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 http://media.jamanetwork.com)

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

Editorial: 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 http://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 http://media.jamanetwork.com)

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

Editorial: 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 http://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 http://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 http://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 http://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 http://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 http://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 http://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 http://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 http://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 http://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 http://media.jamanetwork.com)

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

Editorial: 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 http://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 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 http://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 http://media.jamanetwork.com)

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

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EMBARGOED FOR 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 http://media.jamanetwork.com)

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

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 http://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 http://media.jamanetwork.com)

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

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EMBARGOED FOR 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 http://media.jamanetwork.com)

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

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EMBARGOED FOR 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 http://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 http://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 http://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 http://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 http://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 http://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 http://media.jamanetwork.com)

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

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EMBARGOED FOR 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 http://media.jamanetwork.com)

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

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EMBARGOED FOR 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 http://media.jamanetwork.com)

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

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 http://media.jamanetwork.com)

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

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EMBARGOED FOR 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 http://media.jamanetwork.com)

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

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 http://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, 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 http://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 http://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 http://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 http://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 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 http://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 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 http://media.jamanetwork.com)

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

Editorial: 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 http://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 16, 2013

Electrocardiographic Abnormality Associated With Increased Risk of Atrial Fibrillation, Congestive Heart Failure

“Left anterior fascicular block (LAFB) is considered a benign electrocardiographic (ECG) finding, but its long-term consequences have not been comprehensively studied,” writes Mala C. Mandyam, B.S., of the University of California, San Francisco and colleagues.

As reported in a Research Letter, the authors investigated the long-term outcomes of participants with LAFB in the absence of manifest cardiovascular disease in the Cardiovascular Health Study (CHS). Established in 1989, CHS is a prospective cohort study of individuals 65 years of age or older sampled from Medicare eligibility lists nationwide. Of the 1,664 participants who met the criteria for this analysis, the 39 individuals (2.3 percent) with baseline LAFB were older and more likely male. At follow-up (median [midpoint] 16 years), 380 participants had developed atrial fibrillation (AF); 328, congestive heart failure (CHF); and 954 had died. Sixteen participants (41 percent) with LAFB developed AF; 17 (44 percent), CHF; and 33 (85 percent) died. After adjusting for various factors, LAFB remained significantly associated with AF, CHF, and death.

“Given previous histopathological studies, these findings suggest that LAFB may be a clinically relevant marker of an individual’s propensity to left heart fibrosis. Further research is needed to determine if LAFB is an important predictor of consequent adverse outcomes,” the authors write.

(JAMA. 2013;309[15]:1587-1588. Available pre-embargo to the media at http://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 16, 2013

Media Advisory: To contact corresponding author Andreas M. Zeiher, M.D., email zeiher@em.uni-frankfurt.de.

CHICAGO – Treatment that consisted of shock wave (procedure using high-dose ultrasound)-mediated preconditioning of the target heart tissue prior to administration of bone marrow-derived mononuclear cells was associated with significant, albeit modest improvement in left ventricular ejection fraction (a measure of how well the left ventricle of the heart pumps with each contraction) after 4 months in patients with chronic postinfarction heart failure, according to a study in the April 17 issue of JAMA. The results, which require confirmation in larger trials, demonstrate the potential for this type of therapy to reduce adverse clinical events in these chronically ill patients.

“Regenerative therapies have emerged as a promising novel approach to improve heart function and prevent the development of end-stage heart failure. Application of various cell types including bone marrow-, heart tissue- or adipose tissue-derived cell populations were shown to improve cardiac functional recovery. In patients with acute myocardial infarction [heart attack], recent meta-analyses suggested a moderate but sustained enhancement of left ventricular function and improved clinical outcome following administration of bone marrow-derived mononuclear cells (BMCs),” according to background information in the article. “Extracorporeal shock wave treatment has been experimentally shown to increase homing factors in the target tissue, resulting in enhanced retention of applied BMCs.”

Birgit Assmus, M.D., of Goethe University Frankfurt, Germany, and colleagues conducted a study to test the hypothesis that shock wave-facilitated cell therapy could improve the efficacy of intracoronary application of autologous (the donor and recipient are the same person) BMCs in patients with chronic postinfarction heart failure. The randomized, placebo-controlled trial was conducted between 2006 and 2011. The interventions included low-dose (n=42), high-dose (n=40), or placebo (n=21) shock wave pretreatment targeted to the left ventricular anterior wall. Twenty-four hours later, patients receiving shock wave pretreatment were randomized to receive intracoronary infusion of BMCs or placebo, and patients receiving placebo shock wave received intracoronary infusion of BMCs.

The researchers found that the primary end point (change in LVEF from baseline to 4 months ) was significantly improved in the shock wave + BMCs group (absolute change in LVEF, 3.2 percent), compared with the shock wave + placebo infusion group (1.0 percent). Regional wall thickening improved significantly in the shock wave + BMCs group (3.6 percent) but not in the shock wave + placebo infusion group (0.5 percent). Overall occurrence of major adverse cardiac events was significantly less frequent in the shock wave + BMCs group (n=32 events) compared with the placebo shock wave + BMCs (n=18) and shock wave + placebo infusion (n=61) groups.

“The results demonstrate that shock wave-facilitated infusion of BMCs beneficially affects global and regional left ventricular contractile function [improved pump function of the heart] and may reduce adverse clinical events in these chronically ill patients,” the authors write. “However, the observed beneficial effects on clinical outcome require confirmation in larger clinical end point trials.”

(JAMA. 2013;309(15):1622-1631; Available pre-embargo to the media at http://media.jamanetwork.com)

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

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Media Advisory: To contact corresponding author Luigi Titomanlio, M.D., Ph.D., email luigi.titomanlio@rdb.aphp.fr. To contact editorial co-author Leon G. Epstein, M.D., call Marla Paul at 312-503-8928 or email marla-paul@northwestern.edu.

CHICAGO – In a study including children and adolescents 6 to 18 years of age, those who have experienced migraine headaches were more likely to have had colic as an infant, according to a study in the April 17 issue of JAMA.

“Infantile colic is a common cause of inconsolable crying during the first months of life,” according to background information in the article. “The pathogenesis and the age-specific presentation of colic are not well understood. Infantile colic is usually interpreted as a pain syndrome and may be multifactorial. …  Migraine is a common cause of headache pain in childhood. Whether there is an association between these 2 types of pain in unknown.”

Silvia Romanello, M.D., of the APHP-Hospital Robert Debré, Paris, and colleagues conducted a study to investigate the possible association between migraine and colic. The case-control study included 208 children 6 to 18 years of age presenting to the emergency department and diagnosed as having migraines in 3 European tertiary care hospitals between April 2012 and June 2012. The control group was composed of 471 children in the same age range who visited the emergency department of each participating center for minor trauma during the same period. A structured questionnaire identified personal history of infantile colic for case and control participants, confirmed by health booklets. A second study of 120 children diagnosed with tension-type headaches was done to test the specificity of the association.

The researchers found that children with migraine were more likely to have experienced infantile colic than those without migraine (72.6 percent vs. 26.5 percent). The subgroup analysis for migraine subtypes confirmed the association between infantile colic and either migraine without aura (73.9 percent vs. 26.5 percent) or migraine with aura (69.7 percent vs. 26.5 percent). This association was not found for children with tension-type headache.

“The link between infantile colic and migraine could be based on a pathogenetic mechanism common to migraine without aura and also migraine with aura. We found that among migraine characteristics, only pulsatile pain was more frequent in children with a history of infantile colic than among children with migraine but without infantile colic. Infants with colic might experience a similar sensitization of the perivascular nerve terminals in the gut, although this hypothesis needs to be tested,” the authors write. They add that molecules known to be involved in the modulation of sensory activity could also be involved.

Longitudinal studies are needed to further explore the association between colic and childhood migraines, the researchers conclude.

(JAMA. 2013;309(15):1607-1612; Available pre-embargo to the media at http://media.jamanetwork.com)

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

Editorial: Infantile Colic and Migraine

Leon G. Epstein, M.D., and Phyllis C. Zee, M.D., Ph.D., of the Feinberg School of Medicine, Northwestern University, Chicago, comment in an accompanying editorial on the reasons the study by Romanello et al is important.

“First, both colic and migraine are common conditions. Colic occurs in approximately 16 percent to 20 percent of infants. The prevalence of migraine headache by age groups is 1.2 percent to 3.2 percent from 3 to 7 years old, 4 percent to 11 percent from 7 to 11 years old; and 8 percent to 23 percent from 11 to 15 years old. The morbidity and economic costs associated with these conditions are significant. Second, if colic is an early form of migraine, this suggests that migraine disorders may represent a continuum from colic in infancy to cyclic vomiting syndrome in young children to childhood and adult migraine. The expanding knowledge of the genetics and pathophysiology of migraine may be applicable to these age-specific clinical presentations and offer the potential for new, empirical therapies. Finally, this elegant study demonstrates that observational studies can provide important insights about fundamental scientific questions for common disorders.”

(JAMA. 2013;309(15):1636-1637; Available pre-embargo to the media at http://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 16, 2013

Media Advisory: To contact corresponding author Atul A. Gawande, M.D., M.P.H., call Marjorie Dwyer at 617-432-8416 or email mhdwyer@hsph.harvard.edu. To contact editorial author Uwe E. Reinhardt, Ph.D., call Elisabeth Donahue at 609-258-5988 or email edonahue@Princeton.edu.

CHICAGO – Findings of an analysis that included nearly 35,000 surgical discharges from a 12-hospital system suggest that the occurrence of postsurgical complications was associated with a higher per-encounter hospital contribution margin for patients covered by Medicare and private insurance but a lower one for patients covered by Medicaid and who self-paid, according to a study in the April 17 issue of JAMA.

“The rate of inpatient surgical complications is significant, with estimates ranging from 3 percent to 17.4 percent, depending on type of procedure, type of complications, length of follow-up, and data analyzed. In addition to patient harm, major complications add substantial costs, previously estimated at $11,500 per patient. Effective methods for reducing surgical complications have been identified. However, hospitals have been slow to implement them,” according to background information in the article. The authors write that there may be several factors for slow implementation. Reductions in surgical complication rates “can reduce revenues under per diem reimbursement schemes and even diagnosis related group-based reimbursement because complications can result in severity adjustments or diagnosis related group changes that increase revenues. … Previous estimates suggest that reducing surgical complications could harm hospital financial results but have been limited by use of small data sets or simplified surrogates such as patient length of stay.”

Sunil Eappen, M.D., of Harvard Medical School, Boston and colleagues conducted a study to measure the financial implications associated with postsurgical complications. The goal was to evaluate the fixed and variable hospital costs and revenues associated with the occurrence of 1 or more major postsurgical complications for 4 primary payer types—private insurance, Medicare, Medicaid, and self-payment. The analysis included administrative data for all inpatient surgical discharges during 2010 from a nonprofit 12-hospital system in the southern United States. Discharges were categorized by principal procedure and occurrence of 1 or more postsurgical complications. Nine common surgical procedures and 10 major complications across 4 payer types were analyzed. Hospital costs and revenue at discharge were obtained from hospital accounting systems and classified by payer type. Hospital costs, revenues, and contribution margin (defined as revenue minus variable expenses) were compared for patients with and without surgical complications according to payer type.

Of 34,256 surgical discharges, 1,820 patients (5.3 percent) experienced 1 or more postsurgical complications. The researchers found that the occurrence of 1 or more complications was associated with higher hospital costs in all payer types. The relative difference in hospital revenue varied by payer type. Patients experiencing 1 or more complications were associated with a higher contribution margin of $39,017 per patient with private insurance ($55,953 vs. $16,936) and $1,749 per Medicare patient ($3,629 vs. $1,880) compared with that of patients without complications. “In contrast, for Medicaid and self-pay procedures, those with complications were associated with significantly lower contribution margins than those without complications.”

For this hospital system, occurrence of complications was associated with an $8,084 higher contribution margin per patient ($15,726 vs. $7,642) and with a $7,435 lower per-patient total margin.

The studied hospital system’s inpatient surgical payer mix (Medicare, 45 percent; private, 40 percent; Medicaid, 4 percent; and self-pay, 6 percent) was comparable to that of an average U.S. hospital in 2010.

“Most U.S. hospitals treat patient populations primarily covered by Medicare or private payers, and programs to reduce complications may worsen their near-term financial performance. Some U.S. hospitals, often referred to as safety net hospitals, treat populations primarily covered by Medicaid or self-payment, and complication reduction efforts might improve their financial performance,” the authors write.

(JAMA. 2013;309(15):1599-1606; Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: This research was supported by funding from the Boston Consulting Group and Texas Health Resources. 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: Making Surgical Complications Pay

In an accompanying editorial, Uwe E. Reinhardt, Ph.D., of Princeton University, Princeton, N.J., comments on the findings of this study.

“The study by Eappen et al in this issue of JAMA provides important data on a pressing clinical and financial problem affecting hospitals: how to attribute revenue and cost to specific service lines. Allocating profit and loss is exquisitely sensitive to the many assumptions made in economic modeling and must be performed carefully to provide useful evidence about the financial ramifications of surgical complications and other services.”

(JAMA. 2013;309(15):1634-1635; Available pre-embargo to the media at http://media.jamanetwork.com)

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

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 16, 2013

Media Advisory: To contact Koon Teo, M.B., Ph.D., call Susan Emigh at 905-525-9140, ext. 22555 or email emighs@mcmaster.ca.

CHICAGO – Among patients with a coronary heart disease or stroke event from countries with varying income levels, the prevalence of healthy lifestyle behaviors (such as regular physical activity, eating a healthy diet, and not smoking) was low, with even lower levels in poorer countries, according to a study in the April 17 issue of JAMA.

“Observational data indicate that following an acute coronary syndrome, those who adhere to a healthier lifestyle have a lower risk of recurrent events. Smoking cessation is associated with a lower risk of death and myocardial infarction [heart attack], high-quality diets and regular exercise are associated with lower risk of death or recurrent cardiovascular disease events after a myocardial infarction. Thus, avoidance of smoking or its cessation, improving diet quality, and increasing physical activity level are recommended for secondary prevention of cardiovascular disease,” according to background information in the article. “The proportion of the estimated 100 million individuals worldwide who have vascular disease in the community, especially from lower-income countries, living in rural areas, and who adopt healthy lifestyle behaviors is not known.”

Koon Teo, M.B., Ph.D., of McMaster University, Hamilton, Ontario, Canada, and colleagues examined the prevalence of avoidance or cessation of smoking, eating a healthy diet, and undertaking regular physical activities by individuals with a coronary heart disease (CHD) or stroke event. The Prospective Urban Rural Epidemiology (PURE) was a large, prospective study that used an epidemiological survey of 153,996 adults, 35 to 70 years of age, from 628 urban and rural communities in 3 high-income countries (HIC), 7 upper-middle-income countries (UMIC), 3 lower-middle-income countries (LMIC), and 4 low-income countries (LIC), who were enrolled between January 2003 and December 2009. The main outcome measures for the study were smoking status (current, former, never), level of exercise (low, moderate, or high, as gauged by metabolic equivalent task [MET]-min/wk), and diet (classified by the Food Frequency Questionnaire and defined using the Alternative Healthy Eating Index).

Of the 153,996 enrolled participants, 7,519 (4.9 percent) had a CHD or stroke event. The median (midpoint) interval from event to study enrollment was 5.0 years for CHD and 4.0 years for stroke. Among the 7,519 individuals with self-reported CHD or stroke, 18.5 percent continued to smoke; 35.1 percent undertook high levels of work- or leisure-related physical activity, and 39.0 percent had healthy diets.

“Among the participants who had ever smoked, 52.5 percent had stopped smoking; the prevalence of smoking cessation was highest in the high-income countries (74.9 percent) and lowest in the low-income countries (38.1 percent), with graded decreases by decreasing country income status (56.5 percent in upper-middle-income countries and 42.6 percent in lower-middle-income countries),” the authors write. “Low-income countries had the lowest prevalence who had healthy diets (25.8 percent) compared with the prevalences in high-income countries (43.4 percent), upper-middle-income countries (45.1), and lower-middle-income countries (43.2 percent).”

The researchers add that overall, 14.3 percent of individuals did not have any of the 3 healthy lifestyle behaviors; 42.7 percent had only 1 healthy behavior, 30.6 percent had 2, and only 4.3 percent had all 3 healthy lifestyle behaviors.

Levels of physical activity increased with increasing country income but this trend was not statistically significant.

“These variations in lifestyle prevalence can provide insights into opportunities to enhance cardiovascular disease prevention through adopting healthy lifestyle behaviors,” the authors write. “High-income countries had more comprehensive approaches to tobacco control (e.g., education on tobacco, smoking cessation programs, and active taxation and legislative measures), which likely account for the higher cessation rates.”

“Our data indicate that the prevalence of following the 3 important healthy lifestyle behaviors was low in individuals after their CHD or stroke event. These patterns were observed worldwide but more so in poorer countries. This requires development of simple, effective, and low-cost strategies for secondary prevention that is applicable worldwide.”

(JAMA. 2013;309(15):1613-1621; Available pre-embargo to the media at http://media.jamanetwork.com)

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

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 16 at this link.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 9, 2013

New Approaches to Molecular Diagnosis

“Advances in understanding the molecular basis of rare and common disorders, as well as in the technology of DNA analysis, are rapidly changing the landscape of molecular genetic and genomic testing,” writes Bruce R. Korf, M.D., Ph.D., of the University of Alabama at Birmingham, and Heidi L. Rehm, Ph.D., of the Partners Healthcare Center for Personalized Genetic Medicine, Cambridge, Mass., in a Special Communication.

“Genomic testing may be used to identify risk factors for common disorders, although the clinical utility of such testing is unclear. Genetic and genomic tests may raise new ethical, legal, and social issues, some of which may be addressed by existing genetic non-discrimination legislation, but which also must be addressed in the course of genetic counseling.”

In this article, the authors provide information “to assist physicians in recognizing where new approaches to genetic and genomic testing may be applied clinically and in being aware of the principles of interpretation of test results.”

(JAMA. 2013;309[14]:1511-1521. Available pre-embargo to the media at http://media.jamanetwork.com)

Viewpoints in This Issue of JAMA

Realizing the Opportunities of Genomics in Health Care

April 14, 2013, marks the 10th anniversary of the completion of the Human Genome Project. In this Viewpoint, Geoffrey S. Ginsburg, M.D., Ph.D., of the Institute for Genome Sciences & Policy, Duke University, Durham, N.C., examines the question of how sequencing the human genome has contributed to achieving the health care aims of reducing costs, increasing access, and improving outcomes.

“Pioneering scientists chose to sequence the human genome because it was a bold challenge and because success would substantially advance the understanding of humankind, biology, and of the science of medicine. Ten years later the benefits of genomics in clinical medicine are just beginning to be realized. In the next decade, there is little doubt that genomics and genomic medicine will continue to inform patients, researchers, health care professionals, and society in ways currently unimaginable.”

(JAMA. 2013;309[14]:1463-1464. Available pre-embargo to the media at http://media.jamanetwork.com)

The Indispensable Role of Professional Judgment in Genomic Medicine

Amy L. McGuire, J.D., Ph.D., of the Baylor College of Medicine, Houston, and colleagues discuss the appropriate role for genetic professionals in test ordering, interpretation, and delivery of whole-genome sequencing and whole-exome sequencing results and the decisions that will require professional judgment.

“Both physician-ordered and self-directed genome sequencing have the potential to create preventable risks to patients and downstream negative impacts on the health care system as a whole. As in any other realm of medicine, patients must be included in decisions about genomic testing. Moreover, participants in genomic research should be informed of the potential discovery of clinically relevant findings and consumers should be able to access reliably interpreted, clinically applicable information about their genomic heritage. However, provision of inadequately interpreted results does not empower informed decision making. Individuals who are not sufficiently knowledgeable or adequately trained in genomics do not know how to query the genome or interpret results, and nonclinicians have insufficient expertise to make treatment plans based on the results of sequencing. Thus, to fully realize the promise of genomics in health care, professional judgment must play an indispensable role.”

(JAMA. 2013;309[14]:1465-1466. Available pre-embargo to the media at http://media.jamanetwork.com)

Genomic Medicine, Health Information Technology, and Patient Care

In this Viewpoint, Christopher G. Chute, M.D., Dr.P.H., of the Mayo Clinic, Rochester, Minn., and Isaac S. Kohane, M.D., Ph.D., of Harvard Medical School, Boston, examine how health information technology will contribute to or hamper the promise of genomic medicine.

The authors write that “three criteria must be met to enable health care to address the scope and complexity of the genomic medicine challenge with clinical process automation linked to authoritative genome-scale annotation knowledge bases: (1) the emergence of a coherent, consistent, and uniform naming convention for genomic variants; (2) an authenticated, well-annotated, curated, and freely accessible knowledge base of genomic associations, risks, and warnings in machine-readable form; and (3) modular, standards-based decision-support rules that can be integrated into any electronic health records environment with associated, easily readable documentation and guidance.”

(JAMA. 2013;309[14]:1467-1468. Available pre-embargo to the media at http://media.jamanetwork.com)

Accessing Genomic Medicine – Affordability, Diffusion, and Disparities

Reed V. Tuckson, M.D., of UnitedHealth Group, Minnetonka, Minn., and colleagues describe health care system characteristics that will shape the accessibility, management, and financing for new technologies involving genomic medicine. “In addition, questions of value, clinical management, and patient engagement will influence the emergence of personalized medicine.”

“Medical innovation that enhances human survival and relieves disease burden has been a capstone of the healing sciences and continues to drive advances in genetics and genomics. World realities, however, demand focus on the appropriate use of genomic medicine if all are to experience affordable, safe, and equitable access to their benefits. Health care stakeholders from the ‘bench to the bedside’ have critical roles to play. While the challenges are significant, the opportunities are even greater.”

(JAMA. 2013;309[14]:1469-1470. Available pre-embargo to the media at http://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 9, 2013

Media Advisory: To contact Mingzhao Xing, M.D., Ph.D., call Vanessa Wasta at 410-614-2916 or email wasta@jhmi.edu. To contact editorial co-author Anne R. Cappola, M.D., Sc.M., call Kim Menard at 215-662-6183 or email kim.menard@uphs.upenn.edu.

CHICAGO – Presence of the genetic mutation BRAF V600E was significantly associated with increased cancer-related death among patients with papillary thyroid cancer (PTC); however, because overall mortality in PTC is low and the association was not independent of tumor characteristics, how to use this information to manage mortality risk in patients with PTC is unclear, according to a study in the April 10 issue of JAMA, a Genomics theme issue.

“Papillary thyroid cancer is the most common endocrine malignancy and accounts for 85 percent to 90 percent of all thyroid cancers,” according to background information in the article. “The overall 5-year patient survival rate for PTC is 95 percent to 97 percent. A major clinical challenge is how to reliably distinguish patients who need aggressive treatments to reduce mortality from those who do not. This represents a widely controversial issue in thyroid cancer medicine, particularly because of the low overall mortality of this cancer. The issue has become even more challenging given the high annual incidence of PTC.” BRAF V600E is a prominent oncogene [ a gene, one or more forms of which is associated with cancer] in PTC and “has drawn considerable attention as a potential prognostic factor for PTC. However, the clinical significance of this mutation in PTC-related mortality has not been established.”

Mingzhao Xing, M.D., Ph.D., of the Johns Hopkins University School of Medicine, Baltimore, and colleagues conducted a study to examine and define the association between the BRAF V600E mutation and PTC-related mortality. The study included 1,849 patients (1,411 women and 438 men) with a median (midpoint) age of 46 years and an overall median follow-up time of 33 months after initial treatment at 13 centers in 7 countries between 1978 and 2011.

The overall prevalence of BRAF V600E was 45.7 percent (845/1,849). There were 56 PTC-related deaths among the 1,849 patients, representing an overall mortality of 3.0 percent. Among these deaths, 45 cases (80.4 percent) were positive for BRAF V600E. The overall mortality of all PTC cases was 5.3 percent (45/845) in BRAF V600E-positive patients vs. 1.1 percent (11/1,004) in mutation-negative patients.

When the aggressive tumor features of lymph node metastasis, extrathyroidal invasion, and distant metastasis were also included in the model, the association of BRAF V600E with mortality for all PTC was no longer significant, the authors write. “A higher BRAF V600E-associated patient mortality was also observed in several clinicopathological subcategories, but statistical significance was lost with adjustment for patient age, sex, and medical center.”

“In summary, in this multicenter study, the presence of the BRAF V600E mutation was significantly associated with increased cancer-related mortality among patients with PTC. However, overall mortality in PTC is low, and the association was not independent of tumor behaviors. Therefore, how to use BRAF V600E for the management of mortality risk among patients with PTC is not clear. These findings support further investigation of the prognostic and therapeutic implications of BRAF V600E status in PTC.”

(JAMA. 2013;309(14):1493-1501; Available pre-embargo to the media at http://media.jamanetwork.com)

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

Editorial: Molecular Testing in Thyroid Cancer – BRAF Mutation Status and Mortality

In an accompanying editorial, Anne R. Cappola, M.D., Sc.M., and Susan J. Mandel, M.D., M.P.H., of the University of Pennsylvania, Philadelphia (Dr. Cappola is also Contributing Editor, JAMA), write that “these analyses provide 2 important insights.”

“First, they suggest that the BRAF V600E mutation mediates features of the clinically aggressive tumors that account for the vast majority of PTC mortality. This provides a strong biological rationale for current trials of targeted tyrosine kinase inhibitor therapy for BRAF V600E-positive PTC patients with advanced disease. At the same time, these study results suggest that BRAF V600E testing does not add predictive value for PTC-related mortality beyond the information collected in the process of PTC tumor staging, including postoperative histopathology reporting and clinical evaluation. This is particularly relevant when considering that 45 percent of all PTC tumors are BRAF V600E-positive, and implies that additional tumor or host genomic factors may influence tumor aggressiveness.”

“Although these findings do not support widespread BRAF V600E testing, they do support the need for additional study of how BRAF testing can be used to improve the already excellent prognosis of patients with PTC.”

(JAMA. 2013;309(14):1529-1530; Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Mandel reported membership on the scientific advisory board of Asuragen. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 9, 2013

Media Advisory: To contact corresponding author Michael J. Ackerman, M.D., Ph.D., call Traci Klein at 507-284-5005 or email klein.traci@mayo.edu. To contact editorial co-author Alan E. Guttmacher, M.D., call Robert Bock at 301-496-5133 or email bockr@mail.nih.gov.

CHICAGO – In a molecular genetic evaluation involving 91 cases of intrauterine fetal death, mutations associated with susceptibility to long QT syndrome (LQTS; a heart disorder that increases the risk for an irregular heartbeat and other adverse events) were discovered in a small number of these cases, preliminary evidence that may provide insights into the mechanism of some intrauterine fetal deaths, according to a study in the April 10 issue of JAMA, a Genomics theme issue.

“Intrauterine fetal death is a major public health problem. About 1 million fetal deaths occur in the United States annually, with the vast majority occurring prior to 20 weeks’ estimated gestational age,” according to background information in the article. Fetal death occurring after 20 weeks is defined as stillbirth, and in 2009, an estimated 2.64 million stillbirths occurred worldwide. Postmortem evaluations fail to identify a cause of death in approximately 25 percent to 40 percent of fetal deaths. “However, LQTS has been shown to be a major determinant in young sudden death individuals for which an autopsy was performed but had remained inconclusive and a determinant for as much as 10 percent of sudden infant death syndrome (SIDS). Long QT syndrome may also contribute to sudden unexpected fetal mortality.”

Lia Crotti, M.D., Ph.D., of the University of Pavia, Italy, and Michael J. Ackerman, M.D., Ph.D., of Mayo Clinic, Rochester, Minn., and colleagues conducted a study to determine the spectrum and prevalence of mutations in the 3 most common LQTS-susceptible genes (KCNQ1, KCNH2, and SCN5A) for a group of unexplained fetal death cases. In this case series, retrospective postmortem genetic testing was conducted on a sample of 91 unexplained intrauterine fetal deaths that were collected from 2006-2012 (average estimated gestational age at fetal death, 26.3 weeks; 51 females, 40 males). More than 1,300 ostensibly healthy individuals served as controls. In addition, publicly available exome (the entire portion of the genome consisting of protein-coding sequences) databases were assessed for the general population frequency of identified genetic variants.

Excluding 2 very common genetic variants, the researchers identified 14 genetic variants in 18 intrauterine fetal deaths (19.8 percent) of 91 including 3 of 30 late abortion or miscarriages (10 percent) and 15 of 61 stillbirths  (24.6 percent). “Three variants found in 3 intrauterine fetal death cases (3.3 percent) of 91 were considered putative [supposed] pathogenic mutations based on their absence in more than 1,000 ethnically similar controls, a heterozygote [a person possessing two different forms of a particular gene] frequency below the prevalence of LQTS in the general population (0.05 percent) as determined by analysis of more than 10,000 publicly available exomes, and an abnormal functional electrophysiological profile.”

In addition, 5 intrauterine fetal deaths hosted SCN5A rare nonsynonymous genetic variants (a polymorphism that results in a change in the amino acid sequence of a protein [and therefore may affect the function of the protein]) that conferred in vitro electrophysiological characteristics consistent with potentially pro-arrhythmic phenotypes.

Overall, genetic variants leading to dysfunctional LQTS-associated ion channels (a protein that acts as a pore in a cell membrane and permits the selective passage of ions by means of which electrical current passes in and out of the cell) in vitro were discovered in 8 cases (8.8 percent).

“To our knowledge, this represents the first demonstration of such findings. This preliminary evidence suggests LQTS is one plausible cause of intrauterine fetal death; supports the previously proposed mechanistic link between some cases of intrauterine fetal death, SIDS, and LQTS; and provides precedence for further large-scale investigations into the extent and role of cardiac channelopathies [a disease involving dysfunction of an ion channel] in stillbirth,” the authors write.

(JAMA. 2013;309(14):1473-1482; Available pre-embargo to the media at http://media.jamanetwork.com)

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

Editorial: Long QT Syndrome Susceptibility Mutations and Pregnancy Loss – Another Piece of a Still Unfinished Puzzle?

“Understanding the etiology of stillbirth is essential not just for crafting effective prevention strategies but also for providing families and clinicians with counseling information and the opportunity for a greater sense of closure,” writes Alan E. Guttmacher, M.D., of the National Institutes of Health, Bethesda, Md., and colleagues in an accompanying editorial.

“Recent efforts to fully characterize stillbirths have provided a foundation for identifying the causal factors and include novel technologies to evaluate the genomic alterations in stillbirth. The findings of Crotti and colleagues add another piece to solving this puzzle. If confirmed in well-characterized cohorts and amplified by broader genomic approaches, such work may provide an explanation for many cases of late miscarriage and stillbirth previously labeled as ‘unknown.’”

(JAMA. 2013;309(14):1525-1526; Available pre-embargo to the media at http://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 9, 2013

Media Advisory: To contact corresponding author Richard Mayeux, M.D., M.Sc., call Elizabeth Streich at 212-305-3689 or email estreich@columbia.edu. To contact editorial author Robert L. Nussbaum, M.D., call Kristen Bole at 415-476-2743 or email kristen.bole@ucsf.edu.

CHICAGO – In a meta-analysis of data from nearly 6,000 African Americans, Alzheimer disease was significantly associated with a gene that have been weakly associated with Alzheimer disease in individuals of European ancestry, although additional studies are needed to determine risk estimates specific for African Americans, according to a study in the April 10 issue of JAMA, a Genomics theme issue.

“Late-onset Alzheimer disease (LOAD) is the most common cause of dementia, increasing in frequency from 1 percent at age 65 years to more than 30 percent for people older than 80 years,” according to background information in the article. The incidence of LOAD among African Americans is higher than among whites living in the same community. “Genetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment.”

Christiane Reitz, M.D., Ph.D., of Columbia University, New York, and colleagues conducted a study to identify genetic variants associated with LOAD in African Americans. The Alzheimer Disease Genetics Consortium (ADGC) assembled multiple data sets representing a total of 5,896 African Americans (1,968 case participants, 3,928 control participants) 60 years or older that were collected between 1989 and 2011 at multiple sites. The association of Alzheimer disease with genotyped and imputed single-nucleotide polymorphisms (SNPs; DNA sequence variations that occur when a single nucleotide in the genome sequence is altered) was assessed in case-control and in family-based data sets.

The researchers found that the genotypes with the strongest association with the risk of LOAD among African Americans were ABCA7 (odds ratio, 1.8) and APOE (odds ratio, 2.3), genotypes also associated with increased risk among individuals of European ancestry. However, the association with ABCA7 was 60 percent stronger that than observed among individuals of European ancestry.

“If validated by future replication and functional studies, identification of ABCA7 as a risk gene in LOAD among African Americans not only may help elucidate the disease etiology but also may have major implications for developing targets for genetic testing, prevention, and treatment,” the authors write.

“Identification of the genetic risk variants by resequencing and validation by functional studies would allow refinement of risk estimates and diagnostic and predictive testing protocols specific for African Americans.”

(JAMA. 2013;309(14):1483-1492; Available pre-embargo to the media at http://media.jamanetwork.com)

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

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 9 at this link.

Editorial: Genome-Wide Association Studies, Alzheimer Disease, and Understudied Populations

In an accompanying editorial, Robert L. Nussbaum, M.D., of the University of California, San Francisco, writes about the significance of the findings in this study.

“First, of the many hundreds of genome-wide association studies (GWASs) reported in the National Human Genome Research Institute’s Catalog of Published Genome-Wide Association Studies, only a small fraction involve African American populations. Pursuing research in an understudied ethnic group is important for scientific and for ethical reasons. Second, replicating an association for the same alleles in different ethnic groups strengthens the case for these variants being important in increasing disease susceptibility. Third, the strong replication of the association between variants in 2 genes involved in lipid metabolism underscores how GWASs-can point to pathways that play a role in complex diseases. Proving the functional importance of these genes and variants, however, must await more direct functional studies.”

(JAMA. 2013;309(14):1527-1528; Available pre-embargo to the media at http://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 9, 2013

Media Advisory: To contact corresponding author Mark J. Pallen, M.A., M.D., Ph.D., email m.pallen@warwick.ac.uk. To contact editorial author David A. Relman, M.D., call Margarita Gallardo at 650-723-7897 or email mjgallardo@stanford.edu.

CHICAGO – Researchers have been able to reconstruct the genome sequence of an outbreak strain of Shiga-toxigenic Escherichia coli (STEC) using metagenomics (the direct sequencing of DNA extracted from microbiologically complex samples), according to a study in the April 10 issue of JAMA, a Genomics theme issue.  The findings highlight the potential of this approach to identify and characterize bacterial pathogens directly from clinical specimens without laboratory culture.

“The outbreak of Shiga-toxigenic Escherichia coli, which struck Germany in May-June 2011, illustrated the effects of a bacterial epidemic on a wealthy, modern, industrialized society, with more than 3,000 cases and more than 50 deaths. During an outbreak, rapid and accurate pathogen identification and characterization is essential for the management of individual cases and of an entire outbreak. Traditionally, clinical bacteriology has relied primarily on laboratory isolation of bacteria in pure culture as a prerequisite to identification and characterization of an outbreak strain. Often, however, in vitro culture proves slow, difficult, or even impossible, and recognition of an outbreak strain can be difficult if it does not belong to a known variety or species for which specific laboratory tests and diagnostic criteria already exist,” according to background information in the article. Metagenomics has been used in a clinical diagnostic setting to identify the cause of outbreaks of viral infection.

Nicholas J. Loman, M.B.B.S., Ph.D., of the University of Birmingham, England, and colleagues conducted a study to explore the potential of metagenomics to identify and characterize (by determining genome sequence data) bacterial strains from an outbreak without the need for laboratory culture. For this retrospective investigation, 45 samples were selected from fecal specimens obtained from patients with diarrhea during the 2011 outbreak of Shiga-toxigenic Escherichia coli (STEC) O104:H4 in Germany. Samples were subjected to sequencing (August-September 2012), followed by a 3-phase analysis (November 2012-February 2013).

In phase 1, a draft genome of the outbreak strain was constructed, using data obtained the HiSeq 2500 instrument in rapid-run mode. Outbreak-specific sequences were identified by subtracting sequences from the outbreak metagenome that were present in fecal samples from healthy individuals. In phase 2, the depth of coverage of the outbreak strain genome was determined in each sample. In phase 3, sequences from each sample were compared with sequences from known bacteria to identify pathogens other than the outbreak strain.

“During phase 2, the outbreak strain genome was recovered from 10 samples at greater than 10-fold coverage and from 26 samples at greater than 1-fold coverage. Sequences from the Shiga-toxin genes were detected in 27 of 40 STEC-positive samples (67 percent). In phase 3, sequences from Clostridium difficile, Campylobacter jejuni, Campylobacter concisus, and Salmonella enterica were recovered,” the authors write.

“Using metagenomics, we have been able to recover a draft genome sequence of the German STEC strain without the need for laboratory culture. We found that in most patients with STEC-positive samples, the outbreak strain of E coli accounted for a sizeable proportion of microbial sequences.”

“In conclusion, these results illustrate the potential of metagenomics as an open-ended, culture-independent approach for the identification and characterization of bacterial pathogens during an outbreak of diarrheal disease. Challenges include speeding up and simplifying workflows, reducing costs, and improving diagnostic sensitivity, all of which are likely to depend in turn on improvements in sequencing technologies.”

(JAMA. 2013;309(14):1502-1510; Available pre-embargo to the media at http://media.jamanetwork.com)

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

Editorial: Metagenomics, Infectious Disease Diagnostics, and Outbreak Investigations – Sequence First, Ask Questions Later?

David A. Relman, M.D., of the Stanford University School of Medicine, Stanford, Calif., comments on the findings of this study in an accompanying editorial.

“Microbial genome and community sequence data are destined to affect clinical and public health decision making in a profound manner. However, clinician-investigators know that there remain many critical, clinically relevant questions that demand more than genome sequence data, requiring biological measurements and a deeper understanding of the ecological and clinical setting.”

(JAMA. 2013;309(14):1531-1532; Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Relman reported serving as a consultant to Cepheid Corporation, NanoBio Corporation, Novartis Vaccines, and Procter & Gamble; and owning stock in Cepheid Corporation.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 2, 2013

The Inevitable Application of Big Data to Health Care

“The amount of data being digitally collected and stored is vast and expanding rapidly. As a result, the science of data management and analysis is also advancing to enable organizations to convert this vast resource into information and knowledge that helps them achieve their objectives. Computer scientists have invented the term big data to describe this evolving technology,” writes Travis B. Murdoch, M.D., M.Sc., of the University of Calgary, and Allan S. Detsky, M.D., Ph.D., of the University of Toronto.

In this Viewpoint,  the authors “discuss the application of big data to health care, using an economic framework to highlight the opportunities it will offer and the roadblocks to implementation. We suggest that leveraging the collection of patient and practitioner data could be an important way to improve quality and efficiency of health care delivery.”

(JAMA. 2013;309[13]:1351-1352. Available pre-embargo to the media at http://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 2, 2013

Media Advisory: To contact Vance G. Fowler Jr., M.D., M.H.S., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu. To contact editorial author Preeti N. Malani, M.D., M.S.J., call Beata Mostafavi at 734-764-2220 or email bmostafa@med.umich.edu.

CHICAGO – Use of a vaccine to prevent Staphylococcus aureus infections among patients undergoing cardiothoracic surgery did not reduce the rate of serious postoperative S aureus infections compared with placebo and was associated with increased mortality among patients who developed S aureus infections, according to a study in the April 3 issue of JAMA.

Infections with S aureus following median sternotomy (incision through the midline of the sternum) cause substantial illness and death. “A safe vaccine that provides protection against a majority of S aureus strains during the postoperative period would address an important unmet medical need,” according to background information in the article. A novel vaccine candidate (V710) is immunogenic and generally well tolerated in volunteers, with elevated antibody responses persisting for at least 1 year after vaccination in most patients.

Vance G. Fowler Jr., M.D., M.H.S., of Duke University Medical Center, Durham, N.C., and colleagues conducted a phase 2b/3 study to evaluate the efficacy and safety of preoperative V710 vaccination in preventing serious postoperative S aureus infection in patients undergoing cardiothoracic surgery. The randomized trial was conducted between December 2007 and August 2011 among 8,031 patients 18 years of age or older who were scheduled for full median sternotomy within 14 to 60 days of vaccination at 165 sites in 26 countries. Participants were randomly assigned to receive a single intramuscular injection of either V710 vaccine (n=4,015) or placebo (n=4,016).

The independent data monitoring committee recommended termination of the study after the second interim analysis because of safety concerns and low efficacy. In the primary modified intention-to-treat analysis, V710 vaccine was not significantly more efficacious than placebo in preventing the prespecified primary end point (S aureus bacteremia and/or deep sternal wound infection through postoperative day 90) (22 adjudicated cases in 3,528 evaluable V710 recipients vs. 27 adjudicated cases in 3,517 evaluable placebo recipients). No significant differences in efficacy between the vaccine and placebo groups were observed at any point during the study.

The researchers also found that the V710 vaccine was not significantly more efficacious than placebo in preventing the secondary end points (all S aureus surgical site and invasive infections through postoperative day 90).

Compared with placebo, the V710 vaccine was associated with more adverse experiences during the first 14 days after vaccination (30.8 percent vs. 21.8 percent), including injection site reactions (20.1  percent vs. 9.5 percent) and serious adverse events (1.7 percent vs. 1.3 percent), and a significantly higher rate of multiorgan failure during the entire study (31 vs. 17 events).

Although the overall incidence of vaccine-related serious adverse events (1 in each group) and the all-cause mortality rate (201/3,958 vs. 177/3,967) were not statistically different between groups, the mortality rate in patients with staphylococcal infections was significantly higher among V710 vaccine than placebo recipients (15/73 vs. 4/96).

“In our study of adult patients undergoing cardiothoracic surgery, preoperative vaccination with V710 did not significantly reduce the composite incidence of S aureus bacteremia and deep sternal wound infection,” the authors write. “These findings do not support the use of the V710 vaccine for patients undergoing surgical interventions.”

(JAMA. 2013;309(13):1368-1378; Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: The study was sponsored and funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Whitehouse Station, New Jersey. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Preventing Postoperative Staphylococcus aureus Infections – The Search Continues

Preeti N. Malani, M.D., M.S.J., of the University of Michigan Health System, Ann Arbor, Mich., (and Contributing Editor, JAMA), comments on the findings of this study in an accompanying editorial.

“While the prevention of S aureus infections should remain a priority for future investigation, novel approaches must move beyond vaccine strategies—and for that matter, beyond S aureus. Even if a viable staphylococcal vaccine were to be developed, this would not address non-S aureus infections. Burgeoning antimicrobial resistance results in an urgent, worldwide public health mandate. Progress in this arena will require expansion of preventive efforts and interventions that cover all organisms.”

(JAMA. 2013;309(13):1408-1409; Available pre-embargo to the media at http://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 2, 2013

Media Advisory: To contact Ciaran J. McMullan, M.D., call Tom Langford at 617-534-1605 or email tlangford@partners.org.

CHICAGO – With previous evidence suggesting that melatonin may have a role in glucose metabolism, researchers have found an independent association between decreased secretion of melatonin and an increased risk for the development of type 2 diabetes, according to a study in the April 3 issue of JAMA.

“Melatonin receptors have been found throughout the body in many tissues including pancreatic islet cells, reflecting the widespread effects of melatonin on physiological functions such as energy metabolism and the regulation of body weight,” according to background information in the article. “Loss-of-function mutations in the melatonin receptor are associated with insulin resistance and type 2 diabetes. Additionally, in a cross-sectional analysis of persons without diabetes, lower nocturnal melatonin secretion was associated with increased insulin resistance.” A prospective association between melatonin secretion and type 2 diabetes has not been previously reported.

Ciaran J. McMullan, M.D., of Brigham and Women’s Hospital, Boston, and colleagues conducted a study to investigate the association of melatonin secretion and the incidence of type 2 diabetes. The analysis consisted of a case-control study nested within the Nurses’ Health Study cohort. Among participants without diabetes who provided urine and blood samples at baseline in 2000, the researchers identified 370 women who developed type 2 diabetes from 2000-2012 and matched 370 controls. Statistical analyses for determining associations between melatonin secretion at baseline and incidence of type 2 diabetes included controlling for demographic characteristics, lifestyle habits, measures of sleep quality, and biomarkers of inflammation and endothelial dysfunction.

Secretion of melatonin varied widely among participants in the study; the median (midpoint) urinary ratio of 6-sulfatoxymelatonin to creatinine was 67.0 ng/mg in the highest category compared with 14.4 ng/mg in the lowest category. The median ratio was significantly higher among controls (36.3 ng/mg) than among cases (28.2 ng/mg). Insulin sensitivity was higher among women with higher urinary ratios of 6-sulfatoxymelatonin to creatinine.

The researchers found that after controlling for body mass index and other lifestyle factors, menopausal status, family history of diabetes, history of hypertension, use of beta-blockers or non-steroidal anti-inflammatory drugs, region of the United States, and plasma biomarkers of diabetes risk, participants in the lowest category of urinary ratio of 6-sulfatoxymelatonin to creatinine had a 2.2 times higher odds of developing type 2 diabetes compared to participants in the highest category.

Women in the lowest category of melatonin secretion had an estimated diabetes incidence rate that was more than double that of women in the highest category (as measured by cases per 1,000 person-years).

“It is interesting to postulate from these data, in combination with prior literature, whether there is a causal role for reduced melatonin secretion in diabetes risk. Further studies are needed to determine whether increasing melatonin levels (endogenously via prolonged nighttime dark exposure or exogenously via supplementation) can increase insulin sensitivity and decrease the incidence of type 2 diabetes,” the authors conclude.

(JAMA. 2013;309(13):1388-1396; Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: This work was supported by grants from the National Institutes of Health. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Hu reported serving as a consultant to Novo Nordisk; and receiving grants from Merck and the Walnut Commission. No other author reported disclosures.

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, APRIL 2, 2013

Media Advisory: To contact Karen E. Joynt, M.D., M.P.H., call Todd Datz at 617-432-8413 or email tdatz@hsph.harvard.edu. To contact editorial author John P. A. Ioannidis, M.D., D.Sc., call Margarita Gallardo at 650-723-7897 or email mjgallardo@stanford.edu.

CHICAGO – In an analysis that included data on more than 10 million Medicare beneficiaries admitted to acute care hospitals with a heart attack, congestive heart failure, or pneumonia between 2002 and 2010, 30-day mortality rates for those admitted to critical access hospitals (designated hospitals that provide inpatient care to individuals living in rural communities) increased during this time period compared with patients admitted to other acute care hospitals, according to a study in the April 3 issue of JAMA.

“More than 60 million Americans live in rural areas and face challenges in accessing high-quality inpatient care. In 1997, the U.S. Congress created the Critical Access Hospital (CAH) program in response to increasing rural hospital closures,” according to background information in the article. “Hundreds of hospitals have joined the program over the past decade—by 2010, nearly 1 in 4 of the nation’s hospitals were CAHs. … These hospitals are at high risk of falling behind with respect to quality improvement, owing to their limited resources and vulnerable patient populations. How they have fared on patient outcomes during the past decade is unknown.”

Karen E. Joynt, M.D., M.P.H., of the Harvard School of Public Health, Boston, and colleagues conducted a study to evaluate trends in mortality for patients receiving care at CAHs and compared these trends with those for patients receiving care at non-CAHs. The study included data from Medicare fee-for-service patients admitted to U.S. acute care hospitals with acute myocardial infarction (heart attack; 1,902,586 admissions), congestive heart failure (4,488,269 admissions), and pneumonia (3,891,074 admissions) between 2002 and 2010. In 2010, 1,264 of 4,519 (28 percent) of U.S. hospitals providing acute care services to Medicare beneficiaries and reporting hospital characteristics to the American Hospital Association were designated as CAHs.

The researchers found that there were differences in trends in 30-day mortality rates over time between CAHs and non-CAHs for the 3 conditions examined. “When a composite across the 3 conditions was formally tested, adjusting for teaching status, ownership, region, rurality, poverty, and local physician supply, composite baseline mortality was similar between CAHs and non-CAHs (12.8 percent vs. 13.0 percent). However, between 2002 and 2010, mortality rates increased at CAHs at a rate of 0.1 percent per year, whereas at non-CAHs they decreased 0.2 percent per year, for a difference in change in mortality of 0.3 percent per year. Thus, by 2010, CAHs had higher overall mortality rates (13.3 percent vs. 11.4 percent). In total, CAH admissions were associated with 10.4 excess deaths per 1,000 admissions during the study period.”

The researchers note that although CAHs had higher mortality rates by 2010 for each of the conditions examined, the absolute difference was only 1.8 percent.

Patterns were similar for each of the 3 conditions individually. Comparing CAHs with other small, rural hospitals, similar patterns were found.

“Given the substantial challenges that CAHs face, new policy initiatives may be needed to help these hospitals provide care for U.S. residents living in rural areas,” the authors conclude.

(JAMA. 2013;309(13):1379-1387; Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Dr. Joynt was supported by a grant from the National Heart, Lung, and Blood Institute, National Institutes of Health.  All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Are Mortality Differences Detected by Administrative Data Reliable and Actionable?

In an accompanying editorial, John P. A. Ioannidis, M.D., D.Sc., of the Stanford University School of Medicine, Stanford, Calif., writes that “to rigorously test potential interventions about how to improve the mortality rates at CAHs, cluster randomized controlled trials are needed.”

“These trials could randomize CAHs to different interventions regarding quality improvement initiatives, performance recording, or payment practices. Given the large volume of admissions, with about 20 randomized hospitals, a follow-up of about a year should suffice to obtain conclusive answers about specific tested interventions. If clinicians, administrators, and policy makers believe that administrative database results such as those reported by Joynt et al are clinically meaningful and relevant and not just spurious products of tenuous analyses, the modest cost of conducting such confirmatory randomized trials on health system changes is fully justified.”

(JAMA. 2013;309(13):1410-1411; Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: Dr. Ioannidis is supported in part by an unrestricted gift from Sue and Robert O’Donnell. 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, APRIL 2, 2013

Media Advisory: To contact Ellen M. Lavoie Smith, Ph.D., call Nicole Fawcett at 734-764-2220 or email nfawcett@umich.edu; or call Mary Beth Lewis at 734-763-1682 or email lewismb@umich.edu.

CHICAGO –Among patients with painful chemotherapy-induced peripheral neuropathy, use of the anti-depressant drug duloxetine for 5 weeks re­sulted in a greater reduction in pain compared with placebo, according to a study in the April 3 issue of JAMA.

“Approximately 20 percent to 40 percent of patients with cancer who re­ceive neurotoxic chemotherapy (e.g., taxanes, platinums, vinca alkaloids, bortezomib) will develop pain­ful chemotherapy-induced peripheral neuropathy. Painful chemotherapy-induced neuropathy can persist from months to years beyond chemotherapy completion, causing significant challenges for cancer survivors due to its negative in­fluence on function and quality of life. Chemotherapy-induced pe­ripheral neuropathy is difficult to manage, and most randomized controlled trials testing a variety of drugs with diverse mechanisms of action revealed no effective treatment,” according to background information in the article.

There is evidence that serotonin and norepinephrine dual reuptake inhibitors are effective in treat­ing neuropathy-related pain. Several phase 3 stud­ies have shown that duloxetine is an effec­tive treatment for painful diabetic neu­ropathy.

Ellen M. Lavoie Smith, Ph.D., of the University of Michigan School of Nursing, Ann Arbor, and colleagues conducted a ran­domized phase 3 trial to examine whether duloxetine would lessen chemotherapy-induced peripheral neuropathic pain. The study included 231 patients who were 25 years or older being treated at community and academic settings between April 2008 and March 2011. Study follow-up was com­pleted July 2012. Stratified by chemotherapeutic drug and comorbid pain risk, pa­tients were randomized to receive either duloxetine followed by placebo or placebo followed by duloxetine. Eligibility required that patients have a pain score of at least 4 on a scale of 0 to 10, representing average chemotherapy-induced pain, after paclitaxel, other taxane, or oxaliplatin treatment.

The initial treatment consisted of taking 1 capsule daily of either 30 mg of duloxetine or placebo for the first week and 2 capsules of either 30 mg of du­loxetine or placebo daily for 4 additional weeks.

The researchers found that at the end of the initial treatment pe­riod, patients in the duloxetine-first group reported a larger decrease in av­erage pain (average change score, 1.06) than those in the placebo-first group (average change score 0.34). The observed average differ­ence in the average pain score between the duloxetine-first and placebo-first groups was 0.73. Of the patients treated with dulox­etine first, 59 percent reported any decrease in pain vs. 38 percent of patients treated with placebo first. Thirty percent of duloxetine-treated patients reported no change in pain and 10 percent reported in­creased pain.

The authors note that the results sug­gested that patients who received plati­nums (oxaliplatin) may have experienced more benefit from duloxetine than those who received taxanes.

Pain-related quality-of-life im­proved to a greater degree for those treated with duloxetine during the ini­tial treatment than for those treated with placebo.

“In conclusion, 5 weeks of duloxetine treatment was associated with a statisti­cally and clinically significant improve­ment in pain compared with placebo. Exploratory analyses raise the possibility that duloxetine may work better for oxaliplatin-induced rather than taxane-induced painful chemotherapy-induced peripheral neuropathy,” the researchers write.

(JAMA. 2013;309(13):1359-1367; Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: This study was supported by a grant from the NCI Division of Cancer Preven­tion, the Alliance Statistics and Data Center, and the Alliance Chairman. Drug and placebo were supplied by Eli Lilly. The NCI provided funding for data man­agement and statistical analysis. 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, April 2 at this link.

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 26, 2013

Media Advisory: To contact Josje Altenburg, M.D., email j.altenburg@mca.nl. To contact David J. Serisier, M.B.B.S., D.M., F.R.A.C.P., email david.serisier@mater.org.au. To contact editorial co-author J. Stuart Elborn, M.D., email s.elborn@qub.ac.uk.

CHICAGO – Among patients with the lung disorder non-cystic fibrosis bronchiectasis, treatment with the antibiotic azithromycin or erythromycin resulted in improvement in symptoms but also increased the risk of antibiotic resistance, according to two studies appearing in the March 27 issue of JAMA.

Bronchiectasis is characterized by abnormal widening of the bronchi (air tubes that branch deep into the lungs) and can cause recurrent lung infections, a disabling cough, shortness of breath, and coughing up blood. “If progressive, this process may lead to respiratory failure and the need for lung transplantation or to death,” according to background information in one study. Macrolide (a class of antibiotics) antibiotics have antibacterial and anti-inflammatory properties that conceivably would provide effective treatment of bronchiectasis. These antibiotics have been shown beneficial in treating cystic fibrosis (CF), and findings from small studies suggest a benefit in non-CF bronchiectasis.

Josje Altenburg, M.D., of the Medical Centre Alkmaar, the Netherlands, and colleagues conducted a multicenter trial to investigate whether 1 year of low-dose macrolide treatment added to standard therapy is effective in reducing exacerbation frequency in patients with non-CF bronchiectasis. The randomized, placebo-controlled trial was conducted between April 2008 and September 2010 in 14 hospitals in the Netherlands among 83 outpatients with non-CF bronchiectasis and 3 or more lower respiratory tract infections in the preceding year. Patients received azithromycin (250 mg daily) or placebo for 12 months.

Forty-three participants (52 percent) received azithromycin and 40 (48 percent) received placebo and were included in the modified intention-to-treat analysis. A total of 117 exacerbations treated with antibiotics were reported during 1 year of treatment, 78 of which occurred in the placebo group. “During the treatment period, the median [midpoint] number of exacerbations in the azithromycin group was 0, compared with 2 in the placebo group. Of the 40 participants receiving placebo, 32 (80 percent) had at least 1 exacerbation during the study period. In the 43 participants receiving azithromycin, 20 (46.5 percent) had at least 1 exacerbation in the same period, yielding an absolute risk reduction of 33.5 percent. The number of patients needed to treat with azithromycin to maintain clinical stability was 3.0,” the authors write.

“Gastrointestinal adverse effects occurred in 40 percent of patients in the azithromycin group and in 5 percent in the placebo group but without need for discontinuation of study treatment. A macrolide resistance rate of 88 percent was noted in azithromycin-treated individuals, compared with 26 percent in the placebo group.”

“We conclude that macrolide maintenance therapy was effective in reducing exacerbations in patients with non-CF bronchiectasis. In this trial, azithromycin treatment resulted in improved lung function and better quality of life but involved an increase in gastrointestinal adverse effects and high rates of macrolide resistance,” the authors write.

(JAMA. 2013;309(12):1251-1259; Available pre-embargo to the media at http://media.jamanetwork.com)

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

In another study, David J. Serisier, M.B.B.S., D.M., F.R.A.C.P., of Mater Adult Hospital, South Brisbane, Australia, and colleagues tested the hypothesis that low-dose erythromycin would reduce pulmonary exacerbations in patients with non-CF bronchiectasis with a history of frequent exacerbations.

The study consisted of a 12-month randomized controlled trial of erythromycin in currently nonsmoking, adult patients with non-CF bronchiectasis with a history of 2 or more infective exacerbations in the preceding year. The study was undertaken between October 2008 and December 2011 in a university teaching hospital. Patients received twice-daily erythromycin ethylsuccinate (400 mg) or matching placebo. The primary measured outcome was the annualized average rate of protocol-defined pulmonary exacerbations (PDPEs) per patient. Secondary outcomes included macrolide resistance and lung function.

Six-hundred seventy-nine patients were screened, 117 were randomized (58 placebo, 59 erythromycin), and 107 (91.5 percent) completed the study. The researchers found that erythromycin significantly reduced PDPEs (76 for the erythromycin group vs. 114 for the placebo group; average 1.29 vs. 1.97 respectively, per patient per year). The number of patients treated with erythromycin who had zero PDPEs was 20 (vs. 16 for placebo), and 10 patients had more than 2 PDPEs (vs. 18, respectively).

Erythromycin also reduced PDPEs in the prespecified subgroup with baseline Pseudomonas aeruginosa airway infection. In addition, there were significantly fewer total respiratory events (total PDPEs plus non-PDPEs) in the erythromycin group (111 vs. 176 for placebo; average, 1.88 vs. 3.03 per patient per year).

“Erythromycin reduced 24-hour sputum production and attenuated [lessened] lung function decline compared with placebo. Erythromycin increased the proportion of macrolide-resistant oropharyngeal streptococci,” the authors write.

“In conclusion, long-term low-dose erythromycin significantly reduced exacerbations, protected against lung function decline, reduced sputum production, and significantly increased macrolide resistance in oropharyngeal streptococci. The bacterial resistance caused by macrolide therapy mandates a cautious application of this therapy in clinical practice. Further studies are needed to evaluate the possibility that P aerugmosa-infected individuals with frequent exacerbations may represent an appropriate subgroup for limitation of this therapy.”

(JAMA. 2013;309(12):1260-1267; Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: This study was internally funded by the Mater Adult Respiratory Research Trust Fund. No pharmaceutical company or other agency (including medical writers) had any role in this study. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Macrolides and Bronchiectasis – Clinical Benefit With a Resistance Price

“The important issues for clinicians are to determine which patients with bronchiectasis should be prescribed a macrolide and which macrolide should be used,” writes J. Stuart Elborn, M.D., and Michael M. Tunney, Ph.D., of Queen’s University Belfast, United Kingdom, in an accompanying editorial.

“In the trials in this issue of JAMA, patients were recruited if they had frequent exacerbations, defined as at least 2 or 3 exacerbations in the previous year. Therefore, patients with bronchiectasis who have 2 or more exacerbations in the previous year should be considered for treatment. Erythromycin and azithromycin are both effective for reducing exacerbations and have similar effects on antimicrobial resistance. The effect of long-term macrolide use on antibiotic resistance in these patients is not clear but should dissuade clinicians from prescribing macrolides for patients whose clinical characteristics differ from those for whom a positive effect was seen in these studies.”

(JAMA. 2013;309(12):1295-1296; Available pre-embargo to the media at http://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 3 P.M. (CT) TUESDAY, MARCH 26, 2013

The Economics of Genomic Medicine – Insights From the IOM Roundtable on Translating Genomic-Based Research for Health

In this Viewpoint, W. Gregory Feero, M.D., Ph.D., of the Maine-Dartmouth Family Medicine Residency, Augusta, Maine (Dr. Feero is also Contributing Editor, JAMA), and colleagues discuss several of the issues that became apparent from the July 2012 Institute of Medicine’s (IOM’s) Roundtable on Translating Genomic-Based Research for Health, a meeting designed to identify critical gaps unique to understanding the economics of adopting whole-genome or exome sequence information into health care. “The meeting report, published by the IOM, highlights that genome-scale information challenges traditional economic assessment much as it challenges approaches of traditional health care delivery.”

“The dialogue started at the 2012 IOM meeting should be continued. Immediate next steps could include additional IOM-sponsored stakeholder meetings to further the discussion, publication of articles with detailed proposals for filling knowledge gaps identified by stakeholder groups, and stakeholder engagement in focused efforts to create standardized approaches for clinical use and economic assessment in this area. Additionally, there is an important role for an independent, impartial organization or organizations to help prioritize translational research, understand evidence thresholds, and mediate the development of a consensus approach for assigning value to genome sequencing.”

“Resolving and effectively managing economic factors influencing the use of genome sequencing in health care is a critical task facing the public and private sectors. Early and prompt attention to these issues could prove to be deterministic for both genomics and the U.S. health care system in the decades to come.”

(JAMA. 2013;309[12]:1235-1236. Available pre-embargo to the media at http://media.jamanetwork.com)

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, MARCH 26, 2013

Media Advisory: To contact Sandra Y. Lin, M.D., call David March at 410-955-1534 or email dmarch1@jhmi.edu. To contact editorial author Harold S. Nelson, M.D., call Adam Dormuth at 303-398-1082 or email DormuthA@NJHealth.org.

CHICAGO – In an examination of a type of treatment for allergic rhinitis and asthma that is used in Europe but not approved by the U.S. Food and Drug Administration, researchers found moderate strength in the evidence from previous studies to support the use of sublingual immunotherapy for the treatment of these conditions, according to an article in the March 27 issue of JAMA. Sublingual immunotherapy involves administration of aqueous allergens under the tongue for local absorption to desensitize the allergic individual over an extended treatment period to diminish allergic symptoms.

Allergic rhinitis (an allergic reaction with symptoms similar to a cold) affects approximately 20 percent to 40 percent of the U.S. population. Considerable interest has emerged in the use of sublingual immunotherapy as a treatment. Compared with subcutaneous (under the skin) immunotherapy, sublingual immunotherapy is easy to administer, does not involve administration of injections, and may be administered at home, avoiding office visits. “In 1996, a World Health Organization Task Force on Immunotherapy cited the emerging clinical data on sublingual immunotherapy, and recognized its potential as a viable alternative to subcutaneous therapy,” according to background information in the article. Some physicians in the U.S. use subcutaneous aqueous (watery) allergens, off-label, for sublingual desensitization.

Sandra Y. Lin, M.D., of the Johns Hopkins University School of Medicine, Baltimore, and colleagues conducted a systematic review of previous studies to examine the effectiveness and safety of aqueous sublingual immunotherapy for allergic rhinoconjunctivitis and asthma. After a review of the medical literature, the researchers identified 63 studies with 5,131 participants that met the inclusion criteria for the review. Participants’ ages ranged from 4 to 74 years. Twenty studies (n=1,814 patients) enrolled only children.

The researchers found strong evidence supporting that sublingual immunotherapy improves asthma symptoms, with 8 of 13 studies reporting greater than 40 percent improvement vs. the comparator. “Moderate evidence supports that sublingual immunotherapy use decreases rhinitis or rhinoconjunctivitis symptoms, with 9 of 36 studies demonstrating greater than 40 percent improvement vs. the comparator. Medication use for asthma and allergies decreased by more than 40 percent in 16 of 41 studies of sublingual immunotherapy with moderate grade evidence. Moderate evidence supports that sublingual immunotherapy improves conjunctivitis symptoms (13 studies), combined symptom and medication scores (20 studies), and disease-specific quality of life (8 studies).”

Evidence was similar in strength to support the use of sublingual immunotherapy in children (< 18 years of age) for allergic rhinitis and asthma.

Local reactions were frequent, but there were no reported episodes of anaphylaxis, life-threatening reactions, or death in any treated patients across studies.

“Our review found moderate strength in the evidence to support the use of sublingual immunotherapy for allergic rhinitis and asthma. This indicates moderate confidence that the evidence reflects a true efficacy. However, future research could change the estimate. High-quality studies are needed to answer questions of optimal dosing strategies,” the authors conclude.

(JAMA. 2013;309(12):1278-1288; Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: This study was funded by a grant from the Agency for Healthcare Research and Quality (AHRQ) and is based on research conducted at the Johns Hopkins University Evidence-based Practice Center. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Lin reported serving as a consultant to Wellpoint. No other author reported disclosures.

Editorial: Is Sublingual Immunotherapy Ready for Use in the United States?

Harold S. Nelson, M.D., of National Jewish Health, Denver, writes in an accompanying editorial that “although the publication of many studies has been reassuring regarding issues of efficacy and safety of sublingual immunotherapy, as reported by Lin et al, several concerns regarding use of sublingual immunotherapy in the United States remain.”

“There are no extracts licensed by the U.S. Food and Drug Administration (FDA) available for sublingual administration of immunotherapy. In the absence of any product for which appropriate dosing and safety have been established in the United States, there is no Current Procedural Terminology code for administering sublingual immunotherapy to patients in the United States.”

“Until sublingual immunotherapy gains FDA approval, physicians who choose to administer off-label sublingual immunotherapy will have limited guidance in selecting effective dosing. In addition, clinicians should be aware that the evidence for efficacy of sublingual immunotherapy is derived from studies of treatment with a single allergen extract, not with combinations of unrelated allergens.”

(JAMA. 2013;309(12):1297-1298; Available pre-embargo to the media at http://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Nelson reported receiving honoraria from Merck Research Laboratories and Circassia Ltd. for advisory activities; and receiving a research grant from Circassia Ltd.

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