of mitochondrial disease. Whole-exome sequencing is a complex laboratory process that determines the entire unique sequence of an organism’s exome (the collection of exons, which are relatively small lengths of a whole genome and contain instructions for the body to build proteins).

The study included 53 patients, referred to 2 national centers in the United Kingdom and Germany between 2005 and 2012, who had biochemical evidence of multiple respiratory chain complex defects. The majority (51/53 [96 percent]) of the patients presented during childhood (<15 years old) and most (66 percent) developed symptoms within the first year of life. The most frequent clinical features were muscle weakness, central neurological disease, cardiomyopathy, and abnormal liver function; a combination of these abnormalities was present in most cases.

Following whole-exome sequencing, presumptive causal variants were identified in 28 patients (53 percent) and possible causal variants were identified in 4 (8 percent). Together these accounted for 32 patients (60 percent) and involved 18 different genes.  Distinguishing clinical features included deafness and kidney involvement associated with one gene, and cardiomyopathy with two genes. In 20 patients with prominent heart disease, the causative mutation was detected in 80 percent, while the detection rate was much lower in patients with liver disease (33 percent). It was not possible to confidently identify the underlying genetic basis in 21 patients (40 percent).

“In the pre-exome era, the systematic biochemical characterization of 53 patients with multiple respiratory chain complex defects led to detection of the underlying genetic basis in only 1 patient. The work presented herein demonstrates the effect of whole-exome sequencing in this context, which has defined the genetic etiology in 32 of 53 patients (60 percent) with a confirmed biochemical defect …,” the authors write. “Our findings contrast with large-scale candidate gene analysis using conventional and next-generation sequencing approaches, both of which had a lower diagnostic yield (10 percent-13 percent) and by definition did not discover new potential disease genes.”

“Additional study is required to determine the utility of this approach compared with traditional diagnostic methods in independent patient populations,” the researchers conclude.

(doi:10.1001/jama.2014.7184; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 1, 2014

Media Advisory: To contact Claudia S. Robertson, M.D., call Graciela Gutierrez at 713-798-4710 or email ggutierr@bcm.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.6490

In patients with a traumatic brain injury (TBI), neither the administration of the hormone erythropoietin (EPO) or maintaining a higher hemoglobin concentration through blood transfusion resulted in improved neurological outcome at 6 months, according to a study in the July 2 issue of JAMA. Transfusing at higher hemoglobin concentrations was associated with a higher risk of adverse events.

Patients with severe traumatic brain injury commonly develop anemia. For patients with neurological injury, anemia is a potential cause of secondary injury, which may worsen neurological outcomes. Treatment of anemia may include transfusions of packed red blood cells or administration of erythropoietin. There is limited information about the effect of erythropoietin or a high hemoglobin transfusion threshold (if the hemoglobin concentration drops below a certain level, a transfusion is performed) after a TBI, according to background information in the article.

Claudia S. Robertson, M.D., of the Baylor College of Medicine, Houston, and colleagues conducted a randomized clinical trial that included 200 patients (erythropoietin, n = 102; placebo, n = 98) with a closed head injury at neurosurgical intensive care units in two U.S. level I trauma centers between May 2006 and August 2012.  Patients were enrolled within 6 hours of injury and had to be unable to follow commands after initial stabilization.  Erythropoietin or placebo was initially dosed daily for 3 days and then weekly for 2 more weeks (n = 74). There were 99 patients assigned to a hemoglobin transfusion threshold of 7 g/dL and 101 patients assigned to 10 g/dL.

In the placebo group, 34 patients (38.2 percent) recovered to a favorable outcome (defined as good recovery and moderate disability, as measured by a functional assessment inventory) compared with 17 patients (48.6 percent) in the erythropoietin 1 group (first dosing regimen) and 17 patients (29.8 percent) in the erythropoietin 2 group (second dosing regimen).  Thirty-seven patients (42.5 percent) assigned to the transfusion threshold of 7 g/dL recovered to a favorable outcome compared with 31 patients (33.0 percent) assigned to the transfusion threshold of 10 g/dL.

There was a higher incidence of thromboembolic events for the transfusion threshold of 10 g/dL (21.8 percent) vs (8.1 percent) for the threshold of 7 g/dL.

“Among patients with closed head injury, neither the administration of erythropoietin nor maintaining hemoglobin concentration of at least 10 g/dL resulted in improved neurological outcome at 6 months. These findings do not support either approach in patients with traumatic brain injury,” the authors conclude.

(doi:10.1001/jama.2014.6490; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This study was supported by a grant from the National Institute of Neurological Disorders and Stroke. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 1, 2014

Media Advisory: To contact Andrew X. Zhu, M.D., Ph.D., call Katie Marquedant at 617-726-0337 or email KMarquedant@mgh.harvard.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.7189

Despite strong preclinical data, the drug everolimus failed to improve overall survival in patients with advanced liver cancer, compared to placebo, according to a study in the July 2 issue of JAMA.

Patients with advanced hepatocellular carcinoma (HCC; a type of liver cancer) have a median overall survival of less than l year, largely because of the absence of effective therapies. The drug sorafenib is the only systemic therapy shown to significantly improve overall survival in advanced HCC; however its benefits are mostly transient and modest, and disease eventually progresses. In preclinical models, everolimus prevented tumor progression and improved survival, according to background information in the article.

Andrew X. Zhu, M.D., Ph.D., of the Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, and colleagues randomly assigned 546 adults with advanced HCC whose disease progressed during or after sorafenib or who were intolerant of sorafenib to receive everolimus (n = 362) or placebo (n = 184), both given in combination with best supportive care and continued until disease progression or intolerable toxicity. In this phase 3 study, patients were enrolled from 17 countries between May 2010 and March 2012.

The researchers found no significant difference in overall survival between the two groups: there were 303 deaths (83.7 percent) in the everolimus group and 151 deaths (82.1 percent) in the placebo group. Median overall survival was 7.6 months with everolimus, 7.3 months with placebo. The disease control rate (the percentage of patients with a best overall response of complete or partial response or stable disease) was 56.1 percent (everolimus) and 45.1 percent (placebo).

“The results from [this study, EVOLVE-1] extend the list of failed phase 3 studies in advanced HCC, highlighting the challenge of developing effective therapies for this cancer,” the authors write.

The researchers note that EVOLVE-l and the other failed phase 3 studies have provided several important lessons, including that it is difficult to assess efficacy signals from phase 2 trials; surrogate end points such as time to progression, progression-free survival, and response rate inconsistently predict overall survival in phase 3 trials; and clinical and biologic heterogeneity likely affects the performance of targeted therapies in HCC. “In the absence of well-characterized and validated predictive bio-markers, targeted agents will likely continue to have a high risk of failure if phase 3 trials are conducted in unselected populations.”

(doi:10.1001/jama.2014.7189; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JULY 1, 2014

Media Advisory: To contact Matthew M. Hsieh, M.D., or corresponding author John F. Tisdale, M.D., call Krysten Carrera at 301-435-8112 or email krysten.carrera@nih.gov. To contact editorial co-author John F. DiPersio, M.D., Ph.D., call Jim Goodwin at 314-286-0166 or email jgoodwin@wustl.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.7192

Use of a lower intensity bone marrow transplantation method showed promising results among 30 patients (16-65 years of age) with severe sickle cell disease, according to a study in the July 2 issue of JAMA.

Myeloablative (use of high-dose chemotherapy or radiation) allogeneic hematopoietic stem cell transplantation (HSCT; receipt of hematopoietic stem cells “bone marrow” from another individual) is curative for children with severe sickle cell disease, but associated toxicity has made the procedure prohibitive for adults. The development of nonmyeloablative conditioning regimens (use of lower doses of chemotherapy or radiation to prepare the bone marrow to receive new cells) may facilitate safer application of allogeneic HSCT to eligible adults, according to background information in the article.

Matthew M. Hsieh, M.D., of the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md., and colleagues explored a nonmyeloablative approach in a pilot group of 10 adults with severe sickle cell disease, using a simplified HSCT regimen (with stem cell donation from a immunologically matched sibling), that had few toxic effects, yet all patients continued taking immunosuppression medication. The researchers have since revised the protocol to include an option to stop immunosuppression after 1 year in selected patients (those with donor CD3 engraftment of greater than 50 percent and normalization of hemoglobin). In this report, the authors describe the outcomes for 20 additional patients with severe sickle cell disease, along with updated results from the first 10 patients. All 30 patients (ages 16-65 years) were enrolled in the study from July 2004 to October 2013.

As of October 25, 2013, 29 patients were alive with a median follow-up of 3.4 years, and 26 patients (87 percent) had long-term stable donor engraftment without acute or chronic graft-vs-host disease. Hemoglobin levels improved after HSCT; at 1 year, 25 patients (83 percent) had full donor-type hemoglobin. Fifteen engrafted patients discontinued immunosuppression medication and had no graft-vs-host disease.

The average annual hospitalization rate was 3.2 the year before HSCT, 0.63 the first year after, 0.19 the second year after, and 0.11 the third year after transplant. Eleven patients were taking narcotics long-term at the time of transplant. During the week they were hospitalized and received their HSCT, the average narcotics use per week was 639 mg of intravenous morphine-equivalent dose. The dosage decreased to 140 mg 6 months after the transplant.

There were 38 serious adverse events including pain, infections, abdominal events, and toxic effects from the medication sirolimus.

“In this article, we extend our previous results and show that this HSCT procedure can be applied to older adults, even those with severe comorbid conditions …” the authors write. “These data reinforce the low toxicity of this regimen, especially among patients with significant end-organ dysfunction.”

“In this series of patients who underwent a simplified HSCT regimen to date, … reversal of sickle cell disease phenotype was achieved in the majority of patients. Engrafted patients continued to be disease-free and without graft-vs-host disease,” the researchers write. “Further accrual and follow-up is required to assess longer-term clinical outcomes, adverse events, and transplant tolerance.”

(doi:10.1001/jama.2014.7192; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This work is supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute at the National Institutes of Health. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, July 1 at this link.

Editorial: Reconsideration of Age as a Contraindication for Curative Therapy of Sickle Cell Disease

 Allison A. King, M.D., M.P.H., and John F. DiPersio, M.D., Ph.D., of the Washington University School of Medicine, St. Louis, comment on the findings of this study in an accompanying editorial.

“In a population of relatively older adults with sickle cell disease, these findings offer hope. Based on these exciting results, the role of age as a contraindication for offering adults with sickle cell disease and a matched sibling the chance of curative allogeneic stem cell transplant should be reconsidered.”

(doi:10.1001/jama.2014.7193; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 24, 2014

Media Advisory: To contact corresponding author Jacob M. van Laar, M.D., Ph.D., email j.m.vanlaar@umcutrecht.nl; or Dominique Farge, M.D., Ph.D., email dominique.farge-bancel@sls.aphp.fr. To contact editorial co-author Dinesh Khanna, M.D., M.Sc., call Beata Mostafavi at 734-764-2220 or email bmostafa@med.umich.edu.

Among patients with a severe, life-threatening type of sclerosis, treatment with hematopoietic stem cell transplantation (HSCT), compared to intravenous infusion of the chemotherapeutic drug cyclophosphamide, was associated with an increased treatment-related risk of death in the first year, but better long-term survival, according to a study in the June 25 issue of JAMA.

Systemic sclerosis is an autoimmune connective tissue disease characterized by vasculopathy (a disorder of the blood vessels), low-grade inflammation, and fibrosis (development of excess fibrous connective tissue) in skin and internal organs. Previously, small studies have shown that systemic sclerosis is responsive to treatment with autologous HSCT, although it has been unclear whether HSCT improves survival, according to background information in the article. For this study, autologous HSCT involved a multistep process beginning with infusion of high doses of cyclophosphamide and an antibody against immune cells, followed by reinfusion of the patient’s own stem cells that had been previously collected from blood and purified.

Jacob M. van Laar, M.D., Ph.D., of the University Medical Center Utrecht, Utrecht, the Netherlands and Dominique Farge M.D., Ph.D, of the Assistance Publique – Hopitaux de Paris, Paris 7 Diderot University, France, and colleagues randomly assigned 156 patients with early diffuse cutaneous (widespread skin involvement) systemic sclerosis to receive HSCT (n = 79) or cyclophosphamide (n = 77; 12 monthly infusions).  The phase 3 clinical trial was conducted in 10 countries at 29 centers; patients were recruited from March 2001 to October 2009 and followed up until October 2013.

During a median follow-up of 5.8 years, 53 adverse events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). Patients treated with HSCT experienced more adverse events (including death) in the first year but had better long-term event-free survival than those treated with cyclophosphamide.

Patients in the HCST group experienced higher mortality in the first year but had better long-term overall survival than those treated with cyclophosphamide. During year 1 there were 11 deaths (13.9 percent, including 8 treatment-related deaths) in the HSCT group vs 7 (9.1 percent, no treatment-related deaths) in the control group. After year 2 of follow-up, there were 12 deaths (15.2 percent) in the HSCT group vs 13 (16.9 percent) in the control group. After 4 years of follow-up, there were 13 deaths (16.5 percent) in the HSCT group vs 20 (26.0 percent) in the control group.

The authors add that HSCT was also more effective than intravenous cyclophosphamide on measures evaluating skin, functional ability, quality of life, and lung function, consistent with previous studies.

“Among patients with early diffuse cutaneous systemic sclerosis, HSCT was associated with increased treatment-related mortality in the first year after treatment. However, HCST conferred a significant long-term event-free survival benefit,” the authors conclude.

(doi:10.1001/jama.2014.6368; Available pre-embargo to the media at https://media.jamanetwork.com)

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

 Editorial: Autologous Hematopoietic Stem Cell Therapy in Severe Systemic Sclerosis

Ready for Clinical Practice?

In an accompanying editorial, Dinesh Khanna, M.D., M.Sc., of the University of Michigan, Ann Arbor, and colleagues provide suggestions on which patients should receive HSCT.

“Currently, consideration should be limited to patients with (1) diffuse cutaneous systemic sclerosis within the first 4 to 5 years of onset with mild-to-moderate internal organ involvement (severe internal organ involvement will make patients ineligible because of risks associated with HSCT) or (2) limited cutaneous systemic sclerosis with progressive internal organ involvement. This consideration also should generally be restricted to patients who have failed to improve or have worsened on conventional immunosuppressive agents and who are not active smokers; … Last, the cost-effectiveness of HSCT needs to be established, and multidisciplinary models of treatment decision making coupled with patient decision tools are needed. These approaches will provide a framework to evaluate and understand the trade-off between long-term benefits and short-term treatment-related morbidity and mortality of HSCT in patients with systemic sclerosis.”

(doi:10.1001/jama.2014.6369; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 24, 2014

Media Advisory: To contact Mark D. Neuman, M.D., M.Sc., call Lee-Ann Donegan at 215-349-5660 or email Leeann.Donegan@uphs.upenn.edu.

Among more than 56,000 adults undergoing hip repair between 2004 and 2011, the use of regional anesthesia compared with general anesthesia was not associated with a lower risk of death at 30 days, but was associated with a modestly shorter length of hospital stay, according to a study in the June 25 issue of JAMA.

Each year, more than 300,000 hip fractures occur in the United States, which can lead to functional disability and death. Regional anesthesia for hip fracture surgery may reduce postoperative complications, and practice guidelines have called for broader use of regional anesthesia for hip fracture surgery, according to background information in the article.

Mark D. Neuman, M.D., M.Sc., of the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and colleagues assessed the association of regional (i.e., spinal or epidural) anesthesia vs general anesthesia with 30-day mortality and hospital length of stay after hip fracture surgery. The study included patients 50 years or older who were undergoing surgery for hip fracture at general acute care hospitals in New York State between July 2004 and December 2011.

Of 56,729 patients, 15,904 (28 percent) received regional anesthesia and 40,825 (72 percent) received general anesthesia. Overall, 3,032 patients (5.3 percent) died within 30 days of surgery. The researchers did not observe a statistically significant difference in mortality according to anesthesia technique. They did find that regional anesthesia was associated with approximately a half day shorter length of hospital stay.

“Our findings may have implications for clinical practice and health policy. Regional anesthesia is used as the primary anesthetic technique in a minority of hip fracture surgeries performed in the United States and in other countries, and increasing its use has been proposed as a strategy to improve the quality of hip fracture care.  We found an association between greater use of regional anesthesia and a reduction in length of stay after hip fracture; however, we did not find regional anesthesia to be associated with statistically significant differences in mortality” the authors write.

“These findings do not support a mortality benefit for regional anesthesia in this setting.

(doi:10.1001/jama.2014.6499; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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Media Advisory: To contact Sarah M. Friedewald, M.D., call Mickey Ramirez at 847-723-5637 or email Mickey.Ramirez@advocatehealth.com. To contact editorial co-author Etta D. Pisano, M.D., call Deborah Reynolds at 843-324-0984 or email reynodh@musc.edu.

The addition of tomosynthesis, a 3-dimensional breast imaging technique, to digital mammography in more than 170,000 examinations was associated with a decrease in the proportion of patients called back for additional imaging and an increase in the cancer detection rate, according to a study in the June 25 issue of JAMA.

Screening mammography has played a key role in reducing breast cancer mortality, although it has drawn criticism for excessive false-positive results, limited sensitivity, and the potential of overdiagnosis of clinically insignificant lesions. In 2011, tomosynthesis was approved by the U.S. Food and Drug Administration to be used in combination with standard digital mammography for breast cancer screening. Single-institution studies have shown that adding tomosynthesis to mammography increases cancer detection and reduces false-positive results, according to background information in the article.

Sarah M. Friedewald, M.D., of Advocate Lutheran General Hospital, Park Ridge, Il., and colleagues conducted a study using data from 13 centers to determine if mammography combined with tomosynthesis improves performance of breast screening programs. A total of 454,850 examinations (n = 281,187 digital mammography; n = 173,663 digital mammography + tomosynthesis) were evaluated.

The primary measured outcomes were recall rate (proportion of patients requiring additional imaging based on a screening examination result), cancer detection rate, positive predictive value for recall (proportion of patients recalled after screening who were diagnosed as having breast cancer) and positive predictive value for biopsy (proportion of patients undergoing biopsies who were diagnosed as having breast cancer).

An analysis of the data indicated that the model-adjusted rates per 1,000 screens were as follows: for recall rate, 107 with digital mammography vs 91 with digital mammography + tomosynthesis (an overall decrease in recall rate of 16 per 1,000 screens); for biopsies, 18.1 with digital mammography vs 19.3 with digital mammography + tomosynthesis; for cancer detection, 4.2 with digital mammography vs 5.4 with digital mammography + tomosynthesis; and for invasive cancer detection, 2.9 with digital mammography vs 4.1 with digital mammography + tomosynthesis.

Adding tomosynthesis increased the positive predictive value for recall from 4.3 percent to 6.4 percent and for biopsy from 24.2 percent to 29.2 percent.

“The success of mammography screening in reducing mortality is predicated on the principle of detecting and treating small, asymptomatic cancers before they have metastasized. Accordingly, the preferential increase in invasive cancer detection with addition of tomosynthesis may be of particular value in optimizing patient outcomes from mammography screening,” the authors write.

“The association with fewer unnecessary tests and biopsies, with a simultaneous increase in cancer detection rates, would support the potential benefits of tomosynthesis as a tool for screening. However, assessment for a benefit in clinical outcomes is needed.”

(doi:10.1001/jama.2014.6095; Available pre-embargo to the media at https://media.jamanetwork.com)

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

 There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, June 24 at this link.

 Editorial: Breast Cancer Screening – Should Tomosynthesis Replace Digital Mammography?

 “As Friedewald et al have indicated, tomosynthesis is likely an advance over digital mammography for breast cancer screening, but fundamental questions about screening remain, with all available technologies,” write Etta D. Pisano, M.D., of the Medical University of South Carolina, Charleston, and Martin J. Yaffe, Ph.D., of the University of Toronto.

“Breast cancer remains a major public health problem, with approximately 40,000 U.S. women still dying annually. The continuing controversy surrounding the most effective strategy for deploying the various available technologies continues unabated, and clear consensus is lacking on when to screen, how often, and with what tools, or even which screen-detected cancers could be managed more conservatively. Only an appropriately powered multisite controlled clinical trial of modern technology can answer the remaining questions definitively. The time is now for the National Institutes of Health to fund such a much-needed trial to address many of the remaining issues about breast cancer screening.”

(doi:10.1001/jama.2014.6421; 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: 3 P.M. (CT) TUESDAY, JUNE 17, 2014

Media Advisory: To contact Richard D. Carvajal, M.D., call Courtney DeNicola Nowak at 212-639-3573 or email denicolc@mskcc.org.

In patients with advanced uveal melanoma, treatment with the agent selumetinib, compared with chemotherapy, resulted in an improved cancer progression-free survival time and tumor response rate, but no improvement in overall survival, according to a study in the June 18 issue of JAMA. The modest improvement in clinical outcomes was accompanied by a high rate of adverse events.

Uveal melanoma arises from melanocytes within the choroid layer of the eye. There are about 1,500 new cases of uveal melanoma per year in the U.S., which is biologically distinct from skin related melanoma.  Selumetinib is an oral agent that may help to inhibit the growth of cancer cells by blocking MEK1/2. A subgroup analysis from an earlier trial that included 20 patients with uveal melanoma suggested favorable results with selumetinib treatment, according to background information in the article.

Richard D. Carvajal, M.D., of Memorial Sloan-Kettering Cancer Center, New York, and colleagues randomly assigned patients with metastatic uveal melanoma to receive selumetinib (n = 50; orally twice daily), or chemotherapy (n = 51; temozolomide, orally daily for 5 of every 28 days, or dacarbazine, intravenously every 21 days) until disease progression, death, intolerable adverse effects, or withdrawal of consent. After analysis of the primary outcome, 19 additional patients were registered and 18 treated with selumetinib without randomization, to complete the planned 120-patient enrollment.

The researchers reported that the median progression-free survival time was 7 weeks in the chemotherapy group (median treatment duration, 8 weeks) and 15.9 weeks in the selumetinib group (median treatment duration, 16.1 weeks). The 4-month progression-free survival rate was 8.5 percent with chemotherapy, and 43.1 percent with selumetinib. Median overall survival time was 9.1 months with chemotherapy and 11.8 months with selumetinib, a difference that was not statistically significant.

Tumor regression was uncommon with chemotherapy, whereas 49 percent of patients randomized to selumetinib achieved tumor regression. Treatment-related adverse events were observed in 97 percent of patients treated with selumetinib, with 37 percent requiring at least 1 dose reduction.

“In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival time and rate of response; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high rate of adverse events.” the authors conclude.

(doi:10.1001/jama.2014.6096; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 17, 2014

Media Advisory: To contact Nynne Nyboe Andersen, M.D., email nyna@ssi.dk.

In a study that included more than 56,000 patients with inflammatory bowel disease, use of a popular class of medications known as tumor necrosis factor alpha antagonists was not associated with an increased risk of cancer over a median follow-up of 3.7 years, although an increased risk of malignancy in the long term, or with increasing number of doses, cannot be excluded, according to a study in the June 18 issue of JAMA.

Tumor necrosis factor α (TNF-α) antagonists are drugs that have been shown to be beneficial in reducing the inflammation in inflammatory diseases such as rheumatoid arthritis, and inflammatory bowel disease (IBD) (Crohn disease and ulcerative colitis). The therapeutic benefits of TNF-α antagonists must be weighed against the potential for adverse effects, including a possible increased risk of cancer. “Therefore, long-term observational studies of consequences of treatment with TNF-α antagonists are needed,” the authors write.

Nynne Nyboe Andersen, M.D., of the Statens Serum Institut, Copenhagen, and colleagues studied cancer rates in patients with IBD exposed to TNF-α antagonists, as compared with patients with IBD not exposed to these drugs. The study included 56,146 patients (15 years or older) with IBD identified in the National Patient Registry of Denmark (1999-2012), of whom 4,553 (8.1 percent) were treated with TNF-α antagonists. Cancer cases were identified in the Danish Cancer Registry.

In total, 3,465 patients with IBD unexposed to TNF-α antagonists (6.7 percent) and 81 exposed to TNF-α antagonists (1.8 percent; median follow-up, 3.7 years) developed cancer. The study results indicated that exposure to TNF-α antagonists was not associated with an increased overall cancer risk. In addition, no site-specific cancers were observed in significant excess.

The authors note that because of the relatively small sample size and the small number of cancer cases in this study, statistical power was limited in analyses of site-specific cancer and also for analyses stratified according to certain criteria, such as duration of follow-up.

“An increased risk of malignancy in the long term or with increasing number of cumulative doses of TNF-α antagonists cannot be excluded, and continuous follow-up of exposed patients is needed.”

(doi:10.1001/jama.2014.5613; Available pre-embargo to the media at https://media.jamanetwork.com)

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

 There will also be an audio author interview available for this study at 3 p.m. CT Tuesday, June 17, at JAMA.com.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 17, 2014

Media Advisory: To contact Kao-Ping Chua, M.D., call Todd Datz at 617-432-8413 or email tdatz@hsph.harvard.edu.

Findings of a large survey indicate that since 2010, when young adults could be covered under their parents’ health insurance plans until age 26, self-reported health among this group has improved, along with a decrease in out-of-pocket health care expenditures, according to a study in the June 18 issue of JAMA.

Beginning September 23, 2010, the Affordable Care Act allowed young adults to be covered under their parents’ plans until 26 years of age. This dependent coverage provision increased insurance coverage and access among young adults. However, little is known about the association between implementation of the provision and medical spending, health care use, and overall health, according to background information in the article.

Kao-Ping Chua, M.D., of Harvard University, Cambridge, Mass., and Benjamin D. Sommers, M.D., Ph.D., of the Harvard School of Public Health, Boston, studied adults 19 to 34 years of age who were included in the 2002-2011 Medical Expenditure Panel Survey, an annual survey conducted by the Agency for Healthcare Research and Quality. The study sample consisted of 26,453 individuals in the intervention group (adults 19 to 25 years of age) and 34,052 individuals in the control group (adults 26 to 34 years of age). Overall, the sample was 47 percent male and 74 percent white.

The authors reported that the dependent coverage provision was associated with a 7.2 percentage point increase in insurance coverage among adults ages 19 to 25 years; no statistically significant changes in health care use; an increase of 6.2 percentage points in the probability of reporting excellent physical health; and an increase of 4 percentage points in the probability of reporting excellent mental health.

The researchers also found that compared with the control group, implementation of the dependent coverage provision was associated with a decrease of 3.7 percentage points in out-of-pocket expenditures among adults ages 19 to 25 years with any expenditures. Annual out-of-pocket expenditures declined by approximately 18 percent in the 19-25 year old group, relative to adults aged 26-34.

Results were similar after controlling for household income, education, and employment.

(doi:10.1001/jama.2014.2202; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 17, 2014

Media Advisory: To contact corresponding author Jay Giri, M.D., M.P.H., call Lee-Ann Donegan at 215-349-5660 or email Leeann.donegan@uphs.upenn.edu. To contact editorial author Joshua A. Beckman, M.D., call Jessica Maki at 617-525-6373 or email jmaki3@partners.org.

In an analysis that included data from 16 trials performed over the last 45 years, among patients with pulmonary embolism, receipt of therapy to dissolve the blood clot (thrombolysis) was associated with lower rates of death, but increased risks of major bleeding and intracranial hemorrhage, according to a study in the June 18 issue of JAMA. The authors note that these findings may not apply to patients with low-risk pulmonary embolism.

Pulmonary embolism (PE; a blockage of the main artery of the lung or one of its branches) is an important cause of illness and death, with more than 100,000 U.S. cases annually and as many as 25 percent of patients experiencing sudden death. Pulmonary embolism is also associated with an increased risk of death for up to 3 months after the initial event. Thrombolytic therapy may be beneficial in the treatment of some patients with PE, but to date, no analysis has had adequate statistical power to determine whether this therapy is associated with improved survival, compared with conventional anticoagulation, according to background information in the article.

Saurav Chatterjee, M.D., of St. Luke’s-Roosevelt Hospital Center of the Mount Sinai Health System, New York, and colleagues performed a meta-analysis of 16 randomized clinical trials (n = 2,115 patients) of thrombolytic therapy for PE. Two hundred ten patients (9.9 percent) had low-risk PE, 71 percent had intermediate-risk PE, 1.5 percent had high-risk PE; risk could not be classified in 18 percent.

The researchers found that thrombolytic therapy for PE was associated with a 47 percent lower odds of death; there was 2.2 percent mortality in the thrombolytic therapy group and 3.9 percent mortality in the anticoagulant group at an average duration of follow-up of 82 days. Thrombolytic therapy was associated with a 2.7 times greater risk of major bleeding compared with anticoagulant therapy; there was a 9.2 percent rate of major bleeding in the thrombolytic therapy group and a 3.4 percent rate in the anticoagulation group. Major bleeding was not significantly increased in patients 65 years and younger.

Thrombolysis was associated with a greater intracranial hemorrhage rate (1.5 percent vs 0.2 percent) but also lower risk of recurrent PE (1.2 percent vs 3.0 percent).

In intermediate-risk pulmonary embolism trials, thrombolysis was associated with lower mortality and more major bleeding events.

“Risk stratification models for bleeding in all patients, but especially the elderly, are warranted to identify the individuals at the highest risk of hemorrhagic complications with thrombolytic therapy. Future research should also be directed toward concomitant [accompanying] use of other medications, especially the ‘novel oral anticoagulants’ in conjunction with thrombolytics in patients with hemodynamically stable PE,” the authors write.

(doi:10.1001/jama.2014.5990; Available pre-embargo to the media at https://media.jamanetwork.com)

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

 Editorial: Thrombolytic Therapy for Pulmonary Embolism

“The meta-analysis by Chatterjee et al raises new questions,” writes Joshua A. Beckman, M.D., of Brigham and Women’s Hospital, Boston, in an accompanying editorial.

“For example, should thrombolytic therapy in intermediate-risk patients older than 65 years be avoided? While the risk of bleeding is increased in older patients, the point estimate for mortality is similar to that in younger patients. Risk stratification for bleeding may favor use of thrombolysis in patients older than 65 years. Second, would the net clinical benefit be better with consistent use of catheter-based thrombolysis using lower doses of fibrinolytic agents for significant pulmonary artery thrombus [blood clot] reduction? Additional clinical trials are needed to guide optimal use of thrombolytic therapy in patients with PE.”

(doi:10.1001/jama.2014.5993; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 10, 2014

Media Advisory: To contact Mikael Knip, M.D., D.M.Sc., email mikael.knip@helsinki.fi.

Among infants at risk for type 1 diabetes, the use of a hydrolyzed formula (one that does not contain intact proteins) compared with a conventional formula did not reduce the incidence of diabetes-associated autoantibodies after 7 years of follow-up, according to a study in the June 11 issue of JAMA, a diabetes theme issue.

Type 1 diabetes is characterized by selective loss of insulin-producing beta cells in the pancreatic islets in genetically susceptible individuals.  The disease process leading to clinical type 1 diabetes often starts during the first years of life. Some studies have suggested that exposure to complex foreign proteins in early infancy may increase the risk of beta-cell autoimmunity and type l diabetes in genetically susceptible individuals, indicating that prevention of the initiation of diabetes should start in infancy, according to background information in the article.

Mikael Knip, M.D., D.M.Sc., of the University of Helsinki, Finland, and colleagues randomly assigned infants at risk of type 1 diabetes to be weaned to an extensively hydrolyzed formula (n = 1,078) or a conventional cows’ milk-based formula (n = 1,081). The dietary intervention period lasted until the infant was at least 6 months of age, and up to a maximum of 8 months of age, depending on the amount of exposure to formula (to ensure exposure for at least 60 days). The study was conducted at 78 centers in 15 countries. The primary measured outcome was positivity for at least 2 diabetes-associated autoantibodies out of 4 analyzed during a median observation period of 7 years.

During the follow-up period, 2,070 children (1,035 in each group) provided at least 1 blood sample for determination of diabetes-associated autoantibodies. The researchers found that 139 children in the experimental group (13.4 percent) tested positive for 2 or more autoantibodies, as compared with 117 in the control group (11.3 percent). At least 1 autoantibody developed in 41.6 percent of those in the experimental group and in 40 percent of those in the control group.

The authors write that this study showed that in this large international trial, weaning to a highly hydrolyzed formula during infancy was not associated with any reduction in the signs of cumulative beta-cell autoimmunity. “These findings do not support a benefit from hydrolyzed formula.”

(doi:10.1001/jama.2014.5610; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 10, 2014

Media Advisory: To contact corresponding author Jose C. Florez, M.D., Ph.D., call Haley Bridger at 617-714-7968 or email hbridger@broadinstitute.org.

A genetic analysis of DNA samples of approximately 3,700 Mexican and U.S. Latino individuals identified a gene variant that was associated with a 5-fold increase in the prevalence of type 2 diabetes, findings that may have implications for screening in this population, according to a study in the June 11 issue of JAMA, a diabetes theme issue.

The estimated prevalence of type 2 diabetes in Mexican adults was 14.4 percent in 2006, making it one of the leading causes of death in Mexico. Latino populations (defined as persons who trace their origin to Central and South America, and other Spanish cultures), have one of the highest prevalences of type 2 diabetes worldwide. Identifying genetic factors associated with type 2 diabetes in Latino populations could improve risk prediction and focus treatment choice based on knowledge of the underlying biology of the disease, according to background information in the study.

Karol Estrada, Ph.D., of the Broad Institute of Harvard and MIT, Cambridge, Mass., and colleagues with the SIGMA Type 2 Diabetes Consortium, performed whole-exome (part of the genome) sequencing (which captures both common and rare genetic variants in the protein-coding regions of genes) on DNA samples from 3,756 Mexican and U.S. Latino individuals (1,794 with type 2 diabetes and 1,962 without diabetes) recruited from 1993 to 2013. One variant was further tested for and association with type 2 diabetes in large multiethnic data sets of 14,276 participants.

The researchers found that a single rare variant (c.1522G>A [p.E508K]) of the HNF1A gene was associated with about a 5 times higher odds of type 2 diabetes, but it was not associated with an early-onset form of diabetes. This variant was observed in 0.36 percent of participants without type 2 diabetes and 2.1 percent of participants with it. In the multiethnic replication data sets, the p.E508K variant was seen only in Latino patients. Carriers and noncarriers of this mutation with type 2 diabetes had no significant differences in clinical characteristics, including age at onset.

The effect size of the variant is the largest observed to date for any diabetes variant with a frequency more than 1 in 1,000.

“Further research is warranted to evaluate the clinical relevance of these findings, including the benefits of selective population screening and the choice of genotype-guided therapeutic regimens,” the authors conclude.

(doi:10.1001/jama.2014.6511; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 10, 2014

Media Advisory: To contact Kasia J. Lipska, M.D., M.H.S., call Helen Dodson at 203-436-3984 or email helen.dodson@yale.edu.

Largely attributable to the widespread adoption of insulin analogs, use of insulin among patients with type 2 diabetes increased from 10 percent in 2000 to 15 percent in 2010, and out-of-pocket expenditures per prescription increased from a median of $19 to $36, according to a study in the June 11 issue of JAMA, a diabetes theme issue.

Insulin analogs are molecularly altered forms of insulin. Compared with human synthetic and animal insulin for treatment of type 2 diabetes, short-acting analogs may offer flexible dosing and convenience, long-acting analogs less nocturnal hypoglycemia, but both at greater cost, according to background information in the article.

Kasia J. Lipska, M.D., M.H.S., of the Yale University School of Medicine, New Haven, Conn., and colleagues used data from an administrative claims database of privately insured enrollees from throughout the United States (but with more representation from states in the South and Midwest) to examine trends in insulin use, out-of-pocket expenditures, and severe hypoglycemic events among privately insured U.S. adults with type 2 diabetes. The analysis included adults 18 years or older with at least 2 years of continuous plan enrollment between January 2000 and September 2010.

During the study period, 123,486 patients filled at least 1 prescription for insulin, comprising 9.7 percent of adults with type 2 diabetes in 2000 and 15.1 percent in 2010. Among adults who used insulin, 96.4 percent filled prescriptions for human synthetic insulin in 2000 and 14.8 percent in 2010, whereas 18.9 percent filled prescriptions for insulin analogs in 2000 and 91.5 percent in 2010. Use of animal insulin was less than 1 percent during all years.

The median out-of-pocket costs per prescription for all types of insulin increased from $19 in 2000 to $36 in 2010. Severe hypoglycemic events declined slightly over the study period, but the difference was not statistically significant.

“We found a large increase in the prevalent use of insulin analogs among privately insured patients with type 2 diabetes. The clinical value of this change is unclear,” the authors conclude.

(doi:10.1001/jama.2014.6316; Available pre-embargo to the media at https://media.jamanetwork.com)

 Editor’s Note: This project was supported by a grant from the Agency for Healthcare Research and Quality. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 10, 2014

Media Advisory: To contact Christianne L. Roumie, M.D., M.P.H., call Craig Boerner at 615-322-4747 or email craig.boerner@vanderbilt.edu. To contact editorial author Monika M. Safford, M.D., call Bob Shepard at 205-934-8934 or email bshep@uab.edu.

Among patients with diabetes who were receiving metformin, the addition of insulin compared with a sulfonylurea (a class of antidiabetic drugs) was associated with an increased risk of nonfatal cardiovascular outcomes and all-cause death, according to a study in the June 11 issue of JAMA, a diabetes theme issue.

Diabetes mellitus and its complications represent an enormous health care burden and result in nearly 200,000 deaths annually. The American Diabetes Association and the European Association for the Study of Diabetes recommend that, for patients with preserved kidney function, diabetes treatment begin with metformin and lifestyle changes to achieve a glycated hemoglobin (HbA_lc) level of less than or equal to 7 percent. Often patients will require a second agent to reach this goal, but there is no consensus regarding which medication to choose, according to background information in the study.

Clinicians begin administration of insulin to attain fast and flexible control of blood glucose levels. Because of the promising results of a few trials, there has been an increase in early initiation of insulin and its use as add-on therapy to metformin.

Christianne L. Roumie, M.D., M.P.H., of the Veterans Health Administration-Tennessee Valley Healthcare System Geriatric Research Education Clinical Center, and Vanderbilt University, Nashville, Tenn., and colleagues conducted a study with data from national Veterans Health Administration, Medicare, and National Death Index databases, which included veterans with diabetes initially treated with metformin from 2001 through 2008 who subsequently added either insulin or sulfonylurea. The researchers compared the risk between therapies of a composite outcome of heart attack, stroke, or all-cause death.

Among 178,341 metformin monotherapy patients, 2,948 added insulin and 39,990 added a sulfonylurea.  The authors performed additional propensity matched analysis on a subset of 2,436 patients from the insulin group and 12,180 patients from the sulfonylurea group.  Patients had received metformin for a median of 14 months before adding another therapy; median follow-up after this addition was 14 months. An analysis of the subsequent events indicated that heart attack and stroke rates were statistically similar, whereas there was a higher rate of all-cause death among patients who received insulin.

“Our finding of a modestly increased risk of a composite of cardiovascular events and death in metformin users who add insulin compared with sulfonylurea is consistent with the available clinical trial and observational data. None of these studies found an advantage of insulin compared with oral agents for cardiovascular risk, and several reported increased cardiovascular risk or weight gain and hypoglycemic episodes, which could result in poorer outcomes,” the authors write. “Our study suggests that intensification of metformin with insulin among patients who could add a sulfonylurea offers no advantage in regard to risk of cardiovascular events and is associated with some risk.”

“These findings require further investigation to understand risks associated with insulin use in these patients and call into question recommendations that insulin is equivalent to sulfonylureas for patients who may be able to receive an oral agent.”

(doi:10.1001/jama.2014.4312; Available pre-embargo to the media at https://media.jamanetwork.com)

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

There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, June 10 at this link.

 Editorial: Comparative Effectiveness Research and Outcomes of Diabetes Treatment

 In an accompanying editorial, Monika M. Safford, M.D., of the University of Alabama at Birmingham, comments on comparative effectiveness research, such as the study conducted by Roumie and colleagues.

“Comparative effectiveness research is creating new challenges as it generates much needed new evidence. The very methods that make studies like that of Roumie et al novel also create barriers to interpretation that may make it more difficult to apply their results. Some of the creativity being brought to bear on advancing methods of analysis may also be needed to advance methods of communicating both methods and results to practicing clinicians, and perhaps more importantly, to the patients who are facing decisions that may (or may not) have profound implications for their health and well-being.”

(doi:10.1001/jama.2014.4313; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 10, 2014

Media Advisory: To contact Lars Sjostrom, M.D., Ph.D., email lars.v.sjostrom@medfak.gu.se.

In a study that included long-term follow-up of obese patients with type 2 diabetes, bariatric surgery was associated with more frequent diabetes remission and fewer complications than patients who received usual care, according to a study in the June 11 issue of JAMA, a diabetes theme issue.

Obesity and diabetes have reached epidemic proportions and constitute major health and economic burdens. Worldwide, 347 million adults are estimated to live with diabetes and half of them are undiagnosed. Studies show that type 2 diabetes is preventable. The incidence of diabetes can be reduced by as much as 50 percent by lifestyle and pharmacological interventions, according to background information in the article. Short-term studies show that bariatric surgery results in remission of diabetes. The long-term outcomes for bariatric surgery and diabetes remission and diabetes-related complications have not been known.

Lars Sjostrom, M.D., Ph.D., of the University of Gothenburg, Sweden, and colleagues performed a follow-up of the Swedish Obese Subjects (SOS) study, conducted at 25 surgical departments and 480 primary health care centers in Sweden. Of patients recruited between September 1987 and January 2001, 260 of 2,037 control patients and 343 of 2,010 bariatric surgery patients had type 2 diabetes at baseline. For the current analysis, the presence of diabetes was determined at SOS health examinations and information on diabetes complications was obtained from national health registers. For diabetes complications, the median follow-up time was 17.6 years in the control group, and 18.1 years in the surgery group.

The proportion of patients in remission (defined as blood glucose <110 mg/dL and no diabetes medication) after 2 years was 72.3 percent in the surgery group and 16.4 percent in the control group. At 15 years, the diabetes remission rates decreased to 30.4 percent for bariatric surgery patients and 6.5 percent for control patients. All types of bariatric surgery (adjustable or nonadjustable banding, vertical banded gastroplasty, or gastric bypass) were associated with higher remission rates compared with usual care.

In addition, bariatric surgery was associated with a decreased incidence of microvascular and macrovascular complications.

“In this very long-term follow-up observational study of obese patients with type 2 diabetes, bariatric surgery was associated with more frequent diabetes remission and fewer complications than usual care. These findings require confirmation in randomized trials,” the authors conclude.

(doi:10.1001/jama.2014.5988; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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