EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 11, 2013

Media Advisory: To contact Melissa M. Hudson, M.D., call Summer Freeman at 901-595-3061 or email summer.freeman@stjude.org.

CHICAGO – In an analysis that included more than 1,700 adult survivors of childhood cancer, researchers found a very high percentage of survivors with 1 or more chronic health conditions, with an estimated cumulative prevalence of any chronic health condition of 95 percent at age 45 years, according to a study in the June 12 issue of JAMA.

“Curative therapy for pediatric malignancies has produced a growing population of adults formerly treated for childhood cancer who are at risk for health problems that appear to increase with aging. The prevalence of cancer-related toxic effects that are systematically ascertained through formal clinical assessments has not been well studied. Ongoing clinical evaluation of well-characterized cohorts is important to advance knowledge about the influence of aging on cancer-related morbidity and mortality and to guide the development of health screening recommendations and health-preserving interventions,” according to background information in the article.

Melissa M. Hudson, M.D., of St. Jude Children’s Research Hospital and the University of Tennessee College of Medicine, Memphis, and colleagues conducted a study to determine, through systematic comprehensive medical assessment, the general health status of long-term survivors of childhood cancer and the prevalence of treatment complications following predisposing cancer treatment-related exposures. The presence of health outcomes was ascertained using systematic exposure-based medical assessments among 1,713 adult (median [midpoint] age, 32 years) survivors of childhood cancer (median time from diagnosis, 25 years) enrolled in the St. Jude Lifetime Cohort Study since October 1, 2007, and undergoing follow-up through October 31, 2012. The participants were diagnosed and treated between 1962 and 2001. The primary measured outcomes were the age-specific cumulative prevalence of adverse outcomes by organ system.

The researchers found that impaired pulmonary, auditory, cardiac, endocrine, and nervous system function were most prevalent (detected in 20 percent or more of participants at risk). The crude prevalence of adverse health outcomes was highest for pulmonary (abnormal pulmonary function, 65.2 percent), auditory (hearing loss, 62.1 percent) endocrine or reproductive (any endocrine condition, such as hypothalamic-pituitary axis disorders and male germ cell dysfunction, 62.0 percent), cardiac (any cardiac condition, such as heart valve disorders, 56.4 percent), and neurocognitive (neurocognitive impairment, 48.0 percent) function.

“Among survivors at risk for adverse outcomes following specific cancer treatment modalities, the estimated cumulative prevalence at age 50 years was 21.6 percent for cardiomyopathy, 83.5 percent for heart valve disorder, 81.3 percent for pulmonary dysfunction, 76.8 percent for pituitary dysfunction, 86.5 percent for hearing loss, 31.9 percent for primary ovarian failure, 31.1 percent for Leydig cell failure, and 40.9 percent for breast cancer,” the authors write.

Abnormalities involving hepatic, skeletal, renal, and hematopoietic function were less common (less than 20 percent).

“In this clinically evaluated cohort, 98.2 percent of participants had a chronic health condition,” the researchers note. “The overall cumulative prevalence of a chronic condition was estimated to be 95.5 percent by age 45 years and 93.5 percent 35 years after cancer diagnosis.” At age 45 years, the estimated cumulative prevalence was 80.5 percent for a serious/disabling or life-threatening chronic condition.

“In summary, this study provides global and age-specific estimates of clinically ascertained morbidity in multiple organ systems in a large systematically evaluated cohort of long-term survivors of childhood cancer. The percentage of survivors with 1 or more chronic health conditions prevalent in a young adult population was extraordinarily high. These data underscore the need for clinically focused monitoring, both for conditions that have significant morbidity if not detected and treated early, such as second malignancies and heart disease, and also for those that if remediated can improve quality of life, such as hearing loss and vision deficits.”

(JAMA. 2013;309(22):2371-2381; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by a Cancer Center Support grant from the National Cancer Institute and by the American Lebanese Syrian Associated Charities. 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 11, 2013

Media Advisory: To contact Jeffrey S. Gerber, M.D., Ph.D., call Rachel Salis-Silverman at 267-426-6063 or email Salis@email.chop.edu. To contact editorial author Jonathan A. Finkelstein, M.D., M.P.H., call Meghan Weber at 617-919-3656 or email Meghan.Weber@childrens.harvard.edu.

CHICAGO – An intervention consisting of clinician education coupled with personalized audit and feedback about antibiotic prescribing improved adherence to prescribing guidelines for common pediatric bacterial acute respiratory tract infections, although the intervention did not affect antibiotic prescribing for viral infections, according to a study in the June 12 issue of JAMA.

“Antibiotics are the most common prescription drugs given to children. Although hospitalized children frequently receive antibiotics, the vast majority of antibiotic use occurs in the outpatient setting, roughly 75 percent of which is for acute respiratory tract infections (ARTIs). Unnecessary prescribing for viral ARTIs is well documented and has been declining. However, inappropriate prescribing also occurs for bacterial ARTIs, particularly when broad-spectrum antibiotics are used to treat infections for which narrow-spectrum antibiotics are indicated and recommended,” according to background information in the article. “Antimicrobial stewardship programs have been effective for inpatients, often through prescribing audit and feedback. However, most antimicrobial use occurs in outpatients with acute respiratory tract infections.

Jeffrey S. Gerber, M.D., Ph.D., of The Children’s Hospital of Philadelphia, and colleagues conducted a study to evaluate the effect of an antimicrobial stewardship intervention on antibiotic prescribing for pediatric outpatients. The randomized trial of outpatient antimicrobial stewardship compared prescribing between intervention and control practices using a common electronic health record. After excluding children with chronic medical conditions, antibiotic allergies, and prior antibiotic use, the researchers estimated prescribing rates for targeted ARTIs standardized for age, sex, race, and insurance from 20 months before the intervention to 12 months afterward (October 2008-June 2011). The study included a network of 18 pediatric primary care practices in Pennsylvania and New Jersey (162 clinicians). Overall, there were 1,291,824 office visits by 185,212 unique patients.

The intervention consisted of one 1-hour on-site clinician education session followed by 1 year of personalized, quarterly audit and feedback of prescribing for bacterial and viral ARTIs or usual practice. The researchers measured rates of broad-spectrum (off-guideline) antibiotic prescribing for bacterial ARTIs and antibiotics for viral ARTIs for 1 year after the intervention.

The authors found that among children who were prescribed antibiotics for any indication, the overall proportion of antibiotic prescriptions that were broad-spectrum decreased from 26.8 percent to 14.3 percent in the intervention group and from 28.4 percent to 22.6 percent in control practices (difference of differences [DOD], 6.7 percent) during the 12-months following initiation of education/audit and feedback.

“When stratifying by the individual bacterial ARTIs targeted by the intervention, broad-spectrum (off-guideline) antibiotic prescribing for pneumonia decreased from 15.7 percent to 4.2 percent in the intervention group and from 17.1 percent to 16.3 percent in the control group (DOD, 10.7 percent). Broad-spectrum prescribing for acute sinusitis decreased from 38.9 percent to 18.8 percent in the intervention group and from 40.0 percent to 33.9 percent in the control practices (DOD, 14.0 percent). Broad-spectrum prescribing for streptococcal pharyngitis started and remained low for both the intervention group (from 4.4 percent to 3.4 percent) and the control group (from 5.6 percent to 3.5 percent) (DOD, -1.1 percent),” they write.

In addition, the baseline rate of any antibiotic prescribing for viral infections was low and did not change significantly after the intervention in either the intervention group (from 7.9 percent to 7.7 percent) or the control group (from 6.4 percent to 4.5 percent) (DOD, -1.7 percent).

“This intervention nearly halved prescribing of broad-spectrum antibiotics to children during acute primary care encounters and decreased use of off-guideline antibiotics for children with pneumonia by 75 percent by 1 year after the intervention,” the researchers note.

“Our findings suggest that extending antimicrobial stewardship to the ambulatory setting, where such programs have generally not been implemented, may have important health benefits.”

“This targeted application of antimicrobial stewardship principles to the ambulatory setting has the potential to affect the most common indications for antibiotic use. Future studies should examine the key drivers of these effects on antibiotic prescribing and the generalizability of findings to other health systems and measure the sustainability and clinical outcomes associated with differential prescribing patterns,” the authors conclude.

(JAMA. 2013;309(22):2345-2352; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This research was supported by the Agency for Healthcare Research and Quality. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, 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 11 at this link.

Editorial: Putting Antibiotic Prescribing for Children Into Context

“Gerber et al and the participating practices and clinicians have accomplished meaningful improvement in antibiotic prescribing for ARTIs in their pediatric patients,” writes Jonathan A. Finkelstein, M.D., M.P.H., of Boston Children’s Hospital and Harvard Medical School, Boston, in an accompanying editorial.

“However, broad-spectrum antibiotic overuse continues in humans across age groups and conditions, as well as in agricultural use and other factors that drive emerging resistance. The good news is that a range of effective techniques for promoting judicious prescribing in ambulatory care have been developed and tested; it is also apparent that the influence and benefit of any of these interventions will vary greatly across settings. Tailoring strategies to contextual factors and adapting them further during implementation may well be more effective than merely rolling out the approach with the greatest average effect in the average practice.”

(JAMA. 2013;309(22):2388-2389; 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. Dr. Finkelstein reports previous consultancy for the Institute for Healthcare Improvement.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 4, 2013

Research Finds Retinal Vessel Leakage During High Altitude Exposure

“Exposure to high altitude can cause acute mountain sickness (AMS) and, in severe cases, cerebral or pulmonary edema. Capillary leakage has been hypothesized to play a role in the pathogenesis of AMS, although the mechanism of altitude-related illnesses remains largely unknown,” writes Gabriel Willmann, M.D., of the University of Tubingen, Germany, and colleagues. “Vessel leakage in the retinal periphery has not been investigated. Our objective was to assess retinal vessel integrity at high altitude using fluorescein angiography.”

As reported in a Researcher Letter, the study included 14 healthy, unacclimatized volunteers (7 male and 7 female participants, average age, 35 years) who were studied at baseline (1,119 feet), after ascent to 14,957 feet within 24 hours, and more than 14 days after return by fluorescein angiography. Photographs were independently graded in random order by 4 ophthalmologists for presence and location of leakage.

Retinal abnormalities were not noted at baseline in any of the participants. At high altitude, marked bilateral leakage of peripheral retinal vessels was observed in 7 of 14 participants (50 percent). All findings completely reversed after descent. “Retinal capillary leakage should be considered a part of the spectrum of high-altitude retinopathy,” the authors write.

(JAMA. 2013;309[21]:2210-2212. Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact corresponding author Florian Gekeler, M.D., email gekeler@uni-tuebingen.de.

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 Viewpoints in This Issue of JAMA

The Morality of Using Mortality as a Financial Incentive – Unintended Consequences and Implications for Acute Hospital Care

In this Viewpoint, Joel M. Kupfer, M.D., of Methodist Medical Center and the University of Illinois College of Medicine-Peoria, examines the potential issues of using financial incentives to improve hospital mortality rates.

“Financial incentives can be powerful motivators but the results might not always be beneficial. Changes in program design and more widespread implementation might help overcome prior limitations but the potential for unintended consequences also may increase as the financial imperatives of hospitals to win incentives increases. It is important to move ahead with quality initiatives even though there are gaps in current knowledge. The challenge for policy makers will be to design a balanced system that can lower costs and improve care while preserving the ethical integrity of the medical profession, and respect patients’ rights to make choices about their health care.”

(JAMA. 2013;309[21]:2213-2214. Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact Joel M. Kupfer, M.D., call Dave Haney at 309-671-8404 or email dhaney@uicomp.uic.edu.

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 The Future of Quality Measurement for Improvement and Accountability

“The Affordable Care Act expands access to health insurance and includes numerous provisions focused on delivering care that is high quality, safe, and affordable. Reliable and meaningful quality measurement that focuses on important outcomes, including patient experience throughout the health care system, is an essential prerequisite for achieving this goal,” writes Patrick H. Conway, M.D., M.Sc., of the Department of Health and Human Services, Washington, D.C., and the Centers for Medicare & Medicaid Services, Baltimore, and colleagues.

In this Viewpoint, the authors “describe the characteristics of the quality measurement enterprise of the future, outline a potential roadmap for the transition, and identify a set of opportunities for public- and private-sector collaboration.”

“As measures are increasingly implemented in payment programs based on value, the public and private sectors must collectively work to ensure the implementation of patient-centered measures that matter, minimize clinician burden, focus on improvement, and develop an agile learning measurement enterprise. The measurement enterprise is critical for successful transformation of the health system to achieve better health outcomes as efficiently as possible.”

(JAMA. 2013;309[21]:2215-2216. Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact Patrick H. Conway, M.D., M.Sc., call the CMS press office at 202-690-6145 or email press@cms.hhs.gov.

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Synthesizing Evidence – Shifting the Focus From Individual Studies to the Body of Evidence

“The research enterprise behaves as if a single study could provide the ultimate answer to a clinical question,” write M. Hassan Murad, M.D., M.P.H., and Victor M. Montori, M.D., M.Sc., of the Mayo Clinic, Rochester, Minn. “Researchers offer over optimistic sample-size calculations and other design features to convince funders and institutional review boards that their study will provide the answer. Medical journals and the popular media highlight single studies, too often without regard to similar studies.”

Researchers with the Cochrane Centre have advocated for the results of individual studies to be placed in the context of the totality of evidence for the last 15 years, with limited success.  In this Viewpoint, the authors offer reasons to shift the collective focus from single studies to the accumulating body of evidence.

(JAMA. 2013;309[21]:2217-2218. Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact M. Hassan Murad, M.D., M.P.H., call Shelly Plutowski at 507-284-5005 or email rplutowski@mayo.edu.

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

For More Information: contact The JAMA Network^® Media Relations Department at 312-464-JAMA (5262) or email mediarelations@jamanetwork.org.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 4, 2013

Media Advisory: To contact Melinda Maggard-Gibbons, M.D., M.S.H.S., call Warren Robak at 310-451-6913 or email robak@rand.org.

CHICAGO – A review of more than 50 studies found limited evidence supporting the use of bariatric surgical procedures for non-morbidly obese adults (body mass index [BMI] 30-35) with diabetes or impaired glucose intolerance, according to a study in the June 5 issue of JAMA. For the limited data that was available for this patient group, bariatric surgery was associated with greater improvements in short-term weight loss, intermediate blood glucose levels, blood pressure, and high cholesterol than nonsurgical interventions such as medications, diet, and behavioral changes.

“Bariatric surgery is often used to promote weight loss and manage obesity-related comorbidities [co-existing illnesses] in morbidly obese patients (body mass index [BMI; 35 or greater]). In this population, procedures such as laparoscopic adjustable gastric banding and Roux-en-Y gastric bypass have resulted in better glucose control and more weight loss at 1 or 2 years than nonsurgical therapy,” according to background information in the article. “Bariatric surgical procedures are being advocated as a treatment for diabetes in less-obese individuals (BMI, 30-35). However, this practice remains controversial. In 2006, the Centers for Medicare & Medicaid Services would not approve coverage for patients with lower BMI and diabetes, whereas the U.S. Food and Drug Administration has approved gastric banding for individuals with a BMI of 30 to 35 who have an obesity-related comorbidity.”

Melinda Maggard-Gibbons, M.D., M.S.H.S., of Rand Health, Santa Monica, Calif., and colleagues conducted a systematic review of the relative benefits and risks associated with surgical and nonsurgical therapies for treating diabetes or impaired glucose tolerance in patients with a BMI of 30 to 35. The authors conducted a search of the medical literature and identified 32 surgical studies, 11 systematic reviews on nonsurgical treatments, and 11 large non-surgical studies published after those  reviews that met criteria for the analysis.

The researchers found that bariatric surgery was associated with greater weight loss (range, 32-53 lbs.) and glycemic control during 1 to 2 years of follow-up than nonsurgical treatment in only three randomized clinical trials (RCTs; n=290). None of these trials had substantial numbers of patients meeting the study criteria: 1 trial of 150 patients with type 2 diabetes and an average BMI of 37; 1 trial of 80 patients without diabetes and BMI of 30 to 35; and 1 trial of 60 patients with diabetes and BMI of 30 to 40 [13 patients with BMI <35]).

Bariatric surgery seemed to be associated with weight loss and diabetes control in observational studies having 1 or 2 years of follow-up with indirect comparisons of evidence (approximately 600 patients) and meta-analyses of nonsurgical therapies (containing more than 300 RCTs).

Surgeon-reported adverse events were low (e.g., hospital deaths of 0.3 percent-1.0 percent), but data were from select centers and surgeons. Long-term adverse events are unknown.

“… there are limited data from clinical trials in this specific patient population, and it is unknown whether the benefits observed are durable long-term and if these findings might translate into reductions in the microvascular and macrovascular complications of diabetes. Until such data are available, the evidence is insufficient to reach conclusions about the appropriate use of bariatric surgery in this patient population, performance of these procedures in this target population should be under close scientific scrutiny, and additional studies comparing procedures are warranted,” the authors conclude.

(JAMA. 2013;309(21):2250-2261; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This project was funded under a contract from the AHRQ and U.S. Department of Health and Human Services. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, JUNE 4, 2013

Media Advisory: To contact Sayeed Ikramuddin, M.D., call Matt DePoint at 612-625-4110 or email mdepoint@umn.edu. To contact editorial author Bruce M. Wolfe, M.D., call Mirabai Vogt at 503-494-7986 or email vogtmi@ohsu.edu.

CHICAGO – Among mild to moderately obese patients with type 2 diabetes, adding gastric bypass surgery to lifestyle and medical management was associated with a greater likelihood of improved levels of metabolic risk factors such as blood glucose, LDL-cholesterol and systolic blood pressure, according to a study in the June 5 issue of JAMA.

“The foundation of treatment for type 2 diabetes mellitus is weight loss, achieved through reduction of energy intake and increased physical activity via lifestyle modification. Results from the Look AHEAD (Action for Health in Diabetes) trial show that sustained weight loss through lifestyle modification improves diabetes control, but this is difficult to achieve and maintain over time,” according to background information in the article. “Controlling glycemia, blood pressure, and cholesterol is important for patients with diabetes. How best to achieve this goal is unknown.”

Sayeed Ikramuddin, M.D., of the University of Minnesota, Minneapolis, and colleagues conducted a study to compare Roux-en-Y gastric bypass with lifestyle and intensive medical management to achieve control of comorbid (co-existing) risk factors. The 12-month, 2-group randomized trial was conducted at 4 teaching hospitals in the United States and Taiwan and included 120 participants who had a hemoglobin A_1c (HbA_1c) level of 8.0 percent or higher, body mass index (BMI) between 30.0 and 39.9, C peptide level of more than 1.0 ng/mL, and type 2 diabetes for at least 6 months. The study began in April 2008. The interventions for the trial were lifestyle-intensive medical management intervention and Roux-en-Y gastric bypass surgery. Medications for hyperglycemia, hypertension, and dyslipidemia were prescribed according to protocol and surgical techniques that were standardized.

The composite goal for the study was the goal established by the American Diabetes Association (ADA) for the treatment of diabetes: HbA_1c less than 7.0 percent, low-density lipoprotein cholesterol less than 100 mg/dL, and systolic blood pressure less than 130 mm Hg.

All 120 patients received the Look AHEAD intensive lifestyle-medical management protocol, the protocol used in the Look AHEAD study and considered to be the most successful for treating diabetes in obese patients; 60 of the 120 patients were randomly assigned to undergo Roux-en-Y gastric bypass. The researchers found that at 12 months, 11 participants (19 percent) in the lifestyle-medical management group and 28 (49 percent) in the gastric bypass group achieved the primary composite end point. Among the composite end point components, the only significant treatment effect was for HbA_1c: 18 participants (32 percent) in the lifestyle-medical management group vs. 43 (75 percent) in the gastric bypass group achieved an HbA_lc level of less than 7 percent.

The lifestyle-medical management group lost an average of 7.9 percent of initial body weight at 1 year, whereas the average weight loss in the gastric bypass group was 26.1 percent. “On average, the gastric bypass group used 3.0 fewer medications to manage glycemia, dyslipidemia, and hypertension than did those in the lifestyle-medical management group. The gastric bypass group also had significantly better results for the secondary outcomes of glycemia, HDL cholesterol, triglycerides, and diastolic blood pressure,” the authors write.

Analyses indicated that achieving the composite end point was primarily attributable to weight loss. The gastric bypass group experienced more nutritional deficiency than the lifestyle-medical management group. Overall, there were 22 serious adverse events in the gastric bypass group and 15 in the lifestyle-medical management group.

This study overcame limitations of prior studies of bariatric surgery by using a widely accepted nonsurgical treatment protocol, used endpoints recommended as the major goal for treatment by the ADA, was performed by multiple surgeons of different hospitals and studied a single operative procedure, the Roux-en-Y gastric bypass, considered to be the best procedure for weight loss.

“The merit of gastric bypass treatment of moderately obese patients with type 2 diabetes depends on whether potential benefits make risks acceptable. Bariatric surgery can result in dramatic improvements in weight loss and diabetes control in moderately obese patients with type 2 diabetes who are not successful with lifestyle changes or medical management. The benefits of applying bariatric surgery must be weighed against the risk of serious adverse events,” the researchers conclude.

(JAMA. 2013;309(21):2240-2249; 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 4 at this link.

Editorial: Treating Diabetes With Surgery

In an accompanying editorial, Bruce M. Wolfe, M.D., of Oregon Health and Science University, Portland, and colleagues comment on the two articles in this issue of JAMA regarding weight loss surgery and diabetes.

“Recent large scale trials of intensive medical management for obesity and diabetes have been disappointing. Substantial resources are required to cause modest weight loss and diabetes control. Bariatric surgery does result in substantial weight loss with excellent diabetes control but is offset by initial high cost and risks for surgical complications. The optimal approach for treatment of obesity and diabetes remains unknown. The answer will only come from more well designed, randomized trials such as that performed by Ikramuddin et al that provide definitive answers.”

(JAMA. 2013;309(21):2274-2275; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 21, 2013

Advances in Regulatory Science at the Food and Drug Administration

In this Viewpoint, Bruce M. Psaty, M.D., Ph.D., of the University of Washington, Seattle, and colleagues discuss advances in recent years at the U.S. Food and Drug Administration (FDA) to improve drug evaluation.

“The mark of a highly functional regulatory agency is the timely identification of, and the timely and appropriate response to, safety issues. The FDA’s development of the benefit-risk framework, the creation of the Mini-Sentinel, and the use of Risk Evaluation and Mitigation Strategies (REMS) all deserve praise as key efforts to implement a lifecycle approach to drug evaluation. The optimal use of these new tools nonetheless represents a new challenge for the agency. Adequate funding for the FDA—and additional authorities, such as making REMS assessments enforceable—are essential for the agency to continue to make progress in balancing the need for expeditious approval processes with the need for protecting the health of the public.”

(JAMA. 2013;309[20]:2103-2104. Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact Bruce M. Psaty, M.D., Ph.D., call Leila Gray at 206-685-0381 or email leilag@uw.edu.

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 Medication Nonadherence – A Diagnosable and Treatable Medical Condition

“Medication nonadherence is widely recognized as a common and costly problem. Approximately 30 percent to 50 percent of U.S. adults are not adherent to long-term medications leading to an estimated $100 billion in preventable costs annually,” writes Zachary A. Marcum, Pharm.D., M.S., of the University of Pittsburgh, and colleagues. “How can adherence be improved? We propose that the first step is to view medication nonadherence as a diagnosable and treatable medical condition.”

“Based on identified barriers derived from systematic screening, patient-tailored interventions can be delivered in a safe, effective, and efficient manner, with systematic monitoring over time due to the dynamic process of medication adherence. Consistent with Patient-Centered Outcomes Research Institute goals and priorities, community and patient partners should be identified and included throughout the planning and implementation of future studies. Finally, synergism among multiple disciplines is necessary to successfully improve medication adherence for adults.”

(JAMA. 2013;309[20]:2105-2106. Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact Zachary A. Marcum, Pharm.D., M.S., call Cristina Mestre at 412-586-9776 or email mestreca@upmc.edu.

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Value of Unique Device Identification in the Digital Health Infrastructure

“In recent years, high-profile cases of medical device failure resulting in patient harm—such as implantable cardioverter-defibrillator leads and metal-on-metal hip implants—have received substantial attention both in the medical literature and popular press. These examples illustrate the need for a more effective system of monitoring device performance and protecting patient safety,” write Natalia A. Wilson, M.D, M.P.H., of Arizona State University, Tempe and Joseph Drozda Jr., M.D., of Mercy Health, Chesterfield, Mo.

In this Viewpoint, the authors discuss the Food and Drug Administration’s (FDA’s) establishment of a Unique Device Identification (UDI) System and the UDI’s Final Rule, expected in June 2013, which “will mandate that manufacturers assign unique identifiers to their marketed devices. In addition to enhancing postmarket surveillance, use of UDI should ensure the ability to track a device across health care settings; support safe and accurate device use; create a standard for device documentation in health information technology systems; enhance recall management; improve efficiency; and support health care cost savings.”

(JAMA. 2013;309[20]:2107-2108. Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact Natalia A. Wilson, M.D, M.P.H., call Debbie Freeman at 480-965-9271 or email Debbie.Freeman@asu.edu; or Julie Newberg at 480-727-3116 or email julie.newberg@asu.edu.

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

For More Information: contact The JAMA Network^® Media Relations Department at 312-464-JAMA (5262) or email mediarelations@jamanetwork.org.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 21, 2013

Media Advisory: To contact Duncan Young, D.M., email duncan.young@nda.ox.ac.uk. To contact editorial author Derek C. Angus, M.D., M.P.H., call Rick Pietzak at 412-864-4151 or email pietzakr@upmc.edu.

CHICAGO – For critically ill patients receiving mechanical ventilation, early tracheostomy (within the first 4 days after admission) was not associated with an improvement in the risk of death within 30 days compared to patients who received tracheostomy placement after 10 days, according to a study in the May 22/29 issue of JAMA.

“A tracheostomy is commonly performed when clinicians predict a patient will need prolonged mechanical ventilation,” according to background information in the article. The use of this procedure has increased, such that up to one-third of patients requiring prolonged mechanical ventilation now receive tracheostomy. Perceived beneficial effects of tracheostomies might be maximized if the procedure were performed early in a patient’s illness, the authors write. “There is little evidence to guide clinicians regarding the optimal timing for this procedure.”

Duncan Young, D.M., of John Radcliffe Hospital, Oxford, England, and colleagues conducted a study to examine whether early vs. late tracheostomy would be associated with lower mortality among adult patients requiring mechanical ventilation in critical care units. The randomized clinical trial was conducted between 2004 and 2011 at 70 adult general and 2 cardiothoracic critical care units in 13 university and 59 nonuniversity hospitals in the United Kingdom. The study included 909 adult patients receiving mechanical ventilation for less than 4 days and identified by the treating physician as likely to require at least 7 more days of mechanical ventilation. Patients were randomized 1:1 to early tracheostomy (within 4 days) or late tracheostomy (after 10 days if still indicated).

Of the 455 patients assigned to early tracheostomy, 91.9 percent received a tracheostomy and of 454 patients assigned to late tracheostomy, 44.9 percent received a tracheostomy. The researchers found that the primary outcome, all-cause mortality 30 days from randomization, was not statistically different in the 2 groups: 139 patients (30.8 percent) in the early group and 141 patients (31.5 percent) in the late group died. Two-year mortality was 51.0 percent in the early group and 53.7 percent in the late group.

For the 622 patients receiving tracheostomies, procedure-related complications were reported for a total of 39 patients (6.3 percent): twenty-three (5.5 percent) of 418 patients in the early group and 16 (7.8 percent) of 204 patients in the late group. The most frequent complication was bleeding sufficient to require intravenous fluids or another intervention.

For the 315 survivors of critical care in the early group and the 312 survivors in the late group, the median (midpoint) duration of critical care admission was 13.0 days in the early group and 13.1 days in the late group. Median total hospital stay in those surviving to discharge (256 both groups) was 33 days in the early group and 34 days in the late group.

“The implications, for clinical practice and for patients, from this study are found from the results in the late group. Not only were there no statistically significant difference in mortality between the 2 groups but, through waiting, an invasive procedure was avoided in a third of patients. Avoiding this significant proportion of tracheostomies, a procedure associated with a 6.3 percent acute complication rate in this study (and 38 percent-39 percent overall complication rates in the other recent multicenter studies), did not appear to be associated with any significant increase in health care resource use, as measured by critical care unit or hospital stay. It would appear that delaying a tracheostomy until at least day 10 of a patient’s critical care unit stay is the best policy,” the authors write.

“Early tracheostomy should therefore be avoided unless tools to accurately predict the duration of mechanical ventilation on individual patients can be developed and validated.”

(JAMA. 2013;309(20):2121-2129; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The UK Intensive Care Society funded the research prioritization work that led to this study. The study was funded by the UK Intensive Care Society and the Medical Research Council. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: When Should a Mechanically Ventilated Patient Undergo Tracheostomy?

In an accompanying editorial, Derek C. Angus, M.D., M.P.H., of the University of Pittsburgh School of Medicine (and Contributing Editor, JAMA), writes that the finding in this study that tracheostomy generally should be delayed until at least 10 days after initiating mechanical ventilation has potentially important implications.

“Thus, 2 large, multicenter European trials show very similar findings: a strategy to perform tracheostomy early (within the first week) offers no benefit over a wait-and-see strategy that delays tracheostomy until after 10 days of mechanical ventilation. However, the consistently poor ability of clinicians to predict in the first few days which patients would eventually require prolonged ventilation means the early strategy inadvertently leads to a large increase in the number of unnecessary tracheostomies.”

“Nevertheless, if clinicians were to uniformly adopt a wait-and-see strategy, the number of tracheostomies would decline. Given the significant difference in diagnosis related group (DRG) payments for patients who are mechanically ventilated with and without a tracheostomy, hospital reimbursement also would decline. How hospital profitability would be affected by such a significant change in practice is unclear.”

“In coming years, payment reforms that bundle hospital, physician, and postacute care for inpatient episodes may make this quandary less important. However, as long as hospitals are reimbursed using a DRG system, it would seem prudent to revise the reimbursement strategies for patients facing potentially prolonged mechanical ventilation to better align financial incentives with the best clinical evidence.”

(JAMA. 2013;309(20):2163-2164; 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, MAY 21, 2013

Media Advisory: To contact Wei Jiang, M.D., call Rachel Harrison at 919-419-5069 or email rachel.harrison@duke.edu.

CHICAGO – Among patients with stable coronary heart disease and mental stress-induced myocardial ischemia (MSIMI), 6 weeks of treatment with the antidepressant escitalopram, compared with placebo, resulted in a lower rate of MSIMI, according to a study in the May 22/29 issue of JAMA.

“A robust body of evidence has identified emotional stress as a potential triggering factor in coronary heart disease (CHD) and other cardiovascular events,” according to background information in the article. “During the last 3 decades, the association of emotional distress and myocardial ischemic activity [insufficient blood flow to the heart muscle, often resulting in chest pain] in the laboratory has been well studied. In the laboratory setting, MSIMI occurs in up to 70 percent of patients with clinically stable CHD and is associated with increased risk of death and cardiovascular events.” Few studies have examined therapeutics that effectively modify MSIMI. Recent evidence suggests that selective serotonin reuptake inhibitors (SSRIs) may reduce mental stress-induced hemodynamic response, metabolic risk factors, and platelet activity.

Wei Jiang, M.D., of the Duke University Medical Center, Durham, N.C., and colleagues conducted a study to investigate whether SSRI treatment can improve MSIMI. The randomized trial included patients with clinically stable coronary heart disease and laboratory-diagnosed MSIMI. Enrollment occurred from July 2007 through August 2011 at a tertiary medical center. Eligible participants were randomized 1:1 to receive escitalopram or placebo over 6 weeks. A total of 56 patients in each group completed end point assessments. Occurrence of MSIMI was defined via various measures during 1 or more of 3 mental stressor tasks: mental arithmetic, mirror trace, and public speaking with anger recall.

The researchers found that at the end of 6 weeks, more patients taking escitalopram (34.2 percent) had absence of MSIMI during the 3 mental stressors compared with patients taking placebo (17.5 percent). Analysis showed that the escitalopram group had a significantly higher rate (2.6 times) of no MSIMI compared with the placebo group. Also, hemodynamic responses to mental stress were all lower in the escitalopram group, with differences in systolic blood pressure and heart rate between the groups significant.

In addition, the 6-week escitalopram intervention was associated with greater improvements in certain measures of psychological functioning, including state anxiety and positive affect, during mental stress.

Exercise capacity was not significantly altered at week 6 in participants receiving escitalopram vs. those receiving placebo.

“In summary, 6-week pharmacologic enhancement of serotonergic function superimposed on the best evidence-based management of CHD appeared to significantly improve MSIMI occurrence. These results support and extend previous findings suggesting that modifying central and peripheral serotonergic function could improve CHD symptoms and may have implications for understanding the pathways by which negative emotions affect cardiovascular prognosis,” the authors conclude.

(JAMA. 2013;309(20):2139-2149; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by the NHLBI, Bethesda, Md. Escitalopram and matched placebo were supplied by Forest Research Institute Inc., Germantown, Md. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, 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, May 21 at this link.

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EMBARGOED FOR EARLY RELEASE: 1:00 P.M. (CT) TUESDAY, MAY 21, 2013

Media Advisory: To contact corresponding author David A. Schwartz, M.D., call Mark Couch at 303-724-5377 or email Mark.Couch@ucdenver.edu.

CHICAGO – Variation in the gene MUC5B among patients with idiopathic pulmonary fibrosis was associated with improved survival, according to a study published online by JAMA. The study is being released early online to coincide with its presentation at the American Thoracic Society international conference.

“Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with a median [midpoint] survival of 3 years,” according to background information in the article. The prognosis is variable; patients may remain stable for several years, slowly lose lung function, progress in an intermittent fashion, or experience precipitous acute exacerbations. “Current prediction models of mortality in IPF, which are based on clinical and physiological parameters, have modest value in predicting which patients will progress. In addition to the potential for improving prognostic models, identifying genetic and molecular features that are associated with IPF mortality may provide insight into the underlying mechanisms of disease and inform clinical trials.”

Anna L. Peljto, Dr.P.H., of the University of Colorado Denver, and colleagues conducted a study to determine whether the variation (rs35705950) of the gene MUC5B, previously reported to be associated with the development of pulmonary fibrosis, is associated with survival among patients with IPF. The study included two independent cohorts of patients with IPF: the INSPIRE cohort, consisting of patients enrolled in the interferon-γ1b trial (n=438; December 2003 – May 2009; 81 centers in 7 European countries, the United States, and Canada), and the Chicago cohort, consisting of IPF participants recruited from the Interstitial Lung Disease Clinic at the University of Chicago (n = 148; 2007-2010). The INSPIRE cohort was used to model the association of MUC5B genotype with survival. The Chicago cohort was used for replication of findings.

The median follow-up period was 1.6 years for INSPIRE and 2.1 years for Chicago. During follow-up, there were 73 deaths among the INSPIRE cohort patients and 64 deaths among the Chicago cohort patients. Analysis indicated that the unadjusted 2-year cumulative incidence of death was lower among patients carrying 1 or more copies of the IPF risk allele (an alternative form of a gene) (T) in both the INSPIRE cohort and the Chicago cohort.

According to the authors, “The addition of the MUC5B genotype to the survival models significantly improved the predictive accuracy of the model in both the INSPIRE cohort and the Chicago cohort.”

“These findings suggest that the common polymorphism in the promoter of MUC5B (rs35705950), previously reported to be strongly associated with the development of familial interstitial pneumonia and idiopathic pulmonary fibrosis, is significantly associated with improved survival in IPF. These findings are consistent with a previous report of an association between the MUC5B variant and less severe pathological changes in familial interstitial pneumonia, as well as another report of slower decline in forced vital capacity for patients with IPF. This study is, to our knowledge, the first to demonstrate that a genetic variant is associated with survival in IPF.”

“Further research is necessary to refine the risk estimates and to determine the clinical implications of these findings,” the researchers conclude.

(doi:10.1001/jama.2013.5827; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This research was supported by the National Heart, Lung, and Blood Institute and the Dorothy P. and Richard P. Simmons Endowed Chair for Pulmonary Research (University of Pittsburgh School of Medicine). Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR EARLY RELEASE: 1:00 P.M. (CT) TUESDAY, MAY 21, 2013

Media Advisory: To contact Jorg D. Leuppi, M.D., Ph.D., email joerg.leuppi@ksli.ch. To contact editorial co-author Don D. Sin, M.D., call Justin Karasick at 604-806-8460 or email jkarasick@providencehealth.bc.ca.

CHICAGO – Among patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) requiring hospital admission, a 5-day glucocorticoid treatment course was non-inferior (not worse than) to a 14-day course with regard to re-exacerbation during 6 months of follow-up, according to a study published online by JAMA. The study is being released early online to coincide with its presentation at the American Thoracic Society international conference. The authors write that these findings support a shorter-course glucocorticoid treatment regimen, which would reduce glucocorticoid exposure and the risk of possible adverse effects.

“Acute exacerbations of COPD are a risk factor for disease deterioration, and patients with frequent exacerbations have an increased mortality,” according to background information in the article. “International guidelines advocate a 7- to 14-day course of systemic glucocorticoid therapy in acute exacerbations of COPD. However, the optimal dose and duration of therapy are unknown. … Given the adverse effects of glucocorticoids and the potentially large number of exacerbations occurring in patients with COPD, glucocorticoid exposure should be minimized.”

Jorg D. Leuppi, M.D., Ph.D., of the University Hospital of Basel, Switzerland, and colleagues conducted a study to examine whether a short-term (5 days) systemic glucocorticoid treatment in patients with COPD exacerbation is noninferior to conventional (14 days) treatment with respect to clinical outcome and whether it decreases the exposure to steroids. The randomized trial (REDUCE) was conducted in 5 Swiss teaching hospitals, enrolling 314 patients presenting to the emergency department with acute COPD exacerbation, past or present smokers without a history of asthma, from March 2006 through February 2011. Patients received treatment with 40 mg of prednisone daily for either 5 or 14 days in a placebo-controlled fashion. The predefined noninferiority criterion was an absolute increase in exacerbations of at most 15 percent. The primary measured outcome was time to next exacerbation within 180 days.

Of the 314 randomized patients, 289 (92 percent) of whom were admitted to the hospital, 311 were included in the intention-to-treat analysis and 296 in the per-protocol analysis. A total of 56 patients (35.9 percent) reached the primary end point of COPD exacerbation in the short-term treatment group compared with 57 patients (36.8 percent) in the conventional treatment group. Time to re-exacerbation did not differ between groups.

Among patients who experienced a re-exacerbation during follow-up, the median (midpoint) time to event was 43.5 days in the short-term group and 29 days in the conventional treatment group. Estimates of re-exacerbation rates were 37.2 percent in the short-term and 38.4 percent in the conventional treatment group.

“There was no difference between groups in time to death, the combined end point of exacerbation, death, or both and recovery of lung function. In the conventional group, mean (average) cumulative prednisone dose was significantly higher (793 mg vs. 379 mg), but treatment-associated adverse reactions, including hyperglycemia and hypertension, did not occur more frequently,” the authors write.

During hospital stay, there was no increase in the requirement for mechanical ventilation with the short-term treatment regimen.

“There was no significant difference in recovery of lung function and disease-related symptoms, but the shorter course resulted in a significantly reduced glucocorticoid exposure,” the researchers write. “These findings support the use of a 5-day glucocorticoid treatment in acute exacerbations of COPD.”

(doi:10.1001/jama.2013.5023; 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: Steroids for Treatment of COPD Exacerbations – Less Is Clearly More

Don D. Sin, M.D., and Hye Yun Park, M.D., Ph.D., of the University of British Columbia James Hogg Research Centre and the Institute for Heart and Lung Health, St. Paul’s Hospital, Vancouver, British Columbia, Canada, write in an accompanying editorial that “the clinical implications of this study are clear.”

“Most patients with acute COPD exacerbations can be treated with a 5-day course of prednisone or equivalent (40 mg daily). Furthermore, this regimen can be applied across all GOLD (Global Initiative for Chronic Obstructive Lung Disease) categories of disease severity. This is welcome news for patients with COPD who experience multiple exacerbations annually and are exposed to repeated courses of systemic corticosteroids. These findings will enable clinicians to minimize steroid exposure and reduce the risk of steroid-related toxicity in these patients.”

(doi:10.1001/jama.2013.5644; 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: 1:00 P.M. (CT) MONDAY, MAY 20, 2013

Media Advisory: To contact Gordon S. Doig, Ph.D., email gdoig@med.usyd.edu.au. To contact editorial co-author Juan B. Ochoa Gautier, M.D., call Rick Pietzak at 412-864-4151 or email pietzakr@upmc.edu.

CHICAGO – The early (within 24 hours of intensive care unit [ICU] admission) provision of intravenous nutrition among critically ill patients with contraindications (a condition that makes a particular procedure potentially inadvisable) to early use of enteral nutrition (such as through a feeding tube) did not result in significant differences in 60 day mortality or shorter ICU or hospital length of stay, compared with standard care, according to a study in the May 22/29 issue of JAMA. The study is being released early online to coincide with its presentation at the American Thoracic Society international conference. The intervention did result in a significant reduction in days of invasive mechanical ventilation.

“Parenteral nutrition [PN; intravenous administration of nutritional support] has been in common use since the 1960s and is accepted as the standard of care for patients with chronic nonfunctioning gastrointestinal tracts,” according to background information in the article. In critical illness, controversy surrounds the appropriate use of parenteral nutrition. “Systematic reviews suggest adult patients in ICUs with relative contraindications to early enteral nutrition [EN; feeding through the gastrointestinal tract, such as with the use of a feeding tube] may benefit from PN provided within 24 hours of ICU admission.”

Gordon S. Doig, Ph.D., of the University of Sydney, Australia, and colleagues conducted a multicenter clinical trial to assess the effects of providing parenteral nutrition within 24 hours of ICU admission to adult critically ill patients who would not otherwise receive nutrition therapy because of short-term relative contraindications to enteral nutrition. The randomized trial was conducted between October 2006 and June 2011 in ICUs of 31 community and tertiary hospitals in Australia and New Zealand. Participants were critically ill adults who were expected to remain in the ICU longer than 2 days.

A total of 1,372 patients were randomized (686 to standard care, 686 to early PN). Of 682 patients receiving standard care, 199 patients (29.2 percent) initially began EN, 186 patients (27.3 percent) initially began PN, and 278 patients (40.8 percent) remained unfed. Time to EN or PN in patients receiving standard care was 2.8 days. Patients receiving early PN began PN an average of 44 minutes after enrollment in the trial.

The researchers found that day-60 mortality did not differ significantly between groups (22.8 percent for standard care vs. 21.5 percent for early PN). There were also no significant differences between groups in rates of new infection. Standard care patients experienced significantly greater muscle wasting and significantly greater fat loss over the duration of their ICU stay.

Early PN patients rated day-60 quality of life statistically, but not clinically meaningfully, higher. Early PN patients required fewer days of invasive ventilation, but this did not result in a statistically significant reduction in ICU or hospital length of stay.

No harm was associated with the use of early parenteral nutrition in this trial.

(JAMA. 2013;309(20):2130-2138; 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: Early Nutrition in Critically III Patients – Feed Carefully and in Moderation

“The findings reported by Doig et al add important knowledge to the ongoing debate about when, how much, and through what route critically ill patients should be fed,” write Juan B. Ochoa Gautier, M.D., of the University of Pittsburgh, and Flavia R. Machado, M.D., Ph.D., of the Federal University of Sao Paulo, Brazil, in an accompanying editorial.

“This article joins several articles that suggest either benefit or harm from supplemental parenteral nutrition or whether ‘trophic feeding’ is ‘just as good’ as meeting nutritional goals in medical patients in the ICU during the first 7 days of their hospitalization. A significant amount of additional work is required to determine how to best deliver nutrition interventions in the ICU. It is essential (and indeed ethically imperative) for investigators at the forefront of this debate to be circumspect in their conclusions and clinical recommendations, to avoid their findings being misinterpreted and creating more harm than good. For now clinicians should attempt to optimize oral/enteral nutrition, avoid forced starvation if at all possible, and judiciously use supplemental parenteral nutrition.”

(JAMA. 2013;309(20):2165-2166; 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. Ochoa reported having a license on a patent focused on arginine metabolism and cancer treatment with NewLink. No other disclosures were reported.

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EMBARGOED FOR EARLY RELEASE: 1:00 P.M. (CT) MONDAY, MAY 20, 2013

Media Advisory: To contact Linda L. Chlan, Ph.D., R.N., call Kathryn Kelley at 614-688-1062 or email kelley.81@osu.edu. To contact editorial co-author Elie Azoulay, M.D., Ph.D., email elie.azoulay@sls.aphp.fr.

CHICAGO – Among intensive care unit patients receiving acute ventilatory support for respiratory failure, use of patient-preferred music resulted in greater reduction in anxiety and sedation frequency and intensity compared with usual care, according to a study published online by JAMA. The study is being released early online to coincide with its presentation at the American Thoracic Society international conference.

“Critically ill mechanically ventilated patients receive intravenous sedative and analgesic medications to reduce anxiety and promote comfort and ventilator synchrony,” according to background information in the article. These potent medications are often administered at high doses for prolonged periods and are associated with various adverse effects. “Mechanically ventilated patients have little control over pharmacological interventions to relieve anxiety; dosing and frequency of sedative and analgesic medications are controlled by intensive care unit (ICU) clinicians. Interventions are needed that reduce anxiety, actively involve patients, and minimize the use of sedative medications.” The authors note that “listening to preferred, relaxing music has reduced anxiety in mechanically ventilated patients in limited trials. It is not known if music can reduce anxiety throughout the course of ventilatory support, or reduce exposure to sedative medications.”

Linda L. Chlan, Ph.D., R.N., of Ohio State University, Columbus, and colleagues conducted a study to evaluate if a patient-directed music (PDM) intervention could reduce anxiety and sedative exposure in ICU patients receiving mechanical ventilation. The clinical trial included 373 patients from 12 ICUs at 5 hospitals in the Minneapolis-St. Paul area receiving acute mechanical ventilatory support for respiratory failure between September 2006 and March 2011. Of the patients included in the study, 86 percent were white, 52 percent were female, and the average age was 59 years. Patients were randomized to self-initiated PDM (n=126) with preferred selections tailored by a music therapist whenever desired while receiving ventilatory support; self-initiated use of noise-canceling headphones (NCH; n = 122); or usual care (n = 125). The main outcomes examined were daily assessments of anxiety (on a 100-mm visual analog scale) and 2 aggregate measures of sedative exposure (intensity and frequency).

The PDM patients listened to music for an average of 80 minutes/day; the NCH patients wore the noise-abating units for an average of 34.0 minutes/day. Analysis showed that patients in the PDM group had an anxiety score that was 19.5 points lower than patients in the usual care group.

For an average patient on the fifth study day (the average time patients were enrolled), a usual care patient received 5 doses of any 1 of the 8 study-defined sedative medications. An equivalent PDM patient received 3 doses of sedative medications on the fifth day, a relative reduction of 38 percent. By the end of the fifth day, a PDM patient had a relative reduction of 36 percent in their sedation intensity score and 36.5 percent in their anxiety score.

PDM did not result in greater reduction in anxiety or sedation intensity compared with NCH.

“Music provides patients with a comforting and familiar stimulus and the PDM intervention empowers patients in their own anxiety management; it is an inexpensive, easily implemented nonpharmacological intervention that can reduce anxiety, reduce sedative medication exposure, and potentially associated adverse effects. The PDM patients received less frequent and less intense sedative regimens while reporting decreased anxiety levels,” the authors write.

(doi:10.1001/jama.2013.5670; 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: Music Therapy for Reducing Anxiety in Critically Ill Patients

In an accompanying editorial, Elie Azoulay, M.D., Ph.D., of the Universite Paris-Diderot, Sorbonne Paris-Cite, and colleagues comment on the findings of this study.

“Reducing anxiety and amount of sedation in mechanically ventilated patients is of the utmost importance, particularly because the result may be a decrease in the post-ICU burden, which weighs heavily on many patients, as well as numerous complications related to sedation. The trial by Chlan et al provides preliminary data that create new possibilities for improving the well-being of ICU patients. Further studies are needed to better understand how music therapy might improve the ICU experience for critically ill patients.”

(doi:10.1001/jama.2013.5657; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Azoulay reports serving on the board of Gilead, and receiving payment for lectures and grants from Pfizer, Merck Sharp & Dohme, and Gilead. Ms. Chaize and Dr. Kentish-Barnes report no disclosures.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 14, 2013

No Significant Change Seen in Overall Smokeless Tobacco Use Among U.S. Youths

Tobacco use remains the leading preventable cause of death and disease in the United States. Declines in smoking among youths were observed from the late 1990s. “However, limited information exists on trends in smokeless tobacco use among U.S. youths,” writes Israel T. Agaku, D.M.D., M.P.H., of the Harvard School of Public Health, Boston, and colleagues.

As reported in a Research Letter, the authors analyzed recent trends in prevalence of smokeless tobacco use among youths using the 2000-2011 National Youth Tobacco Survey, a biennial national cross-sectional survey of U.S. middle school and high school students. Samples during 2000 through 2011 ranged from 35,828 students in 324 schools in 2000 to 18,866 students in 178 schools in 2011. Current smokeless tobacco use was defined as use of snuff, chewing, or dipping tobacco for 1 or more days within the past 30 days.

The researchers found that no significant change in overall smokeless tobacco prevalence occurred between 2000 (5.3 percent) and 2011 (5.2 percent). Downward trends were observed in the age groups of 9 to 11 and 12 to 14 years. Prevalence increased in the age group of 15 to 17 years.

“The prevalence of smokeless tobacco use among U.S. youths did not change between 2000 and 2011 and remained generally low. However, subgroup differences were observed. The use of modified traditional smokeless tobacco products, such as moist snuff, coupled with lower taxes on smokeless tobacco products (vs. cigarettes) may have contributed to the stable prevalence of smokeless tobacco (vs. the declining trend for cigarettes),” they write. “… these findings emphasize the need for evidence-based interventions to reduce smokeless tobacco use among youths.”

(JAMA. 2013;309[19]:1992-1994. Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact Israel T. Agaku, D.M.D., M.P.H., call 770-728-3220 or email iagaku@post.harvard.edu.

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Viewpoints in This Issue of JAMA

Two counter Viewpoints address the question: Should religious-based organizations be required to provide contraceptive coverage?

Contraception Is a Fundamental Primary Care Service

The Affordable Care Act (ACA) requires health care plans after August 1, 2012, to cover preventive health services recommended by the Institute of Medicine and endorsed by the Department of Health and Human Services. “Some religious organizations and private employers, however, have demanded exemption from providing contraception, arguing that it violates their religious beliefs,” writes Dana R. Gossett, M.D., M.S.C.I., of the Northwestern University Feinberg School of Medicine, Chicago, and colleagues. “We believe that allowing such an exception is at odds with evidence-based preventive care, inconsistent with actual patterns of contraceptive use among women who are religious, and a sectarian incursion into private health care decisions that is without parallel in the U.S. health care system.”

“Women whose health coverage is provided by a religious organization would face access barriers and additional costs compared with women whose coverage is provided by secular organizations, despite similar rates of demand and use. Lowering economic barriers to the most effective forms of birth control, long-acting reversible contraception, has been demonstrated to improve utilization and decrease rates of abortion and teenage pregnancy.”

“Both men and women engage in sexual activity, but women disproportionately bear the consequences of sexual activity in their risk of pregnancy and its attendant health outcomes. The strategy for managing the health of the nation cannot systematically discriminate against any one group of citizens. It is in the interest of the medical community and society at large to prevent such discrimination.”

(JAMA. 2013;309[19]:1997-1998. Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact Dana R. Gossett, M.D., M.S.C.I., call Erin White at 847-491-4888 or email ewhite@northwestern.edu.

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Contraceptives and the Law – A View From a Catholic Medical Institution

“As faculty members at the Creighton University School of Medicine—one of 4 Catholic medical schools in the United States—we question whether the public health benefits of mandated contraception coverage in the United States are so substantial that individuals and institutions should be forced to take actions that violate their collective moral conscience, thereby doing unnecessary harm to the principle of religious freedom,” writes Eric A. Zimmer, S.J., Ph.D., of the Creighton University School of Medicine and Creighton Center for Health Policy Ethics, Omaha, Neb., and colleagues.

“What is now at issue is whether the U.S. government, in policies that promote dissemination of cost-free birth control as a social imperative, has properly weighed the benefits vs. the harms created by this policy. The government should always strive to respect religious freedom, including that within institutions. If this right is to be restricted for the sake of a public health need, rigorous standards should be applied to validate this need and to weigh the relative value of preventive health care interventions proposed.”

“A careful analysis is required that attempts to balance the value of regulation of reproductive activity against the legal, medical, and ethical implications of this mandate. A thorough evaluation will take time, but the immediate issue to be decided is whether there is such a pressing public health need that the U.S. government should use its ultimate power to overcome the religious objections of employers and force them to provide services inconsistent with their beliefs and value systems.”

(JAMA. 2013;309[19]:1999-2000. Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact corresponding author Marc S. Rendell, M.D., call Jen Homann at 402-280-2864 or email JenniferHomann@creighton.edu.

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

EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 14, 2013

Media Advisory: To contact Ingrid Nygaard, M.D., call Phil Sahm at 801-581-2517 or email phil.sahm@hsc.utah.edu. To contact editorial author Cheryl B. Iglesia, M.D., call Karen Mallet at 215-514-9751 or email km463@georgetown.edu.

CHICAGO – Results after seven years of follow-up suggest that women considering abdominal sacrocolpopexy (surgery for pelvic organ prolapse [POP]) should be counseled that this procedure effectively provides relief from POP symptoms; however, the anatomic support deteriorates over time; and that adding an anti-incontinence procedure decreases, but does not eliminate the risk of stress urinary incontinence, and mesh erosion can be a problem, according to a study in the May 15 issue of JAMA.

“Pelvic organ prolapse occurs when the uterus or vaginal walls bulge into or beyond the vaginal introitus [vaginal opening]. It is a common occurrence and 7 percent to 19 percent of women receive surgical repair,” according to background information in the article. More than 225,000 surgeries are performed annually in the United States for POP. Abdominal sacrocolpopexy is the most durable operation for advanced POP and serves as the criterion standard against which other operations are compared, but little is known about safety and long-term effectiveness.

Ingrid Nygaard, M.D., of the University of Utah School of Medicine, Salt Lake City, and colleagues conducted a study to describe anatomic and symptomatic outcomes up to 7 years after abdominal sacrocolpopexy and to determine whether these are affected by anti-incontinence surgery (Burch urethropexy). The study consisted of a long-term follow-up of the randomized, 2-year Colpopexy and Urinary Reduction Efforts (CARE) trial of women with stress continence who underwent abdominal sacrocolpopexy between 2002 and 2005 for symptomatic POP and also received either concomitant Burch urethropexy or no urethropexy. Ninety-two percent (215/233) of eligible 2-year CARE trial completers were enrolled in the extended CARE study; and 181 (84 percent) and 126 (59 percent) completed 5 and 7 years of follow-up, respectively. The median (midpoint) follow-up was 7 years.

Of 215 women enrolled in the extended CARE study, 104 had undergone abdominal sacrocolpopexy plus Burch urethropexy and 111 had undergone abdominal sacrocolpopexy alone. The researchers found that that POP and urinary incontinence (UI) treatment failure rates gradually increased during the follow-up period. By year 7, the estimated probabilities of POP treatment failure for the urethropexy group and the no urethropexy group, respectively, were 0.27 and 0.22 for anatomic failure; 0.29 and 0.24 for symptomatic failure; and 0.48 and 0.34 for a composite of both.

Overall for the duration of the study, the estimated probability of stress urinary incontinence (SUI) was 0.62 for the urethropexy and 0.77 for the no urethropexy group. The expected time to treatment failure for the SUI outcome in the urethropexy group vs. the no urethropexy group was 131.3 months vs. 40.2 months, respectively.

The probability of mesh erosion at 7 years was 10.5 percent.

“Three key points emerge from these data. First, as a criterion standard for the surgical treatment of POP, abdominal sacrocolpopexy is less effective than desired. … Second, surgical prevention of SUI at the time of abdominal POP surgery involves no clinically significant trade-offs identified to date. … In addition, we found that complications related to synthetic mesh continue to occur over time,” the authors write.

“We anticipate that continued research in mesh development will lead to new materials and applications with fewer adverse events, but our data highlight the importance of careful long-term evaluation of new devices. Comparative effectiveness trials with long-term follow-up of at least 5 years are needed to compare abdominal sacrocolpopexy that we described in this report with vaginal prolapse procedures that include and do not include mesh augmentation.”

“Abdominal sacrocolpopexy effectiveness should be balanced with long term risks of mesh or suture erosion.”

(JAMA. 2013;309(19):2016-2024; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This research was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Office of Research on Women’s Health at the National Institutes of Health. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Please Note: An author podcast on this study will be available post-embargo on the JAMA website.

Editorial: Pelvic Organ Prolapse Surgery – Long-term Outcomes and Implications for Shared Decision Making

“This study has important clinical implications and calls into question the designation of the abdominal sacrocolpopexy as the criterion standard procedure for prolapse repair,” writes Cheryl B. Iglesia, M.D., of the Georgetown University School of Medicine, Washington, D.C., in an accompanying editorial.

“In this era of shared decision making, the next logical question is, ‘How do physicians advise patients who are contemplating pelvic reconstructive surgery for prolapse?’ Rates of prolapse and incontinence surgery are expected to increase substantially during the next 40 years as the population ages. Patients need to discuss with their physicians the available surgical and nonsurgical options for prolapse and incontinence, medical comorbidities, and review of available data. Surgeons and patients should also discuss prophylactic concomitant or staged surgery for stress incontinence at the time of prolapse repair. Timing of prolapse repair based on quality-of-life decisions should also be discussed preoperatively.”

(JAMA. 2013;309(19):2045-2046; 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. Dr. Iglesia reported serving as a consultant to the U.S. Food and Drug Administration on a mesh panel in September 2011.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MAY 14, 2013

Media Advisory: To contact Pamela N. Peterson, M.D., M.S.P.H., call Jenny Bertrand at 303-602-4924 or email Jennifer.bertrand@dhha.org.

CHICAGO – Even though patients receiving an implantable cardioverter-defibrillator (ICD) for primary prevention often receive a dual-chamber ICD, an analysis that included more than 32,000 patients receiving an ICD without indications for pacing finds that the use of a dual-chamber device compared with a single-chamber device was associated with a higher risk of device-related complications and similar 1-year mortality and hospitalization outcomes, according to a study in the May 15 issue of JAMA.

“The central decision regarding ICD therapy is whether to use a single- or dual-chamber device,” according to background information in the article. More complex dual-chamber devices may offer theoretical benefits beyond single-chamber devices for patients without an indication for pacing, but may also have greater risks. In a national sample, more than two-thirds of patients receiving an ICD received a dual-chamber device. “The outcomes of dual- vs. single-chamber devices are uncertain.”

Pamela N. Peterson, M.D., M.S.P.H., of the Denver Health Medical Center, and colleagues conducted a study to compare outcomes, including mortality, hospitalizations, and longer-term implant-related complications between single- and dual-chamber devices. The study included admissions in the National Cardiovascular Data Registry’s (NCDR) ICD registry from 2006-2009 that could be linked to Centers for Medicare & Medicaid Services fee-for-service Medicare claims data. Patients were included if they received an ICD for primary prevention and did not have a documented indication for pacing.

Among 32,034 patients, 12,246 (38 percent) received a single-chamber device and 19,788 (62 percent) received a dual-chamber device. After analysis of the data, the researchers found that rates of complications were lower for single-chamber devices (3.51 percent vs. 4.72 percent), but device type was not significantly associated with 1-year mortality (unadjusted rate, 9.85 percent vs. 9.77 percent), 1-year all-cause hospitalization (unadjusted rate, 43.86 percent vs. 44.83 percent), or hospitalization for heart failure (unadjusted rate, 14.73 percent vs. 15.38 percent).

The authors suggest that their study advances the understanding of the risks of dual-chamber devices. “Because implanting a dual-chamber ICD is a more complex and time-consuming procedure than implanting a single-chamber device, the possibility of device-related complications such as infection and lead displacement requiring device revision is likely to increase. Indeed, we observed a greater risk of complications among patients receiving dual-chamber devices.”

“Many patients receiving primary prevention ICDs receive dual-chamber devices. Dual-chamber devices do not appear to offer any clinical benefit over single-chamber devices with regard to death, all-cause readmission, or heart failure readmission in the year following implant. However, dual-chamber ICDs are associated with higher rates of complications. Therefore, among patients without clear pacing indications, the decision to implant a dual-chamber ICD for primary prevention should be considered carefully.”

(JAMA. 2013;309(19):2025-2034; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Dr. Peterson is supported by a grant from the Agency for Healthcare Research and Quality. This research was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry (NCDR). 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, MAY 7, 2013

Media Advisory:  To contact Jeffrey Ecker, M.D., call Susan McGreevey at 617-724-2764 or email: smcgreevey@partners.org

CHICAGO – A Clinical Crossroads review article in the May 8 issue of JAMA discusses the potential benefits and risks for pregnant women who request cesarean delivery without an indication of need rather than proceeding with a plan for vaginal delivery.

Jeffrey Ecker, M.D., from Massachusetts General Hospital, Boston, is the author of the article that examines this issue of cesarean delivery on maternal request (CDMR).   Dr. Ecker writes the term “refers to cesarean delivery performed without maternal or fetal indication; i.e., with no expectation of improving the physical health of the mother or neonate.”    Dr. Ecker notes that available data indicate that CDMR occurs in less than three percent of all deliveries in the United States.

“Reasons for considering CDMR include fear of specific elements of labor and concern for fetal or maternal morbidities attributable to vaginal delivery,” Dr. Ecker writes.   “Compared with a plan for vaginal delivery, CDMR may be associated with lower rates of hemorrhage, maternal incontinence, and rate but serious neonatal outcomes.  However, CDMR is associated with a higher risk of neonatal respiratory morbidity.”   And Dr. Ecker writes that repeated caesarean deliveries have higher rates of operative complications and placental abnormalities.

The article concludes: “There is no immediate expectation for CDMR to reduce the health risks of mothers or infants.   Accordingly, counseling and decisions regarding CDMR should be made after considering a woman’s full reproductive plans.”

(JAMA. 2013; 309(18):1930-1936)

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, MAY 7, 2013

Study Finds Increase in Fall-Related Traumatic Brain Injuries Among Elderly Men and Women

“Traumatic brain injury (TBI) is a major cause of hospitalization, disability, and death-worldwide, and among older adults, falling is the most common cause of TBI,” writes Niina Korhonen, B.M., of the Injury and Osteoporosis Research Center, Tampere, Finland, and colleagues in a Research Letter. The authors previously reported that the number and incidence of adults 80 years of age or older admitted to the hospital due to fall-induced TBI in Finland increased from 1970 through 1999. This analysis is a follow-up of this population through 2011.

The study included data from the Finnish National Hospital Discharge Register, a nationwide, computer-based register that provides data for severe injuries among the Finnish population. The researchers found that the total number of older Finnish adults with a fall-induced TBI increased considerably from 60 women and 25 men in 1970 to 1,205 women and 612 men in 2011. The age-adjusted incidence of TBI (per 100,000 persons) also showed an increase from 168.2 women in 1970 to 653.6 in 2011 (an increase of 289 percent) and from 174.6 to 724.0, respectively, in men (an increase of 315 percent).

“Our 40-year follow-up shows that the number and age-adjusted incidence of fall-induced TBI in Finnish men and women aged 80 years or older increased considerably between 1970 and 2011. Compared with the data in our previous study, the increase has continued since 1999,” the authors write. “Further studies are needed to better understand the reasons for the increase in fall-related TBI in older persons (aged >80 years) so that effective interventions for falls and injury prevention can be initiated.”

(JAMA. 2013;309[18]:1891-1892. Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact Niina Korhonen, B.M., email njkorhon@student.uef.fi.

Viewpoints in This Issue of JAMA

Investments in Infrastructure for Diverse Research Resources and the Health of the Public

“Active surveillance of drugs and devices in the postmarket setting is an essential component of the lifecycle approach to drug evaluation. The U.S. Food and Drug Administration (FDA) Amendments Act of 2007 required the agency to develop ‘a postmarket risk identification and analysis system.’ In response, scientists from the FDA and investigators from collaborating institutions have been actively and productively engaged in the creation of the Sentinel Initiative, including the Mini-Sentinel pilot program, which has become an exciting and powerful research resource,” write Bruce M. Psaty, M.D., Ph.D., and Eric B. Larson, M.D., M.P.H., of the University of Washington, Seattle.

In this Viewpoint, the authors discuss the Mini-Sentinel program.

“Major benefits and the major harms are often best represented separately—an approach that allows patients and physicians to incorporate their own preferences about particular risks or benefits. In updating the postmarket risk-benefit profile, the FDA should ensure that the full range of expertise is brought to bear on the decision-making process. In some instances, the postmarket active surveillance may also result in regulatory action. For many regulatory actions, Mini-Sentinel can also provide a timely mechanism for tracking their effects on the use of the medicinal product and the health of the public.”

(JAMA. 2013;309[18]:1895-1896. Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact Bruce M. Psaty, M.D., Ph.D., call Clare LaFond at 206-685-1323 or email clareh@uw.edu.

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 Developing Quality Measures to Address Overuse

“Medical societies and other organizations have worked for many years to develop quality measures to assess underuse of beneficial health care services (e.g., failure to use antiplatelet therapy for patients with acute myocardial infarction). More recently, organizations have begun efforts to address unnecessary tests and treatments and the high costs of health care by developing ‘overuse’ measures,” write Jason S. Mathias, M.D., M.S., and David W. Baker, M.D., M.P.H., of the Feinberg School of Medicine, Northwestern University, Chicago. Overuse is defined as the use of a service that is unlikely to improve patient outcomes or for which potential harms exceed likely benefits.

The standards for developing and evaluating overuse measures are not clearly defined and may differ from those for underuse measures. In this Viewpoint, the authors examine two key issues that need “careful consideration in the development, implementation, and evaluation of overuse measures as compared with more typical underuse measures: level of evidence and mitigating potential unintended consequences.”

“Compared with traditional underuse measures, the rules of evidence for developing overuse measures are less well defined, and thoughtful strategies are needed to avoid unintended consequences of overuse measures. When carefully developed, implemented, and monitored, overuse measures have the potential to be part of the solution to the cost, quality, and safety problems in the U.S. health care system.”

(JAMA. 2013;309[18]:1897-1898. Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact David W. Baker, M.D., M.P.H., call Marla Paul at 312-503-8928 or email marla-paul@northwestern.edu.

Editor’s Note: Please see the articles 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, MAY 7, 2013

Media Advisory: To contact corresponding author Markus M. Lerch, M.D., F.R.C.P., email lerch@uni-greifswald.de. To contact editorial author Emad M. El-Omar, M.D., email e.el-omar@abdn.ac.uk.

CHICAGO – Two genome-wide association studies and a subsequent meta-analysis have found that certain genetic variations are associated with susceptibility to Helicobacter pylori, a bacteria that is a major cause of gastritis and stomach ulcers and is linked to stomach cancer, findings that may help explain some of the observed variation in individual risk for H pylori infection, according to a study in the May 8 issue of JAMA.

“[H pylori] is the major cause of gastritis (80 percent) and gastroduodenal ulcer disease (15 percent-20 percent) and the only bacterial pathogen believed to cause cancer,” according to background information in the article. “H pylori prevalence is as high as 90 percent in some developing countries but 10 percent of a given population is never colonized, regardless of exposure. Genetic factors are hypothesized to confer H pylori susceptibility.”

Julia Mayerle, M.D., of University Medicine Greifswald, Greifswald, Germany, and colleagues conducted a study to identify genetic loci associated with H pylori seroprevalence. Two independent genome-wide association studies (GWASs) and a subsequent meta-analysis were conducted for anti-H pylori immunoglobulin G (IgG) serology in the Study of Health in Pomerania (SHIP) (recruitment, 1997-2001 [n =3,830]) as well as the Rotterdam Study (RS-I) (recruitment, 1990-1993) and RS-II (recruitment, 2000-2001 [n=7,108]) populations. Whole-blood RNA gene expression profiles were analyzed in RS-III (recruitment, 2006-2008 [n = 762]) and SHIP-TREND (recruitment, 2008-2012 [n=991]), and fecal H pylori antigen in SHIP-TREND (n=961).

Of 10,938 participants, 6,160 (56.3  percent) were seropositive for H pylori. GWAS meta-analysis identified an association between the gene TLR1 and H pylori seroprevalence, “a finding that requires replication in non-white populations,” the authors write.

“At this time, the clinical implications of the current findings are unknown. Based on these data, genetic testing to evaluate H pylori susceptibility outside of research projects would be premature.”

“If confirmed, genetic variations in TLR1 may help explain some of the observed variation in individual risk for H pylori infection,” the researchers conclude.

(JAMA. 2013;309(18):1912-1920; 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: Helicobacter pylori Susceptibility in the GWAS Era

In an accompanying editorial, Emad M. El-Omar, M.D., of Aberdeen University, Aberdeen, United Kingdom, writes that the authors of this study are appropriate to state, “based on their data, genetic testing to evaluate H pylori susceptibility is premature.”

“This would be superfluous, because nongenetic testing for the infection can be accomplished at a fraction of the cost. There is a bigger picture: understanding genetic susceptibility to H pylori is essential for understanding how to overcome this infection. The current approach to eradication of the infection is limited and based entirely on prescribing a cocktail of antibiotics with an acid inhibitor to symptomatic individuals. However, H pylori antibiotic resistance is increasing steadily, and eventually curing even benign conditions such as peptic ulcer disease arising from H pylori will be difficult. When considering gastric cancer, another H pylori-induced global killer, the necessity for understanding the pathogenesis of the infection and the role of host genetics in susceptibility is even greater. The corollary is that better understanding of infections, including genetic epidemiology, is crucial to design measures to eradicate the downstream consequences of H pylori in large populations.”

(JAMA. 2013;309(18):1939-1940; 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, MAY 7, 2013

Media Advisory: To contact Maurizio Gasparini, M.D., email maurizio.gasparini@humanitas.it. To contact editorial author Merritt H. Raitt, M.D., call Tamara Hargens-Bradley at 503-494-8231 or email hargenst@ohsu.edu.

CHICAGO – Programming an implantable cardioverter-defibrillator (ICD) with a long-detection interval compared with a standard-detection interval resulted in a reduction in anti-tachycardia pacing episodes, ICD shocks delivered, and inappropriate shocks, according to a study in the May 8 issue of JAMA.

“Therapy with ICDs is now the standard of care in primary and secondary prevention. As indications for implants have expanded, concern about possible adverse effects of ICD therapies on prognosis and quality of life has arisen. Several authors have reported that ICD therapies, both appropriate and inappropriate, are associated with an increased risk of death and worsening of heart failure. To reduce these unfavorable outcomes, several studies have focused on identifying the best device programming strategies, either by targeting the anti-tachycardia pacing [ATP; use of pacing stimulation techniques for termination of tachyarrhythmias] algorithms for interrupting fast ventricular tachyarrhythmias [abnormal heart rhythm] or by investigating the use of prolonged arrhythmia detection intervals,” according to background information in the article. “Using more intervals to detect ventricular tachyarrhythmias has been associated with reducing unnecessary ICD therapies.”

Maurizio Gasparini, M.D., of the Humanitas Clinical and Research Center, Rozzano, Italy, and colleagues conducted a study (ADVANCE III) to determine whether using 30 of 40 intervals to detect ventricular arrhythmias (VT) (long detection) during spontaneous fast VT episodes reduces ATP and shock delivery more than 18 of 24 intervals (standard detection). The randomized trial included 1,902 primary and secondary prevention patients (average age, 65 years; 84 percent men; 75 percent primary prevention ICD) with ischemic and nonischemic etiology undergoing first ICD implant at 1 of 94 international centers (March 2008-December 2010). Patients were randomized 1:1 to programming with long (n=948) or standard-detection (n=954) intervals.

Overall, 530 episodes were recorded and classified by the devices as ventricular arrhythmias. During a median (midpoint) follow-up of 12 months, the long-detection group had a 37 percent lower rate of delivered therapies (ATP and shocks) (346 vs. 557) compared to the standard-interval detection group. Estimates of the time to the first ICD therapy (ATP or shock) showed a significantly lower probability of receiving a therapy in the long-detection group.

The researchers also found that the frequency of appropriate shocks was similar between the groups, while the long-detection group was associated with a significantly lower incidence (45 percent lower rate) of inappropriate shocks. In addition, a lower hospitalization rate was observed in the long-detection group. No significant difference in mortality rates was seen between the groups.

“ADVANCE III demonstrated that the use of a long detection setting, in ICDs with the capability of delivering ATP during capacitor charge, significantly reduced the rate of ventricular therapies delivered and inappropriate shocks compared with the standard detection setting,” the authors write. “This programming strategy may be a useful approach for ICD recipients.”

(JAMA. 2013;309(18):1903-1911; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The ADVANCE III study was supported financially by Medtronic Inc. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Reducing Shocks and Improving Outcomes With Implantable Defibrillators

Merritt H. Raitt, M.D., of the Portland Veterans Administration Medical Center and Oregon Health and Science University, Portland, comments on the findings of this study in an accompanying editorial.

“The findings from the ADVANCE III trial by Gasparini et al add important new information to the evidence base of ICD programming for prevention of ventricular arrhythmias. Regardless of whether these programming interventions lead to reduced mortality, the unequivocal reduction in ICD shocks and the reduction in hospitalization without an increase in adverse events such as syncope suggests that this programming approach should be considered for adoption in the care of patients with ICDs and clinical characteristics similar to those enrolled in these studies.”

(JAMA. 2013;309(18):1937-1938; 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 EARLY RELEASE: 6 P.M. (CT) SUNDAY, MAY 5, 2013

Media Advisory: To contact Emily Y. Chew, M.D., call Jean Horrigan at 301-496-5248 or email jh@nei.nih.gov.

CHICAGO – In a large, multicenter, randomized clinical trial that included persons at high risk for progression to advanced age-related macular degeneration (AMD), adding the carotenoids lutein and zeaxanthin, the omega-3 fatty acids DHA and EPA, or both to a formulation of antioxidant vitamins and minerals that has shown effectiveness in reducing risk did not further reduce risk of progression to advanced AMD, according to a study published by JAMA. The study is being released early online to coincide with its presentation at the Association for Research in Vision and Ophthalmology annual meeting.

“Age-related macular degeneration , the leading cause of blindness in the developed world, accounts for more than 50 percent of all blindness in United States,” according to background information in the article. In 2004 it was estimated that 8 million individuals had intermediate AMD and approximately 2 million had advanced AMD, with no effective proven therapies for atrophic AMD. “Without more effective ways of slowing progression, the number of persons with advanced AMD is expected to double over the next 20 years, resulting in increasing socioeconomic burden,” the authors write. “Oral supplementation with the Age-Related Eye Disease Study (AREDS) formulation (antioxidant vitamins C, E, and beta carotene and zinc) has been shown to reduce the risk of progression to advanced AMD. Observational data suggest that increased dietary intake of lutein and zeaxanthin, omega-3 long-chain polyunsaturated fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]), or both might further reduce this risk.”

Emily Y. Chew, M.D., of the National Eye Institute, National Institutes of Health, Bethesda, Md., and colleagues with the Age-Related Eye Disease Study 2 (AREDS2) Research Group examined whether adding lutein + zeaxanthin, DHA + EPA, or both to the AREDS formulation might further reduce the risk of progression to advanced AMD. A secondary goal was to evaluate the effect of eliminating beta carotene, lowering zinc doses, or both in the AREDS formulation. AREDS2, a multicenter, randomized phase 3 study was conducted in 2006-2012, enrolling 4,203 participants 50 to 85 years of age at risk for progression to advanced AMD with bilateral large drusen (tiny yellow or white deposits in the retina of the eye or on the optic nerve head) or large drusen in 1 eye and advanced AMD in the fellow eye.

Participants were randomized to receive lutein (10 mg) and zeaxanthin (2 mg), DHA (350 mg) + EPA (650 mg), lutein + zeaxanthin and DHA + EPA, or placebo. All participants were also asked to take the original AREDS formulation or accept a secondary randomization to 4 variations of the AREDS formulation, including elimination of beta carotene, lowering of zinc dose, or both.

A total of 1,608 participants had experienced at least 1 advanced AMD event by the end of the study (1,940 events in 6,891 study eyes). The researchers found that the probabilities of progression to advanced AMD by 5 years were 31 percent for placebo, 29 percent for lutein + zeaxanthin, 31 percent for DHA + EPA, and 30 percent for lutein + zeaxanthin and DHA + EPA. In the primary analyses, comparisons with placebo demonstrated no statistically significant reductions in progression to advanced AMD.

“There was no apparent effect of beta carotene elimination or lower-dose zinc on progression to advanced AMD. More lung cancers were noted in the beta carotene vs. no beta carotene group (23 [2 percent] vs. 11 [0.9 percent]), mostly in former smokers,” the authors write.

None of the nutrients affected development of moderate or worse vision loss.

The researchers add that “these null results may be attributable to the true lack of efficacy. Other factors to consider include inadequate dose, inadequate duration of treatment, or both.”

“Based on apparent risks of beta carotene and possible benefits that are only evident within exploratory subgroup analyses, lutein + zeaxanthin requires further investigation for potential inclusion in the AREDS supplements.”

(doi:10.1001/jama.2013.4997; 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 6 p.m. CT Sunday, May 5 at this link.

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EMBARGOED FOR EARLY RELEASE: 8:15 A.M. (CT) SUNDAY, MAY 5, 2013

Media Advisory: To contact Barbara Schmidt, M.D., M.Sc., call Alison Fraser at 267-426-6054 or email FraserA1@email.chop.edu. To contact editorial co-author Eduardo Bancalari, M.D., call Lisa Worley at 305-243-5184 or email LWorley2@med.miami.edu.

CHICAGO – In a randomized trial performed to help resolve the uncertainty about the optimal oxygen saturation therapy in extremely preterm infants, researchers found that targeting saturations of 85 percent to 89 percent compared with 91 percent to 95 percent had no significant effect on the rate of death or disability at 18 months, according to a study published by JAMA. The study is being released early online to coincide with its presentation at the Pediatric Academic Societies annual meeting.

“Extremely preterm infants are monitored with pulse oximeters for several weeks after birth because they may require supplemental oxygen intermittently or continuously. The goal of oxygen therapy is to deliver sufficient oxygen to the tissues while minimizing oxygen toxicity and oxidative stress. It remains uncertain what values of arterial oxygen saturations achieve this balance in immature infants, who are especially vulnerable to the harmful effects of oxygen,” according to background information in the article.

Barbara Schmidt, M.D., M.Sc., of the Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, and colleagues conducted a study to compare the effects of targeting lower or higher arterial oxygen saturations in extremely preterm infants on the rate of death or disability. The randomized trial, conducted in 25 hospitals in Canada, the United States, Argentina, Finland, Germany, and Israel, included 1,201 infants with gestational ages of 23 weeks 0 days through 27 weeks 6 days, who were enrolled within 24 hours after birth between December 2006 and August 2010. Follow-up assessments began in October 2008 and ended in August 2012.

Study participants were monitored until postmenstrual ages (the time elapsed between the first day of the mother’s last menstrual period and birth [gestational age] plus the time elapsed after birth [chronological age]) of 36 to 40 weeks with pulse oximeters that displayed saturations of either 3 percent above or below the true values. Caregivers adjusted the concentration of oxygen to achieve saturations between 88 percent and 92 percent, which produced 2 treatment groups with true target saturations of 85 percent to 89 percent (n=602) or 91 percent to 95 percent (n=599). Alarms were triggered when displayed saturations decreased to 86 percent or increased to 94 percent. The primary outcome was a composite of death, gross motor disability, cognitive or language delay, severe hearing loss, or bilateral blindness at a corrected age of 18 months. Secondary outcomes included retinopathy of prematurity and brain injury.

The researchers found that targeting lower compared with higher oxygen saturations had no significant effect on the rate of death or disability at 18 months. “Of the 578 infants with data for this outcome who were assigned to the lower target range, 298 (51.6 percent) died or survived with disability compared with 283 of the 569 infants (49.7 percent) assigned to the higher target range,” the authors write. “Of the 585 infants with known vital status at 18 months in the lower saturation target group, 97 (16.6 percent) had died compared with 88 of 577 (15.3 percent) in the higher saturation target group.”

Targeting lower compared with higher saturations reduced the average postmenstrual age at last use of oxygen therapy, but had no significant effect on any other outcomes, including the rate of severe retinopathy of prematurity.

“Clinicians who try to translate the disparate results of the recent oxygen saturation targeting trials into their practice may find it prudent to target saturations between 85 percent and 95 percent while strictly enforcing alarm limits of 85 percent at all times, and of 95 percent during times of oxygen therapy. Our findings do not support recommendations that targeting saturations in the upper 80 percent range should be avoided. Because it is very difficult to maintain infants in a tight saturation target range, such recommendations may lead to increased tolerance of saturations above 95 percent and an increased risk of severe retinopathy. Although no longer a major cause of bilateral blindness, severe retinopathy remains a marker of serious childhood disabilities,” the authors conclude.

(doi:10.1001/jama.2013.5555; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Funded exclusively by the Canadian Institutes of Health Research. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Oxygenation Targets and Outcomes in Premature Infants

In an accompanying editorial, Eduardo Bancalari, M.D., and Nelson Claure, M.Sc., Ph.D., of the University of Miami Miller School of Medicine, comment on the findings of this and other studies that have examined this issue.

“Oxygen therapy continues to present neonatal clinicians with a difficult conundrum where efforts to reduce complications associated with hyperoxemia in premature infants may affect their survival. How the results of these trials should be translated into clinical practice is still controversial. If the long-term outcomes are not affected by the different saturation targets, should the shorter-term outcomes of death, severe retinopathy of prematurity, and bronchopulmonary dysplasia be used to formulate a recommendation? After all, no other outcome is as important as survival. Until the remaining questions raised by these studies are answered by the combined meta-analysis or new evidence becomes available, minimizing extreme oxygenation levels by targeting saturations between 90 and 95 percent appears to be a reasonable approach.”

(doi:10.1001/jama.2013.5831; 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: 11:15 A.M. (CT) SATURDAY, MAY 4, 2013

Media Advisory: To contact corresponding author Bethany J. Foster, M.D., M.Sc., call Julie Robert at 514-934-1934 ext. 71381; or email julie.robert@muhc.mcgill.ca.

CHICAGO – In a study that included more than 20,000 patients, there was a significant decrease in the United States in mortality rates over time among children and adolescents initiating end-stage kidney disease treatment with dialysis between 1990 and 2010, according to a study in the May 8 issue of JAMA. The study is being released early online to coincide with its presentation at the Pediatric Academic Societies annual meeting.

“Individuals with end-stage kidney disease (ESKD) face a significantly shortened life expectancy. In no group of ESKD patients is the loss of potential years of life larger than in children and adolescents. Although transplant remains the treatment of choice to maximize survival, growth, and development, 75 percent of children with ESKD require treatment with dialysis prior to receiving a kidney transplant. Dialysis is therefore a life-saving therapy for children with ESKD while they await transplant. Nevertheless, all-cause mortality rates in children receiving maintenance dialysis are at least 30 times higher than the general pediatric population, with even higher relative risks in very young children,” the authors write. “There have been substantial improvements in the care of children with ESKD between 1990 and 2010. However, to our knowledge, it is not known if mortality has changed over time in the United States, particularly in recent years.”

Mark M. Mitsnefes, M.D., M.Sc., of Cincinnati Children’s Hospital Medical Center, and colleagues conducted a study to determine if all-cause, cardiovascular, and infection-related mortality rates have changed between 1990 and 2010 among patients younger than 21 years of age with ESKD initially treated with dialysis and if changes in mortality rates over time differed by age at treatment initiation. The researchers used data from the United States Renal Data System. Children with a prior kidney transplant were excluded.

The researchers identified 23,401 children and adolescents who met study criteria. Crude mortality rates during dialysis treatment were higher among children younger than 5 years at the start of dialysis compared with those who were 5 years and older. The authors found that the all-cause mortality risk decreased progressively over calendar time for both those younger than 5 years and those 5 years and older at initiation. There was also a decrease over calendar time for cardiovascular and infection-related mortality risk among children younger than 5 years at initiation and among those 5 years and older.

“Numerous factors may have contributed to the observed reductions in mortality risk over time. Improved pre-dialysis care, advances in dialysis technology, and greater experience of clinicians may each have played a role,” the authors write.

“Almost all children initiating ESKD treatment are considered eligible for transplant. However, most will require dialysis during their lifetime, either before transplant or after allograft loss. In the United States, there was a significant decrease in mortality rates over time among children and adolescents initiating ESKD treatment with dialysis between 1990 and 2010. Further research is needed to determine the specific factors responsible for this decrease.”

(JAMA. 2013;309(18):1921-1929; 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. (ET) TUESDAY, APRIL 30, 2013

Antiretroviral Regimen Associated With Less Virological Failure Among HIV-Infected Children

Elizabeth D. Lowenthal, M.D., M.S.C.E., of the University of Pennsylvania Perelman School of Medicine and Children’s Hospital of Philadelphia, and colleagues conducted a study to determine whether there was a difference in time to virological failure between HIV-infected children initiating nevirapine vs. efavirenz-based antiretroviral treatment in Botswana.

“More than 2 million children worldwide are infected with human immunodeficiency virus (HIV), approximately 90 percent of whom live in sub-Saharan Africa,” according to background information in the article. “Worldwide, the nonnucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine are commonly used in first-line antiretroviral regimens in both adults and children with HIV infection. Data on the comparative effectiveness of these medications in children are limited. … Most countries favor nevirapine-based regimens for the majority of children due to perceived comparable effectiveness at lower cost.”

The study included children (3-16 years of age) who initiated efavirenz-based (n=421) or nevirapine-based (n=383) treatment between April 2002 and January 2011 at a large pediatric HIV care setting in Botswana. The primary outcome was time from initiation of therapy to virological failure, defined as lack of plasma HIV RNA suppression to less than 400 copies/mL by 6 months or confirmed HIV RNA of 400 copies/mL or greater after suppression.

With a median (midpoint) follow-up time of 69 months, the researchers found that 57 children (13.5 percent) initiating treatment with efavirenz and 101 children (26.4 percent) initiating treatment with nevirapine had virological failure. There were 11 children (2.6 percent) receiving efavirenz and 20 children (5.2 percent) receiving nevirapine who never achieved virological suppression.

“In this large cohort of children infected with HIV, time to virological failure was longer among children receiving efavirenz vs. nevirapine. With the majority of the world’s children receiving nevirapine-based antiretroviral therapy, these findings may have significant public health importance,” the authors write. “… more work should be done to make efavirenz a cost-effective option for pediatric antiretroviral treatment programs in resource-limited settings.”

(JAMA. 2013;309[17]:1803-1809. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: To contact Elizabeth D. Lowenthal, M.D., M.S.C.E., call Dana Mortensen at 267-426-6092 or email mortensen@email.chop.edu; or call Steve Graff at 215-349-5653 or email Stephen.graff@uphs.upenn.edu.

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 Study Examines Neurodevelopmental Outcomes For Children Born Extremely Preterm

Fredrik Serenius, M.D., Ph.D., of Uppsala University, Uppsala, Sweden, and colleagues conducted a study to assess neurological and developmental outcome in extremely preterm (less than 27 gestational weeks) children at 2.5 years.

“A proactive approach to resuscitation and intensive care of extremely preterm infants has increased survival and lowered the gestational age of viability. There are concerns that increased survival may come at the cost of later neurodevelopmental disability among survivors. Approximately 25 percent of extremely preterm infants born in the 1990s had a major disability at preschool age, such as impaired mental development, cerebral palsy, blindness, or deafness. More recent studies report decreasing, unchanged, or increasing rates of neurodevelopmental disability at preschool age compared with previous decades,” according to background information in the article.

The study included extremely preterm infants born in Sweden between 2004 and 2007. Of 707 live-born infants, 491 (69 percent) survived to 2.5 years. Survivors were assessed and compared with control infants who were born at term and matched by sex, ethnicity, and municipality. Assessments ended in February 2010 and comparison estimates were adjusted for demographic differences. Cognitive, language, and motor development were assessed. Clinical examination and parental questionnaires were used for diagnosis of cerebral palsy and visual and hearing impairments. Assessments were made by week of gestational age.

At a median (midpoint) age of 30.5 months, 456 of 491 (94 percent) extremely preterm children were evaluated (41 by chart review only). The researchers found that overall, 42 percent of extremely preterm children had no disability (compared with 78 percent of control participants), 31 percent had mild disability, 16 percent had moderate disability, and 11 percent had severe disability. There was an increase in moderate or severe disabilities with decreasing gestational age. Also, the difference in overall outcome between preterm boys and girls was not statistically significant.

“Improved survival did not translate into increasing disability rates, and we like others believe that the neurodevelopmental outcome for extremely preterm children born in the 2000s will be better than for those born in the 1990s. Nevertheless, the impact of prematurity on neurodevelopmental outcome was large, which calls for further improvements in neonatal care, such as better control of infection and postnatal nutrition,” the authors write.

“These results are relevant for clinicians counseling families facing extremely preterm birth.”

(JAMA. 2013;309[17]:1810-1820. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: To contact Fredrik Serenius, M.D., Ph.D., email Fredrik.serenius@kbh.uu.se.

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 No Association Found Between Children with Autism and Markers of Lyme Disease

“A proposed link between Lyme disease and autism has garnered considerable attention. Among individuals with autism spectrum disorders, rates of seropositivity for Lyme disease of greater than 20 percent have been reported. However, controlled studies to assess serological evidence of infection with Borrelia burgdorferi (the causative agent of Lyme disease) in patients with autism are lacking,” writes Mary Ajamian, M.S., of Columbia University Medical Center, New York, and colleagues.

As reported in a Research Letter, the authors performed Lyme disease serological testing on serum samples from children with and without autism. For the analysis, 70 children with autism (58 male; average age, 7.2 years) and 50 unaffected controls (32 male; average age, 9.0 years) were included.

“None of the children with autism or unaffected controls had serological evidence of Lyme disease by 2-tier testing,” the authors write. “The data do not address whether Lyme disease may cause autism-like behavioral deficits in some cases. However, the study’s sample size is large enough to effectively rule out the suggested high rates of Lyme disease or associated seroprevalence among affected children.”

(JAMA. 2013;309[17]:1771-1773. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: To contact corresponding author Armin Alaedini, Ph.D., call Elizabeth Streich at 212-305-3689 or email Eas2125@cumc.columbia.edu.

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 Viewpoints in This Issue of JAMA

EMBARGOED FOR EARLY RELEASE: 10 A.M. (ET) TUESDAY, APRIL 30, 2013

Restoring Science to the National Children’s Study

The National Children’s Study, a National Institutes of Health study (proposed in 2004) was originally designed to enroll 100,000 pregnant women in a nationally representative sample of 105 communities. “Yet, in 2013, the study is still in its pilot phase,” writes Nigel Paneth, M.D., M.P.H., of Michigan State University, East Lansing. In this Viewpoint, Dr. Paneth discusses some of the flaws in the study and provides suggestions for moving forward.

“At the heart of the failure of the National Children’s Study (NCS) is its abandonment of the hypothetico-deductive mode of scientific thinking. Vacillation in study design was inevitable once the National Institutes of Health (NIH ) asserted, in 2010, that the NCS ‘is not designed to answer a set of specific hypotheses. It is a data-gathering platform.’ Without explicit scientific goals, there is no logical way to select an optimal design.”

“Hypothesis-driven research on a large, representative sample of children is needed because progress on prevention of childhood diseases has stalled and many childhood diseases are uncommon,” he writes. “An optimum study design for the NCS would be powered to enumerate, for the first time, the frequency of important maternal and child health conditions in a nationally representative sample. It would also provide unbiased absolute estimates of the risk of those conditions in relation to characteristics such as race, ethnicity, social class, and geography, advancing understanding of the nature of health disparities. Most importantly, it would take the first steps to prevention by rigorously testing clearly delineated hypotheses about the environmental origins of important and burdensome childhood disorders.”

(JAMA. 2013;309[17]:1775-1776. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: To contact Nigel Paneth, M.D., M.P.H., email paneth@epi.msu.edu.

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The Transformation of Child Health Research – Innovation, Market Failure, and the Public Good

Barbara J. Stoll, M.D., of the Emory University School of Medicine and Children’s Healthcare of Atlanta, and colleagues write that “… the pediatric research community faces mounting evidence that the nature and scope of current research are inadequate. … For measurable and sustainable gains in child health, pediatric research should be informed by the changing epidemiology of childhood illness, the need to monitor both survival and long-term outcomes, and the increasing recognition of pediatric origins of adult chronic disease and social determinants of health.”

In this Viewpoint, the authors suggest measures to improve child health research.

“Child health research at its best provides a model for the advancement of knowledge to improve health and health care. The challenges confronting pediatric research reflect the need to respond to the changing milieu of child health and disease and to look beyond survival to consider the long-term consequences of pediatric health and disease. This transition will require innovative partnerships, a cadre of well-trained investigators interested in child health, and creative use of emerging technologies. It will also require linkage of research priorities to larger societal forces and a renewed commitment to advancing the interests of children in an increasingly fractious policy world.”

(JAMA. 2013;309[17]:1779-1780. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: To contact Barbara J. Stoll, M.D., call Melva Robertson at 404-727-5692 or email melva.robertson@emory.edu.

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 Creation and Retention of the Next Generation of Physician-Scientists for Child Health Research

“Over the last 30 years, proportionately fewer physician-scientists capable of sustaining a research program have committed to a hypothesis-driven research career focused on child-health issues,” writes David N. Cornfield, M.D., of the Stanford University School of Medicine, Stanford, Calif., and colleagues.

In this Viewpoint, the authors examine the challenges to increasing the number of physician-scientists for child health research and strategies to address the issue.

“Development of the pediatric physician-scientist pathway can be facilitated by relatively straightforward and resource-efficient investments. Motivating even this relatively modest investment demands explicit acknowledgment of the value of the clinician-scientist. Children will be well served when more children’s hospitals and pediatric departmental resources are focused on creation, retention, and promotion of the engine that has powered their growth and increasing prominence—i.e., physician-scientists creating and translating knowledge into care. Without such recognition and resolve, pediatrics as a discipline may be unable to meet its collective obligation to the next generations.”

(JAMA. 2013;309[17]:1781-1782. Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: To contact David N. Cornfield, M.D., call Erin Digitale at 650-724-9175 or email digitale@stanford.edu.

Editor’s Note: Please see the articles 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. (ET) TUESDAY, APRIL 30, 2013

Media Advisory: To contact David A. Brent, M.D., call Cristina Mestre at 412-586-9776 or email mestreca@upmc.edu.

NEW YORK – Childhood adversity can lead to chronic physical and mental disability in adult life and have an effect on the next generation, underscoring the importance of research, practice and policy in addressing this issue, according to a Viewpoint in the May 1 issue of JAMA, a theme issue on child health.

David A. Brent, M.D., of the University of Pittsburgh School of Medicine and Western Psychiatric Institute and Clinic, Pittsburgh, presented the Viewpoint at a JAMA media briefing.

Dr. Brent and co-author Michael Silverstein, M.D., M.P.H., of the Boston University School of Medi­cine, write that early child adversity, defined as child maltreatment, exposure to domestic violence, or living with a household member with serious mental illness, has been linked to myriad chronic conditions associated with premature death: smoking, substance abuse, obesity, cardiovascular disease, depression, and attempted suicide. They add that causal pathways between early adversity and these multiple outcomes are thought to be mediated by changes in stress responsivity, and that animal models have demonstrated that these effects are transmitted from parent to child through epigenetic (the effect of environment on gene expression) mechanisms. “While the pathways by which adversity exerts its effects have not been as elegantly elaborated in humans, it is posited that these epigenetic changes can contribute to immune dysfunction, insulin resistance, and cognitive difficulties that in turn lead to risky behavior and predispose to emotional lability [instability] and depression.”

“The good news is that, if detected early enough, the impact of family adversity on child health outcomes can be reversed, or at least attenuated.  For example, if maternal depression is treated to remission, the patients’ children show symptomatic and functional gains. Economic interventions that provide local employment and move parents out of poverty have been shown to be temporally related to a decreased risk for behavioral disorders in the children of the assisted families. Earlier foster placement can, to some extent, reverse the deleterious neurobiological and cognitive effects of extreme deprivation in infancy.”

The authors write that these findings about early adversity and its sequelae have important implications for research, practice, and policy. With regard to research, a better understanding of the biological mechanisms by which early adversity exerts its effects, “definition of the critical periods when such effects are particularly deleterious, and identification of effective approaches to their remediation or prevention are warranted. In addition, the shared roots of leading causes of worldwide disability (such as cardiometabolic disease and depression) suggest opportunities for synergy, because interventions that would prevent the development of these conditions would have a substantial effect on public health worldwide.”

“For clinicians, given the potent and long-reaching effects of family adversity on health outcomes, knowledge can be empowering. Physicians must be taught about the effects of adversity, how to detect it, and what steps to take once identified. Screening, referral, and monitoring of the presence of adversity and its effects early in the child’s life may prevent or attenuate the destructive multigenerational effects of dysfunctional parenting that occur as a consequence of untreated psychiatric disorder,” they write.

The authors add that physicians must also be advocates for social policies that can help families achieve what all parents want—a secure environment for their children to develop into competent adults. “Home visitation programs for at-risk families of infants have been shown to have long-term positive effects on physical and mental health, education, employment, and family stability. Access to quality preschool education can help to buffer the deleterious effects of poverty.”

“The economic cost—in excess health care utilization, nonresponse to treatment, incarceration, loss of employment, decrease in productivity, and disability—weighs heavily on families burdened with adversity but ultimately is borne by society as a whole. In the drive to improve quality of health care and contain costs, the huge price tag to society of early adversity cannot be neglected. Through research, clinical care, and advocacy, physicians can shine a light on the dark shadow of adversity and diminish its reach from generation to generation. Society can either invest in combating the effect of adversity on families now, or pay later.”

(JAMA. 2013;309(17):1777-1778; 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. (ET) TUESDAY, APRIL 30, 2013

Media Advisory: To contact Jonathan M. Davis, M.D., call Julie Jette at 617-636-3265 or email jjette@tuftsmedicalcenter.org.

NEW YORK – Among infants with neonatal abstinence syndrome (NAS; caused by in utero opioid exposure), variants in certain genes were associated with a shorter length of hospital stay and less need for treatment, preliminary findings that may provide insight into the mechanisms underlying NAS, according to a study in the May 1 issue of JAMA, a theme issue on child health.

Jonathan M. Davis, M.D., of The Floating Hospital for Children at Tufts Medical Center, Boston, presented the findings of the study at a JAMA media briefing.

“In the past decade, there has been a significant increase in opioid use during pregnancy, estimated to affect 5.6 per 1,000 births,” according to background information in the article. Neonatal abstinence syndrome is a disorder composed of a constellation of signs and symptoms involving dysfunction of the nervous system, gastrointestinal tract, and respiratory system because of in utero drug exposure or iatrogenic (due to therapy) withdrawal after maternal use of drugs for pain control during pregnancy. “The incidence of NAS has tripled in the past decade, affecting 60 percent to 80 percent of infants born to mothers receiving methadone or buprenorphine. Although clinical factors, including maternal smoking, psychiatric medications, and breastfeeding, can affect the incidence and severity of NAS, to our knowledge contributing genetic factors influencing NAS have not been pre­viously identified.”

Variations in the genes OPRM1, ABCB1, and COMT are associated with risk for opioid addiction in adults. Dr. Davis and colleagues conducted a study to determine whether genomic variations in these genes are associated with length of hospital stay (LOS) and the need for treatment of NAS. The study was conducted at 5 tertiary care centers and community hospitals in Massachusetts and Maine between July 2011 and July 2012. DNA samples were genotyped for single-nucleotide polymorphisms (SNPs), and NAS outcomes were correlated with genotype.

Eighty-six of 140 eligible mother-infant dyads (pairs) were enrolled. Infants were eligible if they were 36 weeks’ gestational age or older and exposed to methadone or buprenorphine in utero. Eighty-one (94 percent) of the mothers were receiving opioid substitution therapy from the first trimester, with 17 (20 percent) relapsing into illicit drug use during the third trimester. Average LOS for all infants was 22.3 days; for treated infants, 31.6 days. Fifty-six (65 percent) of all infants were treated for NAS.

The researchers found that infants with the OPRM1 118A>G AG/GG genotype had shortened length of stay (-8.5 days [calculated with linear regression models]) and were less likely to receive any treatment than infants with the AA genotype (48 percent vs. 72 percent). “The COMT 158A>G AG/GG genotype was associated with shortened length of stay (-10.8 days) and less treatment with 2 or more medications (18 percent vs. 56 percent) than the AA genotype. Associations with the ABCB1 SNPs were not significant.”

“To our knowledge, this is the first study to examine the association of genomics with opioid withdrawal in infants and may provide insight into the mechanisms underlying NAS. There is a need for replication of these results before more definitive conclusions can be made of the association between the OPRM1 and COMT variants and NAS,” the authors conclude.

(JAMA. 2013;309(17):1821-1827; 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. (ET) TUESDAY, APRIL 30, 2013

Media Advisory: To contact Simon R. M. Dobson, M.D., call Brian Lin at 604-822-2234 or email brian.lin@ubc.ca. To contact editorial co-author Jessica A. Kahn, M.D., M.P.H., call Nick Miller at 513-803-6035 or email nicholas.miller@cchmc.org.

NEW YORK – With the number of doses and cost of human papillomavirus (HPV) vaccines a barrier to global implementation, researchers have found that girls who received two doses of HPV vaccine had immune responses to HPV-16 and HPV-18 infection that were noninferior to (not worse than) the responses for young women who received three doses, according to a study in the May 1 issue of JAMA, a theme issue on child health. The authors note that more data on the duration of protection are needed before reduced-dose schedules can be recommended.

Simon R. M. Dobson, M.D., of the University of British Columbia, Vancouver, presented the findings of the study at a JAMA media briefing.

“Globally, cervical cancer is the second most common cause of cancer morbidity and mortality in women. Human papillomavirus infection has been identified as a necessary cause for the development of cervical cancer, with HPV genotypes 16 and 18 accounting for approximately 70 percent of cervical cancer cases,” according to background information in the article. “Global use of HPV vaccines to prevent cervical cancer is impeded by cost. A 2-dose schedule for girls may be possible.”

Dr. Dobson and colleagues conducted a study to determine whether average antibody levels to HPV-16 and HPV-18 among girls receiving 2 doses were noninferior to women receiving 3 doses. The authors also looked at antibody levels to HPV-6 and HPV-11, and compared girls given 2 or 3 doses. The randomized, phase 3, multicenter study included 830 Canadian females from August 2007 through February 2011. Follow-up blood samples were provided by 675 participants (81 percent). Girls (9-13 years of age) were randomized 1:1 to receive 3 doses of quadrivalent HPV vaccine at 0, 2, and 6 months (n=261) or 2 doses at 0 and 6 months (n=259). Young women (16-26 years of age) received 3 doses at 0, 2, and 6 months (n=310). Antibody levels were measured at 0, 7, 18, 24, and 36 months.

The researchers found that the geometric mean titer (GMT) antibody levels in girls receiving 2 doses were noninferior to the respective GMTs in women receiving 3 doses for all 4 genotypes, with GMT ratios of 2.07 for HPV-16 and 1.76 for HPV-18. “Girls given 2 doses vs. 3 doses had a noninferior antibody response for all 4 vaccine genotypes,” with GMT ratios of 0.95 for HPV-16 and 0.68 for HPV-18.

“The GMT ratios for girls (2 doses) to women (3 doses) remained noninferior for all genotypes to 36 months. Antibody responses in girls were noninferior after 2 doses vs. 3 doses for all 4 vaccine genotypes at month 7, but not for HPV-18 by month 24 or HPV-6 by month 36.”

The authors write that these are the first data, to their knowledge, “on the duration of the immune response of young adolescent girls to a reduced-dose schedule of quadrivalent HPV vaccine out to 3 years.” However, “The clinically meaningful difference between the 2- and 3-dose schedules cannot yet be determined.”

“Reducing the number of doses affects vaccine and administration costs as well as potentially improving uptake rates. Evidence-based decision making in public health has led to reduced-dose schedules for hepatitis B, pneumococcal, and meningococcal serogroup C vaccine programs. There is a balance to be found between the incremental value of an additional dose on population effectiveness and the opportunity costs of using the resources required for the extra dose in other public health programs. This is especially the case for HPV vaccines at their present cost.”

(JAMA. 2013;309(17):1793-1802; 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, April 30 at this link.

Editorial: HPV Vaccination – Too Soon for 2 Doses?

“… the study by Dobson et al provides encouraging preliminary evidence that a 2-dose quadrivalent HPV vaccine series in girls may be as immunogenic as a 3-dose series in women, although the duration of protection may be less,” writes Jessica A. Kahn, M.D., M.P.H., and David I. Bernstein, M.D., M.A., of the Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, in an accompanying editorial.

“If future studies establish that a 2-dose series leads to a durable immune response and effectively prevents HPV-related cancers in both women and men, the benefits would be substantial for reducing the global burden of cervical cancer and other HPV-related diseases. The potential to further reduce morbidity and mortality due to HPV-related cancers would be especially significant in less developed regions of the world, where the cost of vaccination and implementation of adolescent vaccination programs present significant barriers, but where primary prevention strategies are most urgently needed.”

(JAMA. 2013;309(17):1832-1833; 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. (ET) TUESDAY, APRIL 30, 2013

Media Advisory: To contact Hope Weiler, R.D., Ph.D., email hope.weiler@mcgill.ca. To contact editorial author Steven A. Abrams, M.D., call Dipali Pathak at 713-798-4712 or email pathak@bcm.edu.

NEW YORK – In a comparison of the effect of different dosages of vitamin D supplementation in breastfed infants, no dosage raised and maintained plasma concentrations within a range recommended by some pediatric societies. However, all dosages raised and maintained plasma concentrations within a lower range recommended by the Institute of Medicine, according to a study in the May 1 issue of JAMA, a theme issue on child health.

Hope Weiler, R.D., Ph.D., of McGill University, Montreal, presented the findings of the study at a JAMA media briefing.

“Vitamin D is important during periods of rapid bone mineral accrual. Nursing infants are susceptible to vitamin D deficiency because vitamin D in breast milk is limited,” according to background information in the article. “A supplement of 400 IU of vitamin D per day is thought to support plasma 25-hydroxyvitamin D (25[OH]D) concentrations between 40 and 50 nmol/L; some advocate 75 to 150 nmol/L for bone health. … the lack of well-defined recommendations supports the need for dose-response studies.”

Dr. Weiler and colleagues conducted a study to investigate the efficacy of different dosages of oral vitamin D in supporting 25(OH)D concentrations in infants. The randomized clinical trial, which included 132 one-month-old healthy, term, breastfed infants, was conducted between March 2007 and August 2010. Infants were followed up for 11 months ending August 2011 (74 percent completed the study). Participants were randomly assigned to receive oral cholecalciferol (vitamin D₃) supplements of 400 IU/d (n=39), 800 IU/d (n=39), 1,200 IU/d (n=38), or 1,600 IU/d (n=16).

The researchers found that the percentage of infants achieving the primary outcome of 75 nmol/L of 25(OH)D differed at 3 months by group (for 400 IU/d, 55 percent; for 800 IU/d, 81 percent; for 1,200 IU/d, 92 percent; and for 1,600 IU/d, 100 percent). “This concentration was not sustained in 97.5 percent of infants at 12 months in any of the groups. The 1,600-IU/d dosage was discontinued prematurely because of elevated plasma 25(OH)D concentrations.”

Overall, 97 percent of infants in all treatment groups achieved the secondary outcome of 50 nmol/L or greater of plasma 25(OH)D by 3 months of age, with no differences among groups. This concentration was sustained in 98 percent of infants at 12 months.

Bone mineral concentration increased over time for lumbar spine, femur, and whole body but did not differ by group.

“Our primary objective was to establish a vitamin D dosage that would support a plasma concentration of 25(OH)D of 75 nmol/L or greater in 97.5 percent of infants at 3 months of age. Only the 1,600-IU/d dosage of vitamin D met this criterion; however, this dosage was discontinued because most infants in that group developed elevated plasma 25(OH)D concentrations that have been associated with hypercalcemia [higher-than-normal level of calcium in the blood],” the authors write. “Thus, the primary outcome was not achieved at 3 months, when plasma 25(OH)D concentrations were highest; all dosages failed except the highest dosage, which appears to be too high.”

“Additional studies are required before conclusions can be made regarding higher targets or the needs of high-risk groups.”

(JAMA. 2013;309(17):1785-1792; 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.

Please Note: An author podcast on this study will be available post-embargo on the JAMA website.

Editorial: Targeting Dietary Vitamin D Intakes and Plasma 25-Hydroxyvitamin D in Healthy Infants

Steven A. Abrams, M.D., of the Baylor College of Medicine, Houston, comments on the findings of this study in an accompanying editorial.

“The data reported by Gallo et al do not answer the question of what the target should be for plasma 25(OH)D concentration. If the target is 75 nmol/L or higher, then vitamin D intake of 400 IU/d is not enough for a substantial proportion of infants, especially those in northern parts of the United States or in Canada or who have darker skin pigmentation. … However, another question that needs to be answered is whether there are non-bone health reasons to target a plasma 25(OH)D concentration greater than 75 nmol/L. Answering such questions about non-bone health aspects of vitamin D nutrition can be accomplished only by rigorous clinical trials that include enough participants and establish clear outcomes before the study begins.”

“Pending such information, clinicians can be reassured by the findings from the study by Gallo et al that a daily vitamin D intake of 400 IU/d in infants, as currently recommended, leads to adequate plasma 25(OH)D concentration for identified physiological functioning related to bone health.”

(JAMA. 2013;309(17):1830-1831; 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, APRIL 23, 2013

Study Examines Trends in Firearm Injuries Among Children and Adolescents

“Given recent firearm-related fatalities combined with declining gun research funding, it is important to monitor firearm injuries in youths. Injury death rates are available but provide an incomplete picture of these potentially preventable injuries,” writes Angela Sauaia, M.D., Ph.D., of the University of Colorado School of Public Health, Denver and colleagues.

As reported in a Research Letter, the authors investigated the trends from 2000 to 2008 of both fatal and nonfatal firearm injuries in children and adolescents 4 to 17 years of age presenting to 2 Colorado urban trauma centers (in Denver and Aurora). The researchers compared firearm injuries with other injuries regarding patient characteristics (age, sex, race/ethnicity [white non-Latino vs. others], injury self-infliction, mortality, and intensive care requirement) and analyzed temporal trends regarding patient and injury characteristics as well as outcomes among fatal and nonfatal firearm injuries.

Overall, during this time period 6,920 youths were injured. Firearms caused the injury in 129 of these youths (1.9 percent) (2.1 percent in 2000-2002; 1.9 percent in 2003-2005; 1.6 percent in 2006-2008). Firearm-wounded patients were more likely to be adolescent males, and their injuries were more often self-inflicted compared with youths with other injuries. Sixty-five patients (50.4 percent) with firearm injuries required intensive care vs. 1,311 patients (19.3 percent) with other trauma; 17 patients (13.2 percent) with firearm injuries died vs. 116 (1.7 percent) with other trauma. Firearm injury severity significantly increased over time.

“Firearms were an important mechanism of injury in the youth in this study. Compared with other serious injuries, firearm injuries were more severe, more often required intensive care, and claimed more lives, justifying focusing on pediatric firearm injuries as a prevention priority,” the authors write. “More recent data from other areas with detail on the circumstances of the firearm injury are needed.”

(JAMA. 2013;309[16]:1683-1685. Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact Angela Sauaia, M.D., Ph.D., call David Kelly at 303-503-7990 or email david.kelly@ucdenver.edu.

Viewpoint in This Issue of JAMA

The Clinical Learning Environment – The Foundation of Graduate Medical Education

Kevin B. Weiss, M.D., of the Accreditation Council for Graduate Medical Education (ACGME), Chicago, and colleagues write that the “next step in the evolution of resident physician training is the Next Accreditation System (NAS), which is now being implemented by the ACGME.” In this Viewpoint, the authors discuss the Clinical Learning Environment Review (CLER) program, which is the first component of the NAS to be operationalized nationally.

“Given the broad public need and mandate to improve the quality and safety of medical care in the United States, the future workforce must be trained to recognize opportunities for improvement and actively engage their health care organizations to implement systems-based improvements in patient care. Teaching hospitals and other clinical learning environments must teach quality and safety improvement and incorporate residents and fellows into formal quality and safety structures and initiatives. Through its CLER program, the ACGME seeks to engage U.S. teaching institutions in identifying and implementing the most effective quality improvement strategies that focus on the safety, quality, and value of care. By doing so, the ACGME seeks to enhance the preparation of residents and fellows to best serve their patients in an ever increasingly complex health care environment.”

(JAMA. 2013;309[16]:1687-1688. Available pre-embargo to the media at https://media.jamanetwork.com)

Media Advisory: To contact Kevin B. Weiss, M.D., call Timothy Brigham at 312-755-5000 or email tbrigham@acgme.org.

Editor’s Note: Please see the articles 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, APRIL 23, 2013

Media Advisory: To contact Martin J. London. M.D., call Kristen Bole at 415-476-2743 or email kristen.bole@ucsf.edu.

CHICAGO – Patients at elevated cardiac risk who were treated with beta-blockers on the day of or following noncardiac, nonvascular surgery had significantly lower rates of 30-day mortality and cardiac illness, according to a study in the April 24 issue of JAMA.

“The effectiveness and safety of perioperative beta-blockade [the process of inhibiting beta-receptor activity] for patients undergoing noncardiac surgery remains controversial. Class I recommendations in the current American Heart Association/American College of Cardiology Foundation Guidelines on Perioperative Evaluation and Care for Noncardiac Surgery remain limited to continuation of preexisting beta-blockade,” according to background information in the article. “Recent evidence suggests that use of perioperative beta-blockade may be declining. Contributing factors may include uncertainty about safety and recent data questioning the efficacy of long-term beta-blockade in stable outpatients. Thus, additional multicenter analyses of associations of perioperative beta-blockade with outcome are timely and potentially relevant to clinicians and regulatory agencies promoting perioperative quality and safety efforts.”

Martin J. London. M.D., of the U.S. Department of Veterans Affairs Medical Center and University of California, San Francisco, and colleagues conducted a study to examine the association of perioperative beta-blockade with all-cause 30-day mortality and cardiac morbidity (cardiac arrest or Q-wave [a reading on an electrocardiogram] myocardial infarction) in patients undergoing major noncardiac surgery. The analysis included a population-based sample of 136,745 patients who were 1:1 matched on propensity scores (37,805 matched pairs) treated at 104 VA medical centers from January 2005 through August 2010.

Overall, 45,347 patients (33.2 percent) had an active outpatient prescription for beta-blockers within 7 days of surgery and 55,138 patients (40.3 percent) were potentially exposed to beta-blockers on either postoperative day 0 or 1. Inpatient beta-blocker exposure was higher in the 66.7 percent of 13,863 patients who underwent vascular surgery than in the 37.4 percent of 122,882 patients who underwent nonvascular surgery. The rate of use increased with increasing Revised Cardiac Risk Index variables: 25.3 percent for no factors vs. 71.3 percent for 4 or more factors.

Overall, 1,568 patients (1.1 percent) sustained the primary 30-day mortality outcome and 1,196 patients (0.9 percent) the secondary cardiac morbidity outcome. The researchers found that in the matched cohort, patients in the exposed group had a 27 percent lower risk of mortality. Significant associations of beta-blocker exposure with lower mortality were noted in patients with 2 Revised Cardiac Risk Index factors (37 percent lower mortality risk), 3 factors (46 percent lower risk), or 4 factors or more (60 percent lower risk). This association was limited to patients undergoing nonvascular surgery.

Considering the secondary cardiac morbidity outcome, beta-blocker exposure was associated with a 33 percent lower risk of cardiac complications, also limited to patients undergoing nonvascular surgery.

“In conclusion, our results suggest that early perioperative beta-blocker exposure is associated with significantly lower rates of 30-day mortality and cardiac morbidity in patients at elevated baseline cardiac risk undergoing nonvascular surgery. Although assessment of cumulative number of Revised Cardiac Risk Index predictors might be helpful to clinicians in deciding whether to use perioperative beta-blockade, the current findings highlight a need for a randomized multi-center trial of perioperative beta-blockade in low- to intermediate-risk patients scheduled for noncardiac surgery,” the authors write.

(JAMA. 2013;309(16):1704-1713; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by a grant from the Anesthesia Patient Safety Foundation. 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, APRIL 23, 2013

Media Advisory: To contact Casper Roed, M.D., email casperroed@hotmail.com or call 011-45-404-33438.

CHICAGO – In a study that included nearly 3,000 adults from Denmark, a diagnosis of meningococcal, pneumococcal, or Haemophilus influenzae meningitis in childhood was associated with lower educational achievement and economic self-sufficiency in adult life, according to a study in the April 24 issue of JAMA.

Bacterial meningitis may lead to brain damage due to several factors, and survivors of childhood bacterial meningitis are at particular risk of hearing loss, seizure disorders, motor deficits, and cognitive impairment. Learning disabilities are well documented as a result of the disease. “To our knowledge, no previous study has examined functioning in adult life among persons diagnosed as having bacterial meningitis in childhood,” the authors write.

Casper Roed, M.D., of Copenhagen University Hospital, Copenhagen, Denmark, and colleagues conducted a study to estimate educational achievement and economic self-sufficiency among children surviving bacterial meningitis compared with the general population. The nationwide population-based cohort study used national registries of Danish-born children diagnosed as having meningococcal, pneumococcal, or H influenzae meningitis in the period 1977-2007 (n=2,784 patients). Comparison cohorts from the same population individually matched on age and sex were identified, as were siblings of all study participants. The end of the study period was 2010. The primary measured outcomes were cumulative incidences of completed vocational education, high school education, higher education, time to first full year of economic self-sufficiency, and receipt of disability pension and differences in these outcomes at age 35 years among meningitis patients, comparison cohorts, and siblings.

The study included persons who had a history of childhood meningococcal (n=1,338), pneumococcal (n=455), and H influenzae (n=991) meningitis. Among meningococcal meningitis patients, an estimated 11.0 percent fewer (41.5 percent vs. 52.5 percent) had completed high school and 7.9 percent fewer (29.3 percent vs. 37.2 percent) had obtained a higher education by age 35 compared with members of the population comparison cohort. For pneumococcal meningitis patients, by age 35, an estimated 10.2 percent fewer (42.6 percent vs. 52.8 percent) and 8.9 percent fewer (28.1 percent vs. 37.0 percent) had completed high school and higher education compared with members of the population comparison cohort.

Among H influenzae meningitis patients, 5.5 percent fewer (47.7 percent vs. 53.2 percent) had completed high school and 6.5 percent fewer (33.5 percent vs. 40.0 percent) had completed higher education by age 35 years compared with members of the population comparison cohort.

The authors also found that at end of follow-up, an estimated 3.8 percent, 10.6 percent, and 4.3 percent fewer meningococcal, pneumococcal, and H influenzae meningitis patients, respectively, had been economically self-sufficient compared with the individuals from the comparison cohort, and 1.5 percent, 8.7 percent, and 3.7 percent, respectively, more patients received disability pension.

“Siblings of meningococcal meningitis patients also had lower educational achievements, while educational achievements of siblings of pneumococcal and H influenzae meningitis patients did not differ substantially from those in the general population,” the researchers write.

These findings suggest that the association with lower educational achievement and economic self-sufficiency in adult life may apply particularly to pneumococcal and H influenzae meningitis, whereas for meningococcal meningitis the lower educational achievement may be family related.

“Our study suggests that children diagnosed as having pneumococcal or H influenzae meningitis may benefit from follow-up into adulthood to identify those who could potentially benefit from psychosocial support.”

(JAMA. 2013;309(16):1714-1721; 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, APRIL 23, 2013

Media Advisory: To contact corresponding author Monique V. Chireau, M.D. M.P.H., call Rachel Harrison at 919-419-5069 or email rachel.harrison@duke.edu.

 CHICAGO – For women with abdominal pain or vaginal bleeding during early pregnancy, patient history and clinical examination alone are insufficient to indicate or eliminate the possibility of ectopic pregnancy, while transvaginal sonography appears to be the single best diagnostic method for evaluating suspected ectopic pregnancy, according to an analysis of previous studies reported in the April 24 issue of JAMA.

The rapid identification and accurate diagnosis of women who may have an ectopic pregnancy is critically important for reducing the maternal illness and death associated with this condition. Ectopic pregnancy is the leading cause of first-trimester pregnancy-related death, responsible for up to 6 percent of maternal mortality during early gestation, according to background information in the article. “Fewer than half of the women with an ectopic pregnancy have the classically described symptoms of abdominal pain and vaginal bleeding. In fact, these symptoms are more likely to indicate miscarriage.”

John R. Crochet, M.D., of the Center of Reproductive Medicine, Webster, Texas and colleagues conducted a study to systematically review the accuracy and precision of the patient history, clinical examination, readily available laboratory values, and sonography in the diagnosis of ectopic pregnancy in women with abdominal pain or vaginal bleeding during early pregnancy. The researchers conducted a search of the medical literature and identified 14 studies with 12,101 patients the met the criteria for inclusion in the analysis.

The authors found that presence of an adnexal (structures near the uterus, such as the ovaries and the Fallopian tubes) mass in the absence of an intrauterine pregnancy on transvaginal sonography, and the physical examination findings of cervical motion tenderness, an adnexal mass, and adnexal tenderness all increase the likelihood of ectopic pregnancy. “A lack of adnexal abnormalities on transvaginal sonography decreases the likelihood of ectopic pregnancy. Existing studies do not establish a single serum human chorionic gonadotropin [hCG; a hormone] level that is diagnostic of ectopic pregnancy.”

“Women with abdominal pain or vaginal bleeding during early pregnancy may have an ectopic pregnancy. This systematic review of the literature and meta-analysis confirms that the patient history and clinical examination alone are insufficient to indicate or eliminate the possibility of ectopic pregnancy. In a hemodynamically stable patient, the appropriate evaluation includes transvaginal sonography and quantitative (serial) serum hCG testing. Patients with signs and symptoms of excessive blood loss or hemodynamic collapse should immediately have gynecological evaluation.”

(JAMA. 2013;309(16):1722-1729; 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, APRIL 23, 2013

Media Advisory: To contact Jakob Christensen, Ph.D., email jakob@farm.au.dk. To contact editorial co-author Kimford J. Meador, M.D., call Holly Korschun at 404-727-3990 or email hkorsch@emory.edu.

CHICAGO – Maternal use of valproate (a drug used for the treatment of epilepsy and other neuropsychological disorders) during pregnancy was associated with a significantly increased risk of autism in offspring, according to a study in the April 24 issue of JAMA. The authors caution that these findings must be balanced against the treatment benefits for women who require valproate for epilepsy control.

“Anti-epileptic drug exposure during pregnancy has been associated with an increased risk for congenital malformations and delayed cognitive development in the offspring, but little is known about the risk of other serious neuropsychiatric disorders,” according to background information in the article.

Jakob Christensen, Ph.D., of Aarhus University Hospital, Aarhus, Denmark, and colleagues evaluated the association between maternal use of valproate during pregnancy and the risk of autism spectrum disorder and childhood autism in offspring. The population-based study included all children born alive in Denmark from 1996 to 2006. National registers were used to identify children exposed to valproate during pregnancy and diagnosed with autism spectrum disorders (childhood autism [autistic disorder], Asperger syndrome, atypical autism, and other or unspecified pervasive developmental disorders). Data were analyzed and adjusted for potential confounders (factors that can influence outcomes) such as maternal age at conception, paternal age at conception, parental psychiatric history, gestational age, birth weight, sex, congenital malformations, and parity. Children were followed up from birth until the day of autism spectrum disorder diagnosis, death, emigration, or December 31, 2010, whichever came first.

The analysis included 655,615 children born from 1996 through 2006. The average age of the children at end of follow-up was 8.8 years. During the study period, 5,437 children were diagnosed with autism spectrum disorder, including 2,067 with childhood autism. The researchers identified 2,644 children exposed to antiepileptic drugs during pregnancy, including 508 exposed to valproate. The authors found that use of valproate during pregnancy was associated with an absolute risk of 4.42 percent for autism spectrum disorder and an absolute risk of 2.50 percent for childhood autism.

“In this population-based cohort study, children of women who used valproate during pregnancy had a higher risk of autism spectrum disorder and childhood autism compared with children of women who did not use valproate. Their risks were also higher than those for children of women who were previous users of valproate but who stopped before their pregnancy,” the researchers write.

“Because autism spectrum disorders are serious conditions with lifelong implications for affected children and their families, even a moderate increase in risk may have major health importance. Still, the absolute risk of autism spectrum disorder was less than 5 percent, which is important to take into account when counseling women about the use of valproate in pregnancy.”

(JAMA. 2013;309(16):1696-1703; 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: Risks of In Utero Exposure to Valproate

Kimford J. Meador, M.D., and David W. Loring, Ph.D., of Emory University, Atlanta, write in an accompanying editorial that “women of childbearing potential should be informed of the potential risks of fetal valproate exposure before valproate is prescribed.”

“Despite the established risks of fetal valproate exposure, valproate continues to be a common treatment in women of childbearing age. Valproate is an effective drug, but it appears that it is being prescribed for women of child-bearing potential at a rate that does not fully consider the ratio of benefits to risks. This raises concern as to whether these women are receiving adequate information for informed consent based on a full understanding of the treatment risks and alternative therapies. Given the accumulating evidence linking fetal valproate exposure to congenital malformations, cognitive impairments, and autism, the use of valproate in women of childbearing potential should be minimized. Alternative medications should be sought. If no alternative effective medications can be found, the lowest effective dose of valproate should be used. Because approximately half of the pregnancies in the United States are unplanned, delaying discussions of treatment risks until a pregnancy is considered will leave a substantial number of children at unnecessary risk.”

(JAMA. 2013;309(16):1730-1731; 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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