EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JUNE 2, 2015

Media Advisory: To contact Loreen A. Herwaldt, M.D., call Jennifer Brown at 319-356-7124 or email jennifer-l-brown@uiowa.edu. To contact editorial author Preeti N. Malani, M.D., M.S.J., call Shantell Kirkendoll at 734-764-2220 or email smkirk@umich.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.5387. This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.6018

Multifaceted Intervention Associated With Modest Decrease in Surgical Site Infections

Implementation of a pre-surgical intervention that included screening for the bacteria Staphylococcus aureus, treating patients who were positive for this bacteria, and the administration of antibiotics based on these culture results was associated with a modest reduction in S aureus surgical site infections, according to a study in the June 2 issue of JAMA.

S aureus carriage increases the risk of S aureus surgical site infections (SSIs). The risk for these infections may be decreased by screening patients for nasal carriage of S aureus and decolonizing carriers during the preoperative period. In addition, perioperative prevention with agents such as the antibiotic vancomycin may reduce rates of methicillin-resistant S aureus (MRSA) SSIs. Previous studies suggested that a bundled intervention was associated with lower rates of S aureus SSIs among patients having cardiac or orthopedic operations, according to background information in the article.

Loreen A. Herwaldt, M.D., of the University of Iowa Carver College of Medicine, Iowa City, and colleagues evaluated whether the implementation of an evidence-based bundle is associated with a lower risk of S aureus SSIs in patients undergoing cardiac operations or hip or knee replacement or reconstruction. Twenty hospitals in 9 U.S. states participated in this study; rates of SSIs were collected for a median of 39 months during the pre-intervention period and a median of 21 months during the intervention period.

Patients whose preoperative nasal screens were positive for MRSA or methicillin-susceptible S aureus (MSSA) were asked to apply the antibiotic mupirocin intranasally twice daily for up to 5 days and to bathe daily with chlorhexidine-gluconate (CHG; an antimicrobial agent) for up to 5 days before their operations. MRSA carriers received the antibiotics vancomycin and cefazolin or cefuroxime for perioperative prophylaxis; all others received cefazolin or cefuroxime. Patients who were MRSA-negative and MSSA-negative bathed with CHG the night before and morning of their operations. Patients were treated as MRSA-positive if screening results were unknown.

After a 3-month phase-in period, bundle adherence remained constant at 83 percent (full adherence, 39 percent; partial adherence, 44 percent). The complex (deep incisional or organ space) S aureus SSI rates decreased significantly among patients in the fully adherent group compared with the pre-intervention period, but rates did not decrease significantly in the partially adherent or nonadherent group.

Overall, 101 complex S aureus SSIs occurred after 28,218 operations during the pre-intervention period and 29 occurred after 14,316 operations during the intervention period (average rate per 10,000 operations, 36 for pre-intervention period vs 21 for intervention period). The rates of complex S aureus SSIs decreased for hip or knee arthroplasties (difference per 10,000 operations, -17) and for cardiac operations (difference per 10,000 operations, -6).

“Even though the baseline rate of complex S aureus SSI was low (0.36 per 10,000 operations), the full adherence rate was only 39 percent, and hospitals had implemented some bundle elements before the study began, rates of complex S aureus SSIs decreased significantly,” the researchers write. “Given that approximately 400,000 cardiac operations and 1 million total joint arthroplasties are performed in the United States each year, numerous S aureus SSIs, which can have catastrophic consequences, may be preventable. Moreover, 1 SSI adds from $13,000 to $100,000 to the cost of health care. Thus, implementation of this bundle might reduce patient morbidity and the costs of care substantially.”

(doi:10.1001/jama.2015.5387; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This project was funded by the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services. It also received support from VA Health Services Research and Development.  Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Bundled Approaches for Surgical Site Infection Prevention

In an accompanying editorial, Preeti N. Malani, M.D., M.S.J., of the University of Michigan Health System, Ann Arbor, and Associate Editor, JAMA, writes that although this study is a noteworthy addition to a growing body of high-quality infection prevention trials, many questions remain.

“Although S aureus remains the principal pathogen in terms of prevalence and associated morbidity, many other organisms also cause SSIs. As such, decolonization of MSSA and MRSA can be only one aspect of SSI prevention. Although the current findings demonstrate a decrease in S aureus SSIs, the authors did not find a decrease in gram-negative SSIs or complex SSIs caused by any pathogen. This finding might reflect the overall low rate of infection, but also is a poignant reminder that additional strategies are still needed.”

“Public reporting and nonpayment for preventable complications (including some SSIs) have intensified efforts to eliminate infections—‘to get to zero.’ The low-hanging fruit for SSI prevention has been picked and incremental decreases are unlikely to come from simple interventions. Although getting to zero is unlikely to be achievable, efforts that move closer to this elusive goal hold tremendous value for clinicians, hospitals, payers, and, most importantly, patients.”

(doi:10.1001/jama.2015.6018; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JUNE 2, 2015

Media Advisory: To contact Peter S. Hussey, Ph.D., email Kirsten Holguin at kholguin@rand.org.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.5089

Study Questions Effectiveness of Computerized Clinical Decision Support Systems

An analysis of the use of computerized clinical decision support systems regarding orders for advanced diagnostic imaging found that the systems failed to identify relevant appropriateness criteria for the majority of orders, according to a study in the June 2 issue of JAMA.

Computerized clinical decision support (CDS) systems that match patient characteristics against appropriateness criteria to produce algorithmic treatment recommendations are a potential means of improving care. The Protecting Access to Medicare Act of 2014 mandates use of CDS systems for the ordering of advanced diagnostic imaging in the Medicare program starting in 2017, according to background information in the article.

Peter S. Hussey, Ph.D., of RAND, Boston, and colleagues used data from the Medicare Imaging Demonstration to evaluate the relationship of CDS system use with the appropriateness of ordered images. Between October 2011 and November 2013, clinicians used computerized radiology order entry systems and CDS systems for selected magnetic resonance imaging, computed tomography, and nuclear medicine procedures. During a 6-month baseline period, the CDS systems tracked whether orders were linked with appropriateness criteria but did not provide clinicians with feedback on appropriateness of orders.

During the 18-month intervention period, the CDS systems provided feedback indicating whether the order was linked to appropriateness criteria and, if so, the appropriateness rating, any recommendations for alternative orders, and a link to documentation supporting each rating. National medical specialty societies developed the appropriateness criteria using expert panels that reviewed evidence and completed a structured rating process.

The 3,340 participating clinicians placed 117,348 orders for advanced diagnostic imaging procedures. The CDS systems did not identify relevant appropriateness criteria for 63.3 percent of orders during the baseline period and for 66.5 percent during the intervention period. During the baseline period, 11.1 percent of final rated orders were inappropriate vs 6.4 percent during the intervention period. During the baseline period, 73.7 percent of final rated orders were appropriate vs 81.0 percent during the intervention period. Of orders initially rated as inappropriate, 4.8 percent were changed and 1.9 percent were canceled.

“Most orders were unable to be matched by the CDS systems to appropriateness criteria. Of those matched, there was a small increase in the percentage of orders rated appropriate between the baseline and intervention periods, although few inappropriate orders were changed or canceled immediately following feedback from the CDS systems. Therefore, improvements in appropriate imaging ordering do not appear related to immediate feedback and instead may be related to physician learning or secular changes,” the authors write.

“Implementing CDS systems in real-world settings has many challenges that must be addressed to meaningfully affect patient care.”

(doi:10.1001/jama.2015.5089; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Funding for this project was provided by the Centers for Medicare & Medicaid Services. 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: 8 A.M. (ET) FRIDAY, MAY 29, 2015

Media Advisory: To contact Alexander Zarbock, M.D., email zarbock@uni-muenster.de. To contact editorial co-author David Sheikh-Hamad, M.D., call Julia Parsons at 713-798-4710 or email Julia.Parsons@bcm.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.4189. This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.5085

Intervention Reduces Rate of Kidney Injury Among High-Risk Patients Undergoing Cardiac Surgery

Use of a procedure known as remote ischemic preconditioning reduced the rate of kidney injury and the need for renal replacement therapy (dialysis) after cardiac surgery in high-risk patients, according to a study appearing in JAMA. The study is being released to coincide with its presentation at the 52nd European Renal Association/European Dialysis and Transplant Association Congress.

Remote ischemic preconditioning is performed to help protect organs against a type of tissue damage that can occur when normal blood flow is returned to a tissue that had been temporarily deprived of oxygen, such as during cardiac surgery. The procedure is performed just before surgery and involves placing a blood pressure cuff on a limb and alternately inflating and deflating it to restrict and restore blood flow. Evidence has suggested that remote ischemic preconditioning from brief episodes of ischemia (inadequate blood supply) and reperfusion (the restoration of blood flow) in distant tissue may provide protection from subsequent injury.

Up to 30 percent of patients develop acute kidney injury after cardiac surgery, and to date no interventions have yet been identified to reduce this risk. Three small single-center randomized trials investigating the effect of remote ischemic preconditioning on acute kidney injury after cardiac surgery have shown conflicting results, according to background information in the article.

Alexander Zarbock, M.D., of the University Hospital Munster, Germany, and colleagues randomly assigned 240 cardiac surgery patients at high risk for acute kidney injury to receive either remote ischemic preconditioning (n = 120; 3 cycles of 5-minute ischemia and 5-minute reperfusion in one upper arm after induction of anesthesia) or sham remote ischemic preconditioning (control; n = 120), both via blood pressure cuff inflation. The study was conducted at 4 hospitals in Germany.

The researchers found that significantly fewer patients in the remote ischemic preconditioning group developed acute kidney injury within 72 hours after surgery compared with the control group (37.5 percent vs 52.5 percent; absolute risk reduction, 15.0 percent). Remote ischemic preconditioning significantly reduced the number of moderate and severe acute kidney injury cases compared with that of the control group (12.5 percent vs 25.8 percent). Use of renal replacement therapy (5.8 percent vs 15.8 percent; absolute risk reduction, 10 percent) and length of intensive care unit stay (3 days vs 4 days) were significantly reduced with remote ischemic preconditioning.

There was no significant effect of remote ischemic preconditioning on heart attack, stroke, or death. No adverse events were reported with remote ischemic preconditioning.

“The observed reduction in the rate of acute kidney injury and the need for renal replacement warrant further investigation,” the authors write.

(doi:10.1001/jama.2015.4189; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The study was funded by the German Research Foundation. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Remote Ischemic Preconditioning for Kidney Protection

“Therapeutic strategies to protect against ischemic kidney injury and improve patient outcomes are lacking,” write Jenny Szu-Chin Pan, M.D., and David Sheikh-Hamad, M.D., of the Baylor College of Medicine, Houston, in an accompanying editorial.

“Remote ischemic preconditioning [RIPC], as demonstrated in the study by Zarbock and colleagues, may offer a novel inexpensive and noninvasive clinical intervention to reduce the occurrence and severity of acute kidney injury [AKI]. Further studies are needed to determine whether a longer duration of limb ischemia or earlier induction of RIPC confers better renoprotection; 37.5 percent of the patients in the RIPC group still developed AKI.”

The authors add that before RIPC is adopted for clinical use, the potential risks and adverse effects must be considered carefully. “While remote kidney/cardiac preconditioning after limb muscle ischemia may differ from the changes observed in the heart after kidney ischemia, effects of repeated limb ischemia with RIPC are not known and clinicians should be mindful of potential harms before adopting this approach widely.”

(doi:10.1001/jama.2015.5085; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 26, 2015

Media Advisory: To contact Nicolas Rodondi, M.D., M.A.S., email Nicolas.Rodondi@insel.ch.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.5161

Subclinical Hyperthyroidism Associated With an Increased Risk of Hip and Other Fractures

In an analysis that included more than 70,000 participants from 13 studies, subclinical hyperthyroidism was associated with an increased risk for hip and other fractures including spine, according to a study in the May 26 issue of JAMA. Subclinical hyperthyroidism is a low serum thyroid-stimulating hormone concentration in a person without clinical symptoms and normal thyroid hormone concentrations on blood tests.

Overt hyperthyroidism is an established risk factor for osteoporosis and fractures. Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking, according to background information in the article.

Nicolas Rodondi, M.D., M.A.S., of the Bern University Hospital, Bern, Switzerland, and colleagues assessed the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. The authors searched databases for studies with thyroid function data and subsequent fractures. Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (normal functioning) (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH ≥ 4.50-19.99 mIU/L) with normal thyroxine (a hormone that is made by the thyroid gland) concentrations.

Among 70,298 participants, 4,092 (5.8 percent) had subclinical hypothyroidism and 2,219 (3.2 percent) had subclinical hyperthyroidism. In an analysis of the occurrence of fractures among study participants, the researchers found that subclinical hyperthyroidism was associated with an increased risk for hip, spine and nonspine fracture and any fracture. The highest risks were in individuals with suppressed TSH (<0.10 mIU/L) and in those with endogenous (from within ones own body [vs. exogenous – taking too much thyroid replacement]) subclinical hyperthyroidism. No association was found between subclinical hypothyroidism and fractures.

“Our pooled data analysis demonstrates that subclinical hyperthyroidism was associated with increased fracture risk and provides insight on defined subgroups,” the authors write.

“Current guidelines recommend that treatment of subclinical hyperthyroidism should be strongly considered if TSH is persistently lower than 0.1 mIU/L in all individuals aged 65 years or older and that treatment should also be considered if TSH is low but at least 0.1 mIU/L in individuals who are at least 65 years old. Our results from pooling data of all available prospective cohorts, showing increased fracture risk in subclinical hyperthyroidism with even higher risk for participants with TSH levels of less than 0.10 mIU/L, are consistent with these recommendations.”

The researchers note that further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.

(doi:10.1001/jama.2015.5161; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 26, 2015

Media Advisory: To contact Lewis J. Smith, M.D., call Marla Paul at 312-503-8928 or email marla-paul@northwestern.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.5024

Soy Isoflavone Supplement Does Not Improve Symptoms, Lung Function for Patients with Poorly Controlled Asthma

Although some data have suggested that supplementation with soy isoflavone may be an effective treatment for patients with poor asthma control, a randomized trial that included nearly 400 children and adults found that use of the supplement did not result in improved lung function or clinical outcomes, including asthma symptoms and episodes of poor asthma control, according to a study in the May 26 issue of JAMA. Soy isoflavones are plant (soybean) derived chemicals that have anti-oxidant effects.

Increases in asthma prevalence and severity over the last several decades are likely due at least in part to environmental factors. Diet is one environmental factor that is associated with asthma prevalence and severity. Soy isoflavone supplements are used to treat several chronic diseases, although the data supporting their use are limited.  Some data suggest that supplementation with soy isoflavone may be an effective treatment for patients with poorly controlled asthma.  The soy isoflavone genistein inhibits a key pathway that may contribute to asthma severity. With the increasing cost of prescription drugs for asthma, it is important to identify effective, safe, and less expensive therapies than those currently available, according to background information in the article.

Lewis J. Smith, M.D., of Northwestern University, Chicago, and colleagues randomly assigned 386 adults and children age 12 years or older with symptomatic asthma while taking a “controller” medicine (either inhaled corticosteroids and/or a leukotriene modifier) and low dietary soy intake to receive soy isoflavone supplement containing 100 mg of total isoflavones (n=193) or matching placebo (n=193) in 2 divided doses administered daily for 24 weeks. The trial was conducted at 19 adult and pediatric pulmonary and allergy centers in the American Lung Association Asthma Clinical Research Centers network.

The researchers found that average changes in pre-bronchodilator forced expiratory volume in the first second (FEV₁; a measure of lung function) over 24 weeks were not significantly different between the soy isoflavone group and the placebo group. The supplement also did not improve other aspects of asthma control, including additional measures of lung function, symptoms, quality of life, and airway and systemic inflammation.

“These findings suggest that this supplement should not be used for patients with poorly controlled asthma,” the authors conclude.

(doi:10.1001/jama.2015.5024; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by grants from the National Institutes of Health and the American Lung Association. Archer Daniels Midland (Decatur, Il.) provided the soy isoflavone supplement and the matching placebo. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 26, 2015

Media Advisory: To contact Alexandre Reymond, Ph.D., email alexandre.reymond@unil.ch. To contact editorial author James R. Lupski, M.D., Ph.D., D.Sc., call Glenna Vickers at 713-798-7973 or email

picton@bcm.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.4845 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.4846

Study Examines Association of Genetic Variants with Cognitive Impairment

Individually rare but collectively common intermediate-size copy number variations may be negatively associated with educational attainment, according to a study in the May 26 issue of JAMA. Copy number variations (CNVs) are regions of the genome that differ in the number of segments of DNA.

The Database of Genomic Variants catalogs approximately 2.4 million DNA CNVs. Some of them have been previously implicated as causal of a wide variety of traits and conditions. According to background information in the article large (defined as larger than 500 kb), recurrent CNVs have been particularly associated with developmental delay and intellectual disability (characterized by limited intellectual functioning and impaired adaptive behavior in everyday life) in symptomatic individuals ascertained in clinical settings.

Alexandre Reymond, Ph.D., and Katrin Männik, Ph.D., of the University of Lausanne, Switzerland, and colleagues used the population biobank of Estonia, which contains samples from 52,000 participants to explore the consequences of CNVs in a presumptively healthy population. General practitioners examined participants and filled out a questionnaire of health- and lifestyle-related questions, as well as reported diagnoses. For example, information was available regarding attained level of education for participants.   Copy number variant analysis was conducted on a random sample of 7,877 individuals and genotype-phenotype associations with education and disease traits were evaluated.  Phenotype is a characteristic of an individual that is the result of the interaction of the person’s genetic makeup (genotype) and his or her environment.

Of the 7,877 in the Estonian cohort, the researchers identified 56 carriers of recurrent large CNVs associated with known syndromes. Many of these individuals had phenotypic features similar to symptomatic individuals ascertained in previous clinical studies.

A genome-wide evaluation of rare intermediate size CNVs (frequency ≤ 0.05 percent; ≥ 250 kb) identified 831 carriers (10.5 percent) in the tested population sample. This group of carriers had increased prevalence of intellectual disability and decreased education attainment. Eleven of 216 (5.1 percent) of carriers of a deletion of at least 250 kb and 5.9 percent of carriers of a duplication of at least l Mb had an intellectual disability compared with 1.7 percent in the Estonian cohort without detected CNVs.

Of the deletion carriers, 33.5 percent did not graduate from high school while 39.1 percent of duplication carriers did not graduate high school compared to 25.3 percent in the Estonian population at large. These evidences for an association between rare intermediate size CNVs and lower educational attainment were further supported by analyses of cohorts including an intellectually high-functioning group of Estonians and 3 geographically distinct populations in the United Kingdom, the United States and Italy.

“Replication of these findings in additional population groups is warranted given the potential implications of this observation for genomics research, clinical care, and public health.”
(doi:10.1001/jama.2015.4845; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Cognitive Phenotypes and Genomic Copy Number Variations

“The results reported by Mannik et al indicate that individually rare but collectively common intermediate-size CNVs contribute to the variance in educational attainment,” writes James R. Lupski, M.D., Ph.D., D.Sc., of the Baylor College of Medicine, Houston, in an accompanying editorial.

“This phenotype is an objectively quantifiable trait that could trigger ordering of a genomic study capable of detecting CNV used in clinical care. With the recognition of a potentially causal mutation in an individual, tailored behavioral and educational interventions could be initiated with patients and family that could improve educational outcomes. Although changing a person’s genome is not possible, identifying those with CNVs related to cognitive phenotypes could provide an opportunity to help them reach their fullest potential.”

(doi:10.1001/jama.2015.4846; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 26, 2015

Media Advisory: To contact Catterina Ferreccio, M.D., M.P.H., email catferre@gmail.com.

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Study Finds Association Between Exposure to Aflatoxin and Gallbladder Cancer

In a small study in Chile that included patients with gallbladder cancer, exposure to aflatoxin (a toxin produced by mold) was associated with an increased risk of gallbladder cancer, according to a study in the May 26 issue of JAMA.

In Chile, gallbladder cancer is a leading cause of cancer death in women. Exposure to aflatoxin, a liver carcinogen, is associated with gallbladder cancer in primates. Aflatoxin contamination has been identified in Chile, including in aji rojo (red chili peppers). Aji rojo is associated with gallbladder cancer; however, the association of aflatoxin with gallbladder cancer in humans has not been directly evaluated, according to background information in the article.

Catterina Ferreccio, M.D., M.P.H., of the Pontificia Universidad Catolica de Chile, Santiago, Chile, and colleagues evaluated plasma aflatoxin-albumin adducts (a compound) and gallbladder cancer in a pilot study conducted from April 2012 through August 2013. Aflatoxin forms adducts with albumin in peripheral blood that accumulate up to 30-fold higher with chronic vs single exposure. The researchers assessed aflatoxin B₁-lysine adduct (AFB₁ adduct) in participants. Aji rojo consumption was determined via questionnaire.

The final analysis included 36 patients (cases) with gallbladder cancer, 29 controls with gallstones, and 47 community controls. Cases and controls had similar characteristics except for aji rojo consumption (greater percentage of case patients had weekly consumption). AFB₁-adducts were detected in 23 cases (64 percent), 7 controls with gallstones (18 percent), and 9 community controls (23 percent). AFB₁-adduct levels were highest in cases.

“Despite the small number of participants, the associations between aflatoxin exposure and gallbladder cancer were statistically significant. Recall bias may affect self-reported variables, but not exposure measurement. We cannot rule out reverse causation (i.e., cancer may affect AFB₁-adduct detection) using cross-sectional data. Larger and longitudinal efforts are needed to substantiate these preliminary findings, obtain more precise effect estimates, and identify sources of aflatoxin. These findings, if confirmed, may have implications for cancer prevention,” the authors write.

(doi:10.1001/jama.2015.4559; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 19, 2015

Media Advisory: To contact Harley Goldberg, D.O., call Traci Mogil at 415-262-5973 or email Traci.Mogil@creation.io.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.4668

Oral Steroids for Herniated Disk Results in Modest Improvement in Function, No Improvement in Pain

Among patients with acute radiculopathy (sciatica) due to a herniated lumbar disk, a short course of oral steroids, compared with placebo, resulted in modest improvement in function and no significant improvement in pain, according to a study in the May 19 issue of JAMA.

Many patients with sciatica endure substantial pain and disability. For those who do not recover quickly, invasive procedures such as epidural steroid injections (ESIs) and surgery are commonly performed. Oral administration of steroid medication may provide similar anti-inflammatory activity, can be delivered quickly by primary care providers, carries less risk, and would be much less expensive than an ESI. Oral steroids are used by many community physicians and have been included in some clinical guidelines; however, no appropriately powered clinical trials of oral steroids for radiculopathy have been conducted to date, according to background information in the article.

Harley Goldberg, D.O., of the Kaiser Permanente Northern California Spine Care Program, San Jose, Calif., and colleagues randomly assigned 269 adults with radicular pain for 3 months or less, a herniated disk, and a certain minimum measure on a disability index (Oswestry Disability Index [ODI]), to receive a tapering 15-day course of an oral steroid (prednisone; 5 days each of 60 mg, 40 mg, and 20 mg; total cumulative dose = 600 mg: n = 181) or matching placebo (n = 88).

The researchers found a small, statistically significant improvement in function (change in baseline ODI) at both 3 weeks and 52 weeks favoring the prednisone-treated group but no difference in lower extremity pain scores. Several secondary outcomes showed small but inconsistent improvements in the active treatment group relative to the placebo group.

“An important rationale for using oral steroids is the potential to decrease the need for more invasive interventions,” the authors write. In this trial, there was no significant difference between the two groups in the likelihood of undergoing spine surgery at 52-week follow-up.

(doi:10.1001/jama.2015.4668; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the U.S. National Institutes of Health to Drs. Goldberg and Avins. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 4:15 P.M. (ET) SUNDAY, MAY 17, 2015

Media Advisory: To contact Francois Stephan, M.D., Ph.D., email f.stephan@ccml.fr. To contact editorial author Niall D. Ferguson, M.D., M.Sc., email Liam Mitchell at liam.mitchell@utoronto.ca.

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Newer Method of Oxygen Delivery Shows Benefits for Patients at Risk of Respiratory Failure after Surgery

A relatively new, easier to implement, and better-tolerated method to provide supplemental oxygen to patients at risk of respiratory failure after surgery did not result in a worse rate of treatment failure compared to a more commonly used method, according to a study appearing in JAMA. The study is being released to coincide with its presentation at the American Thoracic Society 2015 International Conference.

After cardiothoracic surgery, acute respiratory failure is common and associated with an increased risk of illness and death. When low-flow oxygen therapy is insufficient to correct hypoxemia (abnormally low level of oxygen in the blood), noninvasive ventilation is often used to avoid reintubation (reinsertion of a breathing tube) and improve outcomes. A moderate level of evidence supports noninvasive ventilation to treat postoperative respiratory failure. However, this technique is difficult to implement, requires substantial resources, and may cause patient discomfort. High-flow nasal oxygen therapy is continuous oxygen delivery through a nasal cannula (a device that consists of a tube that splits into two prongs placed in the nostrils). High flow nasal oxygen therapy is increasingly used because of ease of application, tolerability for patients, and other theoretical clinical benefits and may constitute an important alternative to noninvasive ventilation, according to background information in the article.

Francois Stephan, M.D., Ph.D., of the Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France, and colleagues randomly assigned 830 patients who had undergone cardiothoracic surgery (such as coronary artery bypass grafting or heart valve repair) to receive high-flow nasal oxygen therapy delivered continuously through a nasal cannula (flow, 50 L/min; n = 414) or bilevel positive airway pressure (BiPAP) delivered with a full-face mask for at least 4 hours per day (n = 416). Patients were included when they developed acute respiratory failure or were deemed at risk for respiratory failure after extubation (removal of a breathing tube) due to preexisting risk factors. The study was conducted at 6 French intensive care units. The primary outcome for the trial was treatment failure, defined as reintubation, switch to the other study treatment, or premature treatment discontinuation (patient request or adverse effects).

The researchers found that high-flow nasal oxygen therapy was not inferior (not worse than) to BiPAP: with BiPAP, treatment failure occurred in 91of 416 patients (21.9 percent) compared with 87 of 414 (21.0 percent) with high-flow nasal oxygen. No significant differences were found for intensive care unit mortality (23 patients with BiPAP [5.5 percent] and 28 patients with high-flow nasal oxygen therapy [6.8 percent]) or for any of the other secondary outcomes, including number of nurse interventions for unplanned device readjustment and respiratory complications.

Dyspnea (labored breathing) and comfort scores during the first 3 days were similar in both groups.

“Among patients undergoing cardiothoracic surgery with or at risk for respiratory failure, the use of high-flow nasal oxygen compared with intermittent BiPAP did not result in a worse rate of treatment failure. The findings support the use of high­flow nasal oxygen therapy in this patient population,” the authors write.

(doi:10.1001/jama.2015.5213; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: High-Flow Nasal Cannulae or Noninvasive Ventilation for Management of Postoperative Respiratory Failure

In an accompanying editorial, Lorenzo Del Sorbo, M.D., and Niall D. Ferguson, M.D., M.Sc., of the University of Toronto, comment on findings of this trial.

“How should clinicians apply the results of the trial by Stephan et al in clinical practice? The answer is, as usual, it depends. In centers with considerable expertise with noninvasive ventilation (NIV) and for patients who are hypercapnic [an excess of carbon dioxide in the blood], a reasonable approach would be to favor NIV in this setting. Alternatively, based on these data and others, for many postoperative patients high-flow nasal cannulae appear to be a viable alternative that is better tolerated and may lead to noninferior clinical outcomes.”

(doi:10.1001/jama.2015.5304; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 19, 2015

Media Advisory: To contact Robert J. Wong, M.D., M.S., call Jerri Applegate Randrup at 510-437-4732 or email jrandrup@alamedahealthsystem.org.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.4260

Study Finds High Prevalence of Metabolic Syndrome in U.S.

Nearly 35 percent of all U.S. adults and 50 percent of those 60 years of age or older were estimated to have the metabolic syndrome in 2011-2012, according to a study in the May 19 issue of JAMA.

The metabolic syndrome is combination of health conditions (such as obesity, high blood pressure, type 2 diabetes, poor lipid profile) that contribute to cardiovascular illness and death. Data from the National Health and Nutrition Examination Survey (NHANES) 1999-2006 reported a metabolic syndrome prevalence of 34 percent. Understanding updated prevalence trends may be important given the potential effect of the metabolic syndrome and its associated health complications on the aging U.S. population, according to background information in the article.

Robert J. Wong, M.D., M.S., of the Alameda Health System-Highland Hospital, Oakland, Calif., and colleagues used 2003-2012 NHANES data (a probability sample of the U.S. population) to evaluate trends in the metabolic syndrome among adults age 20 years or older. The researchers stratified metabolic syndrome prevalence by sex, race/ethnicity, and age groups (20-39, 40-59, and 60 years or older).

From 2003-2004 to 2011-2012, overall prevalence of the metabolic syndrome increased from 32.9 percent to 34.7 percent. When evaluating trends from 2007-2008 to 2011-2012, overall prevalence of the metabolic syndrome remained stable, as did prevalence trends among men and all race/ethnic groups, whereas prevalence among women decreased from 39.4 percent in 2007-2008 to 36.6 percent in 2011-2012.

From 2003 to 2012, prevalence was higher in women compared with men. When stratified by race/ethnicity, the highest prevalence was seen in Hispanics, followed by non-Hispanic whites and blacks.

Prevalence increased by age groups, increasing from 18.3 percent among those 20 to 39 years of age to 46.7 percent among those 60 years or older. Among this age group, more than 50 percent of women and Hispanics had the metabolic syndrome. The authors write that the high prevalence among the oldest age group is “a concerning observation given the aging U.S. population.”

The researchers add that greater awareness of the metabolic syndrome and its health consequences may have contributed to improvements in optimizing treatment of risk factors such as hypertension and diabetes. “Furthermore, recent NHANES data demonstrate that obesity prevalence in the United States also appears to have stabilized, which also may contribute to the stabilizing prevalence of the metabolic syndrome.”

(doi:10.1001/jama.2015.4260; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 19, 2015

Media Advisory: To contact Willemijn J. Jansen, M.Sc., email willemijn.jansen@maastrichtuniversity.nl. To contact Pieter Jelle Visser, M.D., Ph.D., email pj.visser@maastrichtuniversity.nl. To contact Rik Ossenkoppele, Ph.D., email r.ossenkoppele@vumc.nl. To contact editorial author Roger N. Rosenberg, M.D., email Gregg Shields at Gregg.Shields@utsouthwestern.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the 1^st study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.4668 This link to the 2nd study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.4669  This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.5361

Studies Examine Prevalence of Amyloid among Adults and its Association with Cognitive Impairment

Two studies in the May 19 issue of JAMA analyze the prevalence of the plaque amyloid among adults of varying ages, with and without dementia, and its association with cognitive impairment.

Alzheimer disease (AD) is the most common cause of dementia, with a worldwide prevalence of about 25 million in 2010, expected to be doubled by 2030 because of increased life expectancy. The earliest recognizable pathological event in AD is cerebral amyloid-β aggregation (protein fragments that clump together to form plaque). This pathology may be present up to 20 years before the onset of dementia. Prevalence estimates of amyloid pathology in persons without dementia are needed to better understand the development of AD and to facilitate the design of AD prevention studies. Initiation of treatment for AD in the pre-dementia phase, when neuronal damage is still limited, may be crucial to have clinical benefit.

In one study, Willemijn J. Jansen, M.Sc., and Pieter Jelle Visser, M.D., Ph.D., of Maastricht University, Maastricht, the Netherlands and colleagues used individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers (on positron emission tomography or in cerebrospinal fluid) in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). Databases were searched to identify relevant biomarker studies, which were included if they provided individual participant data for participants without dementia. Individual records were provided for 2,914 participants with normal cognition, 697 with SCI, and 3,972 with MCI (ages 18 to 100 years) from 55 studies.

The researchers found that the prevalence of amyloid pathology increased from age 50 to 90 years from 10 percent to 44 percent among participants with normal cognition; from 12 percent to 43 percent among patients with SCI; and from 27 percent to 71 percent among patients with MCI. Apolipoprotein E (APOE)-ε4 (a gene associated with an increased risk of developing AD) carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at onset of amyloid positivity was associated with cognitive status and the APOE genotype. At age 90 years, about 40 percent of the APOE-ε4 noncarriers and more than 80 percent of APOE-ε4 carriers with normal cognition were amyloid positive.

The researchers write that this study has several implications for understanding the development of AD. “The observation that key risk factors for AD-type dementia are also risk factors for amyloid positivity in cognitively normal persons provides further evidence for the hypothesis that amyloid positivity in these individuals reflects early AD. … Our study also indicates that development of AD pathology can start as early as age 30 years, depending on the APOE genotype. Comparison with prevalence and lifetime risk estimates of AD-type dementia suggests a 20- to 30-year interval between amyloid positivity and dementia, implying that there is a large window of opportunity to start preventive treatments.”

The authors note that the exact interval between the onset of amyloid positivity and onset of AD-type dementia needs to be assessed by long-term follow-up studies because not all persons with amyloid pathology will become demented during their lifetime, and not all individuals with a clinical diagnosis of AD-type dementia have amyloid pathology. “Because of the uncertainty about whether and when an amyloid-positive individual without dementia will develop dementia, amyloid positivity in these individuals should not be equated with impending clinical dementia but rather be seen as a risk state. Our prevalence rates can be used as an inexpensive and noninvasive approach to select persons at risk for amyloid positivity.”

(doi:10.1001/jama.2015.4668; Available pre-embargo to the media at https://media.jamanetwork.com)

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

In another study, Rik Ossenkoppele, Ph.D., of VU University Medical Center Amsterdam, the Netherlands, and colleagues used individual participant data meta-analysis to estimate the prevalence of amyloid positivity on positron emission tomography (PET) in a wide variety of dementia syndromes.

The clinical utility of amyloid PET imaging is potentially limited by a proportion of patients with non-AD dementia and cerebral amyloid-β plaques. To correctly interpret the clinical significance of amyloid PET results, clinicians need to understand the prevalence of amyloid positivity across different types of dementia and how this is associated with demographic, genetic, and cognitive factors. Most amyloid PET studies to date come from single centers with modest sample sizes, according to background information in the article.

After a search of databases for amyloid PET studies, the authors included data for 1,359 participants with clinically diagnosed AD and 538 participants with non-AD dementia. The reference groups were 1,849 healthy control participants (based on amyloid PET) and an independent sample of 1,369 AD participants (based on autopsy).

In AD dementia, the average prevalence of amyloid positivity was 88 percent. The prevalence decreased with age from 93 percent at age 50 to 79 percent at age 90. This association differed according to APOE ε4 status. In APOE ε4 carriers, the prevalence remained at least 90 percent regardless of age, whereas the prevalence in noncarriers declined from 86 percent at age 50 years to 68 percent at age 90 years. Similar associations of age and APOE ε4 with amyloid positivity were observed in participants with AD dementia at autopsy. In most non-AD dementias, amyloid positivity increased with both age (from 60 to 80 years) and APOE ε4 carriership.

“The main findings of this individual participant meta-analysis were that the prevalence of amyloid on PET decreased with age in participants diagnosed with AD (greatest in APOE ε4 noncarriers) and increased with age in most non-AD dementias. The convergence of amyloid positivity across dementias with increasing age suggests that amyloid imaging might have the potential to be most helpful for differential diagnosis in early-onset dementia, particularly if the goal is to rule-in AD dementia,” the authors write.

“However, the high concordance between PET and pathology suggests that amyloid imaging might have the potential to be used to rule-out AD dementia regardless of age. Furthermore, amyloid in non-AD dementia may be clinically important as amyloid positivity was associated with worse global cognition. Data from this study may inform research into the clinical application of amyloid PET and highlight the necessity of biomarker-based participant selection for clinical trials.”

(doi:10.1001/jama.2015.4669; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Defining Amyloid Pathology in Persons With and Without Dementia Syndromes

“Jansen et al and Ossenkoppele et al provide succinct meta-analyses of considerable clinical value,” writes Roger N. Rosenberg, M.D., of the University of Texas Southwestern Medical Center at Dallas, and Editor, JAMA Neurology, in an accompanying editorial.

“Persons without dementia have an increasing prevalence of cerebral amyloid pathology with age, APOE genotype, and cognitive loss as measured by PET imaging or cerebrospinal fluid findings. Similarly, among persons with dementia, the prevalence of amyloid pathology was related to clinical diagnosis, age, and APOE genotype. Together, these data show the immense potential clinical use of amyloid imaging to make the correct diagnosis in early-onset dementia and, more specifically, to establish the diagnosis of AD-type dementia and noncarrier APOE-ε4 genotype among persons older than 70 years.”

(doi:10.1001/jama.2015.5361; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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This issue of JAMA is a theme issue on professionalism and self-governance in medicine across the spectrum of physician education and clinical practice, with particular attention to maintenance of certification, which has become highly contentious. Nineteen Viewpoints and 3 Editorials by leading scholars and academic leaders consider the roles and responsibilities of governing and accrediting bodies and of professional organizations and societies for ensuring effective governance and professionalism in medicine.

The following Viewpoints and Editorials are available pre-embargo at https://media.jamanetwork.com/.

Viewpoints Appearing in this Issue of JAMA

Embargoed for Release: 11 a.m. ET Tuesday, May 12, 2015

Self-Governance and Self-Regulation

Ensuring Competency and Professionalism Through State Medical Licensing

Humayun J. Chaudhry, D.O., M.S., Federation of State Medical Boards, Euless, Texas, and colleagues

Professionalism, Self-Regulation, and Motivation – How Did Health Care Get This So Wrong?

James L. Madara, M.D., and Jon Burkhart, American Medical Association, Chicago

Aiming Higher to Enhance Professionalism – Beyond Accreditation and Certification

Mark R. Chassin, M.D., M.P.P., M.P.H., and David W. Baker, M.D., M.P.H., The Joint Commission, Oakbrook Terrace, Il.

Education and Professionalism

Undergraduate Medical Education and the Foundation of Physician Professionalism

Darrell G. Kirch, M.D., Association of American Medical Colleges, Washington, D.C., and colleagues

Enhancing Professionalism Through Management

Ezekiel J. Emanuel, M.D., Ph.D., University of Pennsylvania, Philadelphia

Professionalism and its Implications for Governance and Accountability of Graduate Medical Education in the United States

Thomas J. Nasca, M.D., M.A.C.P., Accreditation Council for Graduate Medical Education, ACGME International, Chicago

Postgraduate Education of Physicians – Professional Self-Regulation and External Accountability

Donald M. Berwick, M.D., M.P.P., Institute for Healthcare Improvement, Cambridge, Mass.

Board Certification and Lifelong Learning

Of the Profession, by the Profession, and for Patients, Families, and Communities – ABMS Board Certification and Medicine’s Professional Self-Regulation

Lois Margaret Nora, M.D., J.D., M.B.A., American Board of Medical Specialties, Chicago, and colleagues

Professional Self-Regulation in a Changing World – Old Problems Need New Approaches

Richard J. Baron, M.D., American Board of Internal Medicine, Philadelphia

The Role of Maintenance of Certification Programs in Governance and Professionalism

Paul S. Teirstein, M.D., and Eric J. Topol, M.D., Scripps Health, La Jolla, Calif.

Medicine’s Continuous Improvement Imperative

Robert S. Huckman, Ph.D., and Ananth Raman, Ph.D., M.B.A., Harvard Business School, Boston

Reforming the Continuing Medical Education System

Steven E. Nissen, M.D., Cleveland Clinic, Cleveland, Ohio

Professionalism and Employment

Redesigning Metrics to Integrate Professionalism Into the Governance of Health Care

Vivian S. Lee, M.D., Ph.D., M.B.A., University of Utah, Salt Lake City

Physician Professionalism in Employed Practice

Francis J. Crosson, M.D., former executive director of the Permanente Federation, Kaiser Permanente

Professionalism, Fiduciary Duty, and Health-Related Business Leadership

Joshua D. Margolis, Ph.D., M.A., Harvard Business School, Boston

Perspectives on Medical Professionalism

The Transformation of U.S. Physicians

Victor R. Fuchs, Ph.D., and Mark R. Cullen, M.D., Stanford University, Stanford, Calif.

Governance and Professionalism in Medicine – A UK Perspective

Harvey Marcovitch, F.R.C.P., F.R.C.P.C.H., Honeysuckle House, Oxfordshire, England

Maintaining Physician Competence and Professionalism – Canada’s Fine Balance

1. David Naylor, M.D., D.Phil., University of Toronto, Canada

Medical Professionalism and the Future of Public Trust in Physicians

Noam N. Levey, Los Angeles Times/Tribune Washington Bureau, Washington, D.C.

Editorials Appearing in this Issue of JAMA

Embargoed for Release: 11 a.m. ET Tuesday, May 12, 2015

Professionalism, Governance, and Self-Regulation of Medicine

Howard Bauchner, M.D., JAMA, Chicago

Medical Professionalism

Catherine D. DeAngelis, M.D., M.P.H., Johns Hopkins Schools of Medicine and Public Health, Baltimore

Tasking the “Self” in the Self-Governance of Medicine

Jordan J. Cohen, M.D., Arnold P. Gold Foundation, Englewood Cliffs, N.J.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 12, 2015

Media Advisory: To contact Kate Smolina, Ph.D., call Heather Amos at 604-822-3213 or email heather.amos@ubc.ca.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.3642

Public Health Advisories Associated With Reductions in Dispensing of Codeine to Postpartum Women

Public health advisories from the U.S. Food and Drug Administration (FDA) and Health Canada were associated with significant reductions in the rate of dispensing of codeine to postpartum women, according to a study in the May 12 issue of JAMA.

Some patients are ultra-rapid metabolizers of codeine, with prevalence ranging from 2 percent to 40 percent. Nursing mothers who take codeine may be putting their infant at risk if they carry the gene variants for elevated activity of an enzyme that metabolizes codeine to morphine. High levels of morphine in breast milk may lead to infant death from a drug-induced respiratory problem. The U.S. FDA released a public health advisory in August 2007 warning about the potentially life-threatening adverse effects in infants of breast-feeding mothers taking codeine. Health Canada published a similar advisory in October 2008, according to background information in the article.

Kate Smolina, Ph.D., of the University of British Columbia, Vancouver, Canada, and colleagues examined postpartum codeine use among all women with live births between January 2002 and December 2011 in British Columbia to evaluate the rate of codeine dispensations before and after the two regulatory advisories. Information about prescription dispensations came from BC PharmaNet, a comprehensive database of every prescription filled outside of acute care hospitals, regardless of patient age or insurance status.

During the study period, there were 320,351 live births to 225,532 women. Of these, new mothers filled at least 1 codeine prescription during 47,095 postpartum periods. Before the FDA advisory, the monthly average for the proportion of postpartum mothers filling at least 1 codeine prescription was 17 percent, which declined to a monthly average of 9 percent from September-December 2011, a 45 percent relative reduction over 4 years.

The authors write that the reduction may reflect the adoption of the recommendations by clinicians. “Some of the reduction could also reflect changes in patient behavior, including not filling written prescriptions, not asking for codeine, or both. The speed and the magnitude of the response suggests that regulatory warnings regarding postpartum drug safety can have a strong influence on prescribing patterns.”

(doi:10.1001/jama.2015.3642; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by a Canadian Institutes for Health Research (CIHR) grant. Dr. Smolina is funded in part by a CIHR Banting postdoctoral fellowship. 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: 10 A.M. (ET) MONDAY, MAY 4, 2015

Media Advisory: To contact Rahul Rajkumar, M.D., J.D., call Raymond Thorn of CMS Media Relations at 202-690-6145 or email press@cms.hhs.gov. To contact Lawrence P. Casalino, M.D., Ph.D., email Jennifer Gundersen at jeg2034@med.cornell.edu. To contact Mark McClellan, M.D., Ph.D., email Michelle Shaljian at mshaljian@brookings.edu.

To place an electronic embedded link to this study and editorials in your story This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.4930. This will be the link to the 1^st editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.5086. This will be the link to the 2^nd editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.5087.

Pioneer Accountable Care Organization Model Shows Smaller Increases in Medicare Spending

In the first 2 years of the Pioneer Accountable Care Organization (ACO) Model, beneficiaries aligned with these ACOs, as compared with general Medicare fee-for-service beneficiaries, showed smaller increases in total Medicare expenditures, with an estimated savings of approximately $385 million, according to a study published by JAMA. The study is being released to coincide with an announcement by the Centers for Medicare & Medicaid Services (CMS) about the performance of the Pioneer ACO model.

In 2012, the CMS launched the Pioneer ACO Model and the Medicare Shared Savings Program as alternative payment approaches to engage physicians and health care organizations willing to assume collective responsibility for the cost and quality outcomes of a specified population of fee-for-service (FFS) Medicare beneficiaries. As part of the incentive to participate, Pioneer ACOs with an annual spending level lower than a projected spending level can receive a portion of the difference between their spending and the projection as shared savings with CMS, conditional on their performance on a set of 33 quality measures. The Pioneer ACO Model is one of several attempts to test the viability of the ACO concept as means to improve quality of care and reduce spending in the U.S. health care system, according to background information in the article.

Rahul Rajkumar, M.D., J.D., of the Centers for Medicare & Medicaid Services, Baltimore, and colleagues determined whether FFS beneficiaries aligned with 32 Pioneer ACOs (n = 675,712 in 2012; n = 806,258 in 2013) had smaller increases in spending and utilization than other FFS beneficiaries (a comparison group of alignment-eligible beneficiaries in the same markets [n = 13,203,694 in 2012; n = 12,134,154 in 2013]) while retaining similar levels of care satisfaction in the first 2 years of the Pioneer ACO Model.

The researchers found that total spending for beneficiaries aligned with Pioneer ACOs in 2012 or 2013 increased from baseline (2010-2011) to a lesser degree relative to comparison populations. Differential changes in spending were approximately -$35.62 per-beneficiary-per-month (PBPM) in 2012 and -$11.18 PBPM in 2013, which amounted to aggregate reductions in increases of approximately -$280 million in 2012 and -$105 million in 2013.

A large portion of the smaller increase in spending was from decreases in inpatient utilization among ACO-aligned beneficiaries, although greater decreases in primary care evaluation and management office visits, and smaller increases in the use of tests, procedures, and imaging services also were related to the observed differences in changes in spending. There was no difference in all-cause readmissions within 30 days of discharge, but follow-up visits after hospital discharge increased more for ACO-aligned beneficiaries.

Compared with other Medicare beneficiaries, ACO-aligned beneficiaries reported higher average scores for timely care and for clinician communication.

“These results are encouraging, given how historically challenging it has been for physicians to achieve spending reductions in Medicare demonstration projects,” the authors write. “Despite decreases in spending growth, results from this study and previously reported data on Pioneer ACOs’ performance on clinical quality measures suggest it is possible to reduce expenditure growth while maintaining or improving quality in a FFS payment environment.”

(doi:10.1001/jama.2015.4930; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Pioneer Accountable Care Organizations – Traversing Rough Country

Lawrence P. Casalino, M.D., Ph.D., of Weill Cornell Medical College, Healthcare Policy and Research, New York, comments on the findings of this study in an accompanying editorial.

“Nyweide et al estimated that Pioneer ACOs achieved savings for CMS of $280 million in their first year. This represents a savings of approximately 4 percent. This amount may seem small, but if this rate of savings could be sustained, and achieved throughout a large part of the U.S. health care system, it would be more than enough to ‘bend the cost curve’ so that health care expenditures do not continue to increase as a percentage of the gross domestic product and the federal budget.”

“Can this rate of savings be sustained? The Pioneer ACOs produced savings in year 2 that were one-third of year 1 savings. It is possible that during the first year these ACOs were able to ‘grasp the low hanging fruit’—to address relatively easy ways to control costs—and that the savings they generate will be much smaller, at best, in subsequent years. Alternatively, it may be that it will take time for ACOs to develop better processes to improve the care of their patients and that they will be able to continue to lower costs for years to come.”

“The number of ACO­like contracts between private insurers is increasing rapidly. The next 5 years will be critical in determining if ACOs can indeed maintain or improve quality of care at a time when new therapies are emerging and simultaneously control the rise of health care costs.”

(doi:10.1001/jama.2015.5086; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Accountable Care Organizations and Evidence-Based Payment Reform

“This early evidence moves the effects of ACOs from speculation to reality and highlights the importance of further evaluation as alternative payment models are refined,” writes Mark McClellan, M.D., Ph.D., of The Brookings Institution, Washington, D.C., in an accompanying editorial. “Payment reform moving away from FFS is now part of the policy landscape, but the exact form it will take is less clear. Evaluations like this derived from actual payment reforms can provide more clarity.”

“Incorporating evaluations like this alongside the implementation of further ACO payment reforms would help ensure that many health care organizations do not end up in alternative payment models that are not improving care and also would provide more evidence that clinicians could use to succeed in ACOs. Payment reform has a long way to go, but it is possible for further steps to be guided by the development of better evidence. Reforming care to achieve better outcomes and lower costs is not easy, even with financing that is better aligned. Nonetheless, an increasing number of diverse health care organizations are demonstrating that it is possible.”

(doi:10.1001/jama.2015.5087; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 5, 2015

Media Advisory: To contact Fred Poordad, M.D., call Rosanne Fohn at 210-567-3026 or email fohn@uthscsa.edu. To contact Andrew J. Muir, M.D., call Samiha Khanna at 919-419-5069 or email samiha.khanna@duke.edu. To contact editorial author Hari Conjeevaram, M.D., M.Sc., call Shantell Kirkendoll at 734-764-2220 or email smkirk@umich.edu.

To place an electronic embedded link to these studies and editorial in your story This link to the 1^st study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.3860. This link to the 2^nd study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.3868. This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.4368.

Studies Show Effectiveness of New Combination Treatment for HCV Patients With or Without Cirrhosis

In two studies appearing in the May 5 issue of JAMA, patients with chronic hepatitis C virus (HCV) genotype 1 infection and with or without cirrhosis achieved high rates of sustained virologic response after 12 weeks of treatment with a combination of the direct-acting-antiviral drugs daclatasvir, asunaprevir, and beclabuvir.

Current estimates indicate that 130 million to 150 million people worldwide are chronically infected with HCV, resulting in up to 350,000 deaths per year. Of the 7 HCV genotypes identified, genotype 1 is the most prevalent worldwide, accounting for approximately 60 percent of infections. Treatment options for HCV genotype 1 are evolving rapidly from interferon-based regimens to all-oral, direct-acting antiviral only regimens.

In one study, Fred Poordad, M.D., of the University of Texas Health Science Center, San Antonio, Texas, and colleagues determined the rates of sustained virologic response (SVR) in patients receiving a twice-daily combination of daclatasvir, asunaprevir and beclabuvir (DCV-TRIO regimen). The study included both treatment-naive (n = 312) and patients who had previously received treatment (n = 103) for HCV genotype 1 infection and who did not have cirrhosis. This international study (UNITY-1) was conducted at 66 sites in the United States, Canada, France, and Australia. Sustained virologic response was defined as HCV-RNA <25 IU/ml at post-treatment week 12 (SVR12).

Overall, SVR12 was observed in 379 of 415 patients (91.3 percent): 287 of 312 treatment-naive patients (92 percent) and 92 of 103 treatment-experienced patients (89.3 percent). Virologic failure occurred in 8 percent of patients.

One patient died at post-treatment week 3: this was not considered related to study medication. There were 7 serious adverse events, all considered unrelated to study treatment, and 3 adverse events (<1 percent) leading to treatment discontinuation. The most common adverse events (in ≥ 10 percent of patients) were headache, fatigue, diarrhea, and nausea.

“This study demonstrates that 12 weeks of therapy with the DCV-TRIO regimen without ribavirin was associated with high rates of SVR12 in patients with HCV genotype 1 infection,” the authors write.

(doi:10.1001/jama.2015.3860; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by Bristol-Myers Squibb. Editorial support was provided by Andrew Street, Ph.D., of Articulate Science and was funded by Bristol-Myers Squibb. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

In another study, Andrew J. Muir, M.D., of the Duke University Medical Center, Durham, N.C., and colleagues evaluated the effectiveness of treatment with daclatasvir, asunaprevir, and beclabuvir in patients who were treatment-naive and treatment-experienced with chronic HCV genotype 1 infection and cirrhosis.

An estimated 20 percent of patients with chronic HCV infection will develop cirrhosis, with the prevalence increasing. Patients with cirrhosis are at increased risk for liver cancer and death. Effective and well-tolerated, interferon-free regimens are needed for these patients.

This study (UNITY-2) was conducted at 49 outpatient sites in the United States, Canada, France and Australia. Patients were treated for 12 weeks with the 3-drug combination regimen, with 24 weeks of follow-up after completion of treatment. Patients with cirrhosis were enrolled in 2 cohorts: HCV treatment-naive or HCV treatment-experienced; patients within each cohort were also stratified according to HCV genotype 1 subtype (1a or 1b) and randomly assigned to receive weight-based ribavirin (1,000-1,200 mg/d) or matching placebo.

One hundred twelve patients in the treatment-naive group and 90 patients in the treatment-experienced group were treated and included in the analysis. In the treatment-naive group, sustained virologic response at post-treatment week 12 (SVR₁₂) was achieved by 93 percent of patients receiving DCV-TRIO alone and by 98 percent of patients with ribavirin added; and corresponding SVR₁₂ rates for the treatment­ experienced group were 87 percent for patients receiving DCV-TRIO alone and 93 percent for patients with ribavirin added. SVR₁₂ was achieved by 51 of 52 patients (98 percent) with genotype 1b infection overall; and SVR₁₂ rates in patients with genotype 1a were 86 percent to 97 percent across all treatment groups.

Three serious adverse events were considered to be treatment related and there were 4 adverse event-related discontinuations.

The authors note that the contribution of ribavirin to SVR₁₂ remains uncertain because of the small sample sizes; results suggest that inclusion of ribavirin with the regimen may be considered for patients with genotype 1a infection.

“In this open-label, uncontrolled study, patients with chronic HCV genotype 1 infection and cirrhosis who received a 12-week oral fixed-dose regimen of daclatasvir, asunaprevir, and beclabuvir, with or without ribavirin, achieved high rates of SVR₁₂.”

(doi:10.1001/jama.2015.3868; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by Bristol-Myers Squibb. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Continued Progress Against Hepatitis C Infection

“These 2 studies add to the armamentarium of all-oral interferon-free regimens that have revolutionized management of hepatitis C, not only for patients who are treatment naive with no significant liver disease but also for those who are treatment experienced and those with cirrhosis,” writes Hari Conjeevaram, M.D., M.Sc., of the University of Michigan, Ann Arbor, in an accompanying editorial.

“Despite the progress and the success of viral eradication, numerous questions remain unanswered such as response based on race, still difficult-to-treat situations such as patients with end-stage liver disease or undergoing hemodialysis, access to and affordability of these therapies, improvement in quality of life, and cost-effectiveness. It is time to reflect on these challenges and find solutions because the influence of HCV infection on global society is an ongoing challenge.”

(doi:10.1001/jama.2015.4368; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MAY 5, 2015

Media Advisory: To contact Dale N. Gerding, M.D., call Stasia Thompson at 708-216-5155 or email thoms@lumc.edu.

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Oral Administration of Non-Aggressive Strain of C difficile Reduces Risk of Recurrence of C difficile Infection

Among patients with Clostridium difficile infection (CDI) who recovered following standard treatment with the antibiotics metronidazole or vancomycin, oral administration of spores of a strain of C difficile that does not produce toxins colonized the gastrointestinal tract and significantly reduced CDI recurrence, according to a study in the May 5 issue of JAMA.

C difficile is the cause of one of the most common and deadly health care–associated infections, linked to 29,000 U.S. deaths each year. Rates of CDI remain at unprecedented high levels in U.S. hospitals. Clinical infection also has a recurrence rate of 25 percent to 30 percent among affected patients. Not all strains of C difficile produce toxins. Nontoxigenic C difficile strains that lack the genes for toxin production are also found in the hospital environment and can colonize hospitalized patients, although patients are usually asymptomatic. Gastrointestinal colonization by these nontoxigenic C difficile strains (in both humans and hamsters) has shown promising results as a potential way to prevent CDI, according to background information in the article.

Dale N. Gerding, M.D., of the Edward Hines Jr. VA Hospital, Hines, Il., and Loyola University Chicago, Maywood, Il., and colleagues randomly assigned 173 adult patients who were diagnosed as having CDI (first episode or first recurrence) to receive 1 of 4 treatments: oral liquid formulation of nontoxigenic C difficile strain M3 (VP20621; NTCD-M3), 10⁴ spores/d for 7 days (n = 43), 10⁷ spores/d for 7 days (n = 44), 10⁷ spores/d for 14 days (n = 42), or placebo for 14 days (n = 44). Prior to enrollment, these patients had all successfully completed treatment with metronidazole, oral vancomycin, or both at 44 study centers in the United States, Canada, and Europe.

Among 168 patients who started treatment, 157 completed treatment. Clostridium difficile infection recurrence was 30 percent among patients receiving placebo compared with 11 percent among all patients receiving NTCD-M3. The lowest recurrence was in 5 percent of patients receiving 10⁷ spores/d for 7 days. Fecal colonization with NTCD-M3 occurred in 69 percent of NTCD-M3 patients: 71 percent with 10⁷ spores/d and 63 percent with 10⁴ spores/d. Colonization with NTCD correlated with reduced recurrence of CDI: recurrence occurred in 2 percent patients who were colonized vs 31 percent of patients who received NTCD-M3 but were not colonized.

One or more treatment-emergent adverse events were reported in 78 percent of patients receiving NTCD-M3 and 86 percent of patients receiving placebo. Diarrhea and abdominal pain were reported in 46 percent and 17 percent of patients receiving NTCD-M3 and 60 percent and 33 percent of placebo patients, respectively. Serious treatment-emergent adverse events were reported in 7 percent of patients receiving placebo and 3 percent of all patients who received NTCD-M3. Headache was reported in 10 percent of patients receiving NTCD-M3 and 2 percent of placebo patients.

The researchers write that the mechanism by which NTCD prevents recurrent CDI is not known; however, there may be an association with the presence of NTCD in the stool (colonization) with reduced infection from toxigenic C difficile and in animal models with prevention of CDI when challenged with toxigenic strains. “The most likely hypothesized mechanism of action of NTCD-M3 is that it occupies the same metabolic or adherence niche in the gastrointestinal tract as does toxigenic C difficile and, once established, is able to outcompete resident or newly ingested toxigenic strains.”

The authors note that the sample size of the study was small, so many of the findings should be confirmed in larger studies.

(doi:10.1001/jama.2015.3725; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was sponsored by ViroPharma Incorporated, which is now part of the Shire group of companies. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 28, 2015

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Emergency Department Intervention Improves Rate of Treatment for Opioid Dependence

Among opioid-dependent patients presenting for emergency care, treatment with buprenorphine initiated in the emergency department, compared with a brief intervention and referral, significantly increased the likelihood of receiving formal addiction treatment, reduced self-reported illicit opioid use, and decreased use of inpatient addiction treatment services but did not significantly decrease the rates of urine samples that tested positive for opioids or of HIV risk, according to a study in the April 28 issue of JAMA. Buprenorphine is a medication for opioid use disorder that decreases withdrawal symptoms, craving, and opioid use.

Dependence on prescription opioids and heroin is a major public health problem that is increasing in the United States and internationally. Opioid agonist treatment, including methadone and buprenorphine, is the most effective treatment. Patients with opioid dependence are at increased risk of adverse health consequences and often seek medical care in emergency departments (EDs). Currently, the primary option available to the ED for opioid dependence is referral to addiction treatment services. The introduction of buprenorphine/naloxone may provide ED physicians the opportunity to initiate effective medication treatment in conjunction with a brief intervention and referral, according to background information in the article.

Gail D’Onofrio, M.D., M.S., of the Yale School of Medicine, New Haven, Conn., and colleagues randomly assigned opioid-dependent patients who were treated at an urban teaching hospital ED to screening and referral to treatment (referral; n = 104); screening, brief intervention and facilitated referral (brief intervention; n = 111), or screening, brief intervention, ED-initiated treatment with buprenorphine/naloxone, and referral to primary care for 10-week follow-up (buprenorphine; n = 114).

The primary outcome for the study was enrollment in and receiving addiction treatment 30 days after randomization. Eighty-nine of 114 patients (78 percent) in the buprenorphine group were engaged in treatment at significantly higher rates than patients in the referral group (37 percent) or patients in the brief intervention group (45 percent). The buprenorphine group reported greater reductions in the average number of days of illicit opioid use per week—from 5.4 days to 0.9 days, compared to the referral group, which decreased from 5.4 days to 2.3 days, and the brief intervention group, which decreased from 5.6 days to 2.4.

The rates of opioid negative urine toxicology test results did not differ statistically across the treatment groups, with 54 percent in the referral group, 43 percent in the brief intervention group, and 58 percent in the buprenorphine group having tested negative for opioid use. There were no statistically significant differences in HIV risk across groups.

Eleven percent of patients in the buprenorphine group used inpatient addiction treatment services, whereas 37 percent in the referral group and 35 percent in the brief intervention group used these services.

“Our findings demonstrate that ED-initiated buprenorphine with coordinated follow-up for ongoing treatment was more effective than referral with or without brief intervention,” the authors write. “Although this single-site study supports this ED-initiated treatment strategy, these findings require replication in other centers before widespread adoption.”

(doi:10.1001/jama.2015.3474; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The study was supported by a grant from the National Institute on Drug Abuse (NIDA), and Reckitt-Benckiser Pharmaceuticals provided buprenorphine through NIDA. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 28, 2015

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Medication to Treat Frequent Pain Crises in Sickle Cell Anemia Underused

Despite evidence demonstrating the benefits of the medication hydroxyurea for patients with sickle cell anemia and frequent pain crises, an analysis suggests that more than 3 of 4 patients who might benefit were not treated with this safe and inexpensive drug, according to a study in the April 28 issue of JAMA.

The recommendation from the 2014 National Heart, Lung, and Blood Institute guidelines to treat all adults with sickle cell anemia (SCA) and 3 or more moderate to severe pain crises within 1 year with hydroxyurea was rated as strong based on high-quality evidence reviewed in 2008. Despite benefits in reducing pain crises, hospitalizations, and blood transfusions, it is thought that hydroxyurea is underused, although the extent of its use is unknown, according to background information in the article.

Nicolas Stettler, M.D., M.S.C.E., of the Lewin Group, Falls Church, Va., and colleagues examined the use of hydroxyurea when indicated for SCA in the Optum Normative Health Informatics database, a nationwide sample of commercial health and pharmacy claims from more than 36 million residents in all 50 states and Washington, D.C. Adults (18 years or older) with 1 or more inpatient or outpatient claims between January 2009 and June 2013 for SCA were identified. Patients were selected when they had 3 or more hospitalizations, emergency department (ED) visits, or both within 12 months that included 1 of the 5 most frequent diagnosis codes used for patients with SCA and pain crises. Treatment was defined as filling 1 or more hydroxyurea prescriptions during the 3, 6, or 12 months of continued enrollment following the third episode.

Of an enrolled population of 26,631,901, the researchers identified 2,086 adults with probable SCA. Of these, 677 had at least 3 pain-related hospitalizations or ED visits within 12 months and 570 had at least 3 months of coverage after the third episode. Among them, 86 (15 percent) were treated with hydroxyurea within 3 months of their third encounter. The percentage of treated patients increased slightly to 18 percent at 6 months and to 23 percent at 12 months.

The authors write that several barriers to treatment have been identified, including fear of adverse events, lack of clinician training, and failure to engage in shared decision making. “Our estimate reflects the combined effect of all barriers to treatment, regardless of source.”

“Our data do not include the large uninsured or publicly insured population who may have more limited access to health care or awareness of treatment options. Therefore, these findings may not be representative of the entire U.S. population with SCA and may be a conservative estimate of the hydroxyurea treatment gap. To address this gap, it may be necessary to enhance patient outreach and clinician training and develop health care quality measures aimed at increasing the use of hydroxyurea for all patients who would benefit.”

(doi:10.1001/jama.2015.3075; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 28, 2015

Media Advisory: To contact Anne Barton, Ph.D., F.R.C.P., email anne.barton@manchester.ac.uk. To contact editorial co-author David T. Felson, M.D., M.P.H., call Gina DiGravio at 617-638-8480 or email ginad@bu.edu.

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Certain Genetic Factors Associated With Rheumatoid Arthritis Severity, Risk of Death and Response to Treatment

Genetic variations associated with the risk of susceptibility to rheumatoid arthritis are also associated with responsiveness to treatment, the risk of death, and severity of the disease as measured by imaging, according to a study in the April 28 issue of JAMA.

Advances have been made in identifying genetic susceptibility loci (the specific site of a particular gene on its chromosome) for autoimmune diseases, but evidence is needed regarding their association with disease prognosis and treatment response, according to background information in the article.

Anne Barton, Ph.D., F.R.C.P., of the University of Manchester, England, and colleagues examined whether specific HLA-DRBl (a gene) haplotypes (a set of DNA or genetic variations) associated with rheumatoid arthritis (RA) susceptibility are also associated with severity (as measured by radiological imaging), death, and response to medications (tumor necrosis factor [TNF] inhibitor drugs). For the analysis, the researchers used data from several sources that totaled 2,112 patients to evaluate radiologic severity; 2,432 patients to assess mortality; and 1,846 patients to examine treatment response to TNF inhibitor therapy. All patients were from the United Kingdom.

The researchers found that the HLA-DRBl locus was associated with radiological severity of RA, risk of death, and response to treatment with TNF inhibitor therapy.

“Replication of these findings in other cohorts is needed as a next step in evaluating the role of HLA-DRBl haplotype analysis for management of RA,” authors write.

(doi:10.1001/jama.2015.3435; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: The Genetics of Rheumatoid Arthritis

The results of this study are important for 3 reasons, write David T. Felson, M.D., M.P.H., of the Boston University School of Medicine, and Lars Klareskog, M.D., Ph.D., of the Karolinska Institutet/Karolinska University Hospital, Stockholm, in an accompanying editorial.

“First, these findings may add to the ability to predict outcomes of RA, thus helping to optimize therapeutic strategies for different patients. Second, the findings may add to the understanding of the molecular mechanisms that determine disease course and mortality. … Third, the findings by Viatte et al also help to inform understanding of disease pathogenesis by strongly implicating HLA-dependent immune events not only for the onset of RA, but also for disease course and mortality.”

“Although the findings reported by Viatte and colleagues may not have immediate clinical implications, identification of the precise HLA variants that influence disease course is of great interest. These observations open the door to further research, including replication for this haplotype and discovery related to its combination with other determinants of disease development and progression. Such discoveries will prove helpful both to understand and predict the variable disease course and response to therapy that occurs in patients with rheumatoid arthritis.”

(doi:10.1001/jama.2015.1710; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Supported by a grant from the National Institutes of Health. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 28, 2015

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Use of Vena Cava Filter Does Not Reduce Risk of Recurrent Blood Clot for Patients Receiving Anticoagulant

Among hospitalized patients with severe acute pulmonary embolism (a life-threatening blood clot in a lung), the use of a retrievable inferior vena cava filter plus anticoagulation compared with anticoagulation alone did not reduce the risk of recurrent pulmonary embolism or death, according to a study in the April 28 issue of JAMA.

An inferior vena cava (the largest vein in the body) filter is a type of vascular filter that is implanted to prevent blood clots. Observational studies show a sharp increase in the placement of inferior vena cava filters over the past 3 decades, including their use as add-on therapy to anticoagulant therapy in patients presenting with a blood clot. However, due to the lack of reliable data, the benefit vs risk is uncertain, according to background information in the article.

Patrick Mismetti, M.D., Ph.D., of the Centre Hospitalier Universitaire de Saint-Etienne, France and colleagues randomly assigned hospitalized patients with acute, symptomatic pulmonary embolism associated with lower-limb vein thrombosis and at least 1 criterion for severity to retrievable inferior vena cava filter implantation plus anticoagulation (n = 200) or anticoagulation alone with no filter implantation (control group; n = 199). Initial hospitalization with ambulatory follow-up occurred in 17 French centers; follow-up was 6-months. Filter retrieval was planned at 3 months from placement.

In the filter group, the filter was successfully inserted in 193 patients and was retrieved as planned in 153 of the 164 patients in whom retrieval was attempted. By 3 months, pulmonary embolism had recurred in 6 patients (3.0 percent) in the filter group and 3 patients (1.5 percent) in the control group. All episodes in the filter group and 2 of 3 in the control group were fatal. One additional pulmonary embolism recurrence was observed in each group between 3 and 6 months.

No difference was observed between the 2 treatment groups for deep vein thrombosis, major bleeding, or death from any cause at 3 and 6 months.

“The availability of retrievable inferior vena cava filters has probably contributed to the increasing use of filters for managing acute venous thromboembolism, including their use in addition to full-dose anticoagulant therapy in patients with pulmonary embolism, a large clot burden, a poor cardiopulmonary reserve, or a suspected increased risk for recurrence, as advocated by several guidelines. The results of the present study do not support such a strategy,” the authors write. “These findings do not support the use of this type of filter in patients who can be treated with anticoagulation.”

(doi:10.1001/jama.2015.3780; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 21, 2015

Media Advisory: To contact Anjali Jain, M.D., call Christine Farazi at 952-500-0592 or email christine.farazi@optum.com; or call Stephen Puleo at 617-774-9322 or email steve.puleo@optum.com. To contact editorial author Bryan H. King, M.D., M.B.A., call Leila Gray at 206-685-0381 or email leilag@uw.edu.

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No Association Found Between MMR Vaccine and Autism, Even Among Children at Higher Risk

In a study that included approximately 95,000 children with older siblings, receipt of the measles-mumps-rubella (MMR) vaccine was not associated with an increased risk of autism spectrum disorders (ASD), regardless of whether older siblings had ASD, findings that indicate no harmful association between receipt of MMR vaccine and ASD even among children already at higher risk for ASD, according to a study in the April 21 issue of JAMA, a theme issue on child health.

Although a substantial body of research over the last 15 years has found no link between the MMR vaccine and ASD, parents and others continue to associate the vaccine with ASD. Surveys of parents who have children with ASD suggest that many believe the MMR vaccine was a contributing cause. This belief, combined with knowing that younger siblings of children with ASD are already at higher genetic risk for ASD compared with the general population, might prompt these parents to avoid vaccinating their younger children, according to background information in the article.

Anjali Jain, M.D., of the Lewin Group, Falls Church, Va., and colleagues examined ASD occurrence by MMR vaccine status in a large sample of U.S. children who have older siblings with and without ASD. The researchers used an administrative claims database associated with a large commercial health plan. Participants included children continuously enrolled in the health plan from birth to at least 5 years of age during 2001-2012 who also had an older sibling continuously enrolled for at least 6 months between 1997 and 2012.

Of the 95,727 children included in the study, 1,929 (2.01 percent) had an older sibling with ASD. Overall, 994 (1.04 percent) children in the cohort had ASD diagnosed during follow-up. Among those who had an older sibling with ASD, 134 (6.9 percent) were diagnosed with ASD, compared with 860 (0.9 percent) diagnosed with ASD among those with siblings without ASD. The MMR vaccination rate (l dose or more) for the children with unaffected siblings (siblings without ASD) was 84 percent (n = 78,564) at 2 years and 92 percent (n = 86,063) at age 5 years. In contrast, the MMR vaccination rates for children with older siblings with ASD were lower (73 percent at age 2 years and 86 percent at age 5 years). Analysis of the data indicated that MMR vaccine receipt was not associated with an increased risk of ASD at any age.

“Consistent with studies in other populations, we observed no association between MMR vaccination and increased ASD risk among privately insured children. We also found no evidence that receipt of either 1 or 2 doses of MMR vaccination was associated with an increased risk of ASD among children who had older siblings with ASD. As the prevalence of diagnosed ASD increases, so does the number of children who have siblings diagnosed with ASD, a group of children who are particularly important as they were undervaccinated in our observations as well as in previous reports,” the authors write.

(doi:10.1001/jama.2015.3077; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Promising Forecast for Autism Spectrum Disorders

In an accompanying editorial, Bryan H. King, M.D., M.B.A., of the University of Washington and Seattle Children’s Hospital, Seattle, comments on the findings of this study.

“Some parents of children with ASD may have chosen to delay immunization in subsequent children until they were certain any risk had passed. Such behavior, which arguably could enrich the immunization rate in the nonautism subgroup relative to the group that may have been showing early atypical development, might create the impression that MMR vaccine is actually reducing risk for ASD. Indeed, Jain et al report relative risks of less than 1.0. Even so, short of arguing that MMR vaccine actually reduces the risk of ASD in those who were immunized by age 2 years, the only conclusion that can be drawn from the study is that there is no signal to suggest a relationship between MMR and the development of autism in children with or without a sibling who has autism.”

“Taken together, some dozen studies have now shown that the age of onset of ASD does not differ between vaccinated and unvaccinated children, the severity or course of ASD does not differ between vaccinated and unvaccinated children, and now the risk of ASD recurrence in families does not differ between vaccinated and unvaccinated children.”

(doi:10.1001/jama.2015.2628; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 21, 2015

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Parent Training Program Helps Reduce Disruptive Behavior of Children with Autism

A 24 week parent training program, which provided specific techniques to manage disruptive behaviors of children with autism spectrum disorder, resulted in a greater reduction in disruptive and noncompliant behavior compared to parent education, according to a study in the April 21 issue of JAMA, a theme issue on child health.

Autism spectrum disorder (ASD) affects an estimated 6 per 1,000 children worldwide and is a major public health challenge. As many as 50 percent of children with ASD exhibit behavioral problems, including tantrums, noncompliance, aggression, and self-injury. Behavioral interventions are used to treat disruptive behavior but have not been evaluated in large-scale randomized trials, according to background information in the article.

Lawrence Scahill, M.S.N., Ph.D., of Children’s Healthcare of Atlanta and Emory University, Atlanta, and colleagues conducted a study in which children (age 3-7 years) with ASD were randomly assigned to parent training (n = 89) or parent education (n = 91) at 6 centers (Emory University, Indiana University, Ohio State University, University of Pittsburgh, University of Rochester, Yale University).

Parent training provided specific strategies to manage disruptive behavior and was delivered individually to the parents in 11 core sessions of 60 to 90 minutes’ duration, up to 2 optional sessions, 1 home visit, and up to 6 parent-child coaching sessions over 16 weeks. Parent training also included 1 home visit and 2 telephone booster sessions between weeks 16 and 24. Parent education provided information about autism but no behavior management strategies and included 12 sessions of 60 to 90 minutes and 1 home visit over 24 weeks.

On parent-rated measures of disruptive and noncompliant behavior, parent training, compared to parent education, showed a greater reduction on two scales: a 48 percent vs 32 percent decline on the Aberrant Behavior Checklist-Irritability subscale; and a 55 percent vs 34 percent decline on the Home Situations Questionnaire-Autism Spectrum Disorder.  Both treatment groups improved over time, although neither measure met the prespecified minimal clinically important difference. The authors suggest that one possible explanation for the smaller than anticipated differences between groups is the larger than predicted improvement in the parent education group.

Parent training was superior to parent education on a measure of overall improvement as judged by a clinician who was blinded to research assignment (69 percent vs 40 percent).

The authors write that the cost-effectiveness of the 2 interventions needs to be investigated, and that future analyses may identify child and family characteristics that predict success with parent training or parent education.

“To our knowledge, this is the largest randomized trial of any behavioral intervention for children with ASD. The results of this multisite study provide empirical support for wider implementation of this structured, relatively brief parent training intervention for young children with ASD.”

(doi:10.1001/jama.2015.3150; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Promising Forecast for Autism Spectrum Disorders

“Although specific behavioral training was superior, both groups reported considerable improvement over baseline, suggesting that even regular intensive education about autism provided value to parents and translated to perceived behavioral improvements in their children,” writes Bryan H. King, M.D., M.B.A., of the University of Washington and Seattle Children’s Hospital, Seattle, in an accompanying editorial.

“Some challenges for the future include what can be learned about the children who did not respond to behavioral intervention and why some children of parents who were not educated about behavioral principles also improved. Autism is a diverse condition, and a better understanding of how psychosocial interventions work will be critical for determining how to personalize treatment.”

(doi:10.1001/jama.2015.2628; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 21, 2015

Media Advisory: To contact Ezio Bonifacio, Ph.D., email ezio.bonifacio@crt-dresden.de. To contact editorial author Jay S. Skyler, M.D., email Jennifer Smith at Jennifer.Smith@med.miami.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.2928 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.2054

High-Dose Oral Insulin Shows Potential for Preventing Type 1 Diabetes in High-Risk Children

In a pilot study that included children at high risk for type 1 diabetes, daily high-dose oral insulin, compared with placebo, resulted in an immune response to insulin without hypoglycemia, findings that support the need for a phase 3 trial to determine whether oral insulin can prevent islet autoimmunity and diabetes in high-risk children, according to a study in the April 21 issue of JAMA, a theme issue on child health.

A few specific proteins are often the trigger for immune responses that cause autoimmune diseases. This has led to the experimental use of antigen­specific therapies (using a substance to initiate an immune response) to prevent, stabilize, or reverse immune­related diseases, such as allergies and multiple sclerosis. Type 1 diabetes is an autoimmune disease that can be detected in asymptomatic individuals by the presence of islet autoantibodies that develop in children. Antigen-specific therapy using insulin before the development of autoantibodies may induce protective immune responses that prevent the emergence of autoimmunity and subsequent type 1 diabetes in genetically at-risk children, according to background information in the article.

Ezio Bonifacio, Ph.D., of the DFG Center for Regenerative Therapies Dresden, Technische Universitat Dresden, Germany and colleagues randomly assigned autoantibody-negative, genetically at-risk children to receive oral insulin at varying doses (n = 15) or placebo (n = 10) once daily for 3 to 18 months to assess whether oral insulin can induce a potentially protective immune response without causing adverse effects. The study (Pre-POINT) was performed between 2009 and 2013 in Germany, Austria, the United States, and the United Kingdom and enrolled children age 2 to 7 years with a family history of type 1 diabetes.

Immune responses to insulin were observed in 2 of 10 (20 percent) placebo-treated children, in 1 of 6 (16.7 percent) children treated with 2.5 mg of insulin, 1 of 6 (16.7 percent) treated with 7.5 mg, 2 of 6 (33.3 percent) treated with 22.5 mg, and 5 of 6 (83.3 percent) treated with 67.5 mg of insulin.

The incidence and type of adverse events were not different between children who received placebo and children who received oral insulin, regardless of the insulin dose. Hypoglycemia was not observed at any of the tested doses.

“The Pre-POINT pilot study demonstrated that daily oral administration of 67.5 mg of insulin to genetically at-risk healthy children without signs of islet autoimmunity resulted in an immune response without hypoglycemia. The immune response observed in insulin-treated children did not display the features typically associated with type 1diabetes,” the authors write.

(doi:10.1001/jama.2015.2928; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Toward Primary Prevention of Type 1 Diabetes

“It is now possible to identify children at increased risk for type 1 diabetes at birth, and there is an identifiable sequence of events that culminates in impaired insulin secretion and overt type 1 diabetes,” writes Jay S. Skyler, M.D., of the University of Miami Miller School of Medicine, in an accompanying editorial.

“What is missing are interventions to arrest this process prior to irreversible damage to the pancreatic beta cell. The promise of autoantigen-specific therapy for prevention of type 1 diabetes in humans has yet to be realized. The Pre-POINT study provides additional evidence to inform trial design and increases enthusiasm for cautiously moving forward with a study of primary prevention in genetically screened children.”

(doi:10.1001/jama.2015.2054; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 21, 2015

Media Advisory: To contact Arleta Rewers, M.D., Ph.D., call Mark Couch at 303-724-5377 or email mark.couch@ucdenver.edu.

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Incidence of Serious Diabetes Complication May Be Increasing Among Youth in U.S.

The incidence of a potentially life-threatening complication of diabetes, diabetic ketoacidosis, in youth in Colorado at the time of diagnosis of type 1 diabetes increased by 55 percent between 1998 and 2012, suggesting a growing number of youth may experience delays in diagnosis and treatment, according to a study in the April 21 issue of JAMA, a theme issue on child health.

Diabetic ketoacidosis (DKA) at the time of type 1 diabetes (T1D) diagnosis has detrimental long-term effects and is characterized by dangerously high blood sugar and the presence of substances in the blood known as ketones. It may reflect delayed access to health care, lower quality of care, or income inequality. Little is known about long-term trends of DKA in the United States, according to background information in the article.

Arleta Rewers, M.D., Ph.D., of the University of Colorado School of Medicine, Aurora, and colleagues examined trends in DKA at T1D diagnosis between 1998 and 2012 in Colorado and factors associated with DKA. Between this time period, youth diagnosed with T1D before age 18 years at any medical facility were included in the study if a Colorado resident and followed up at the Barbara Davis Center for Diabetes in Denver, which serves more than 80 percent of youth with diabetes in Colorado. Standard criteria were used to define DKA. Data were extracted from medical records.

Diabetic ketoacidosis was present in 1,339 of 3,439 youth (39 percent) at T1D diagnosis. Youth with DKA had a median age of 9.4 years, 54 percent were male, and 76 percent were white. The proportions with DKA increased significantly, especially after 2007 (30 percent in 1998; 35 percent in 2007; 46 percent in 2012). The only characteristic that changed over time was insurance, with those covered by public insurance increasing from 17.1 percent in 2007 to 37.5 percent in 2012. Younger age and African American race were associated with higher risk, whereas private insurance and history of T1D in a first-degree relative were associated with lower risk.

The authors note that the incidence of DKA found in this study is consistent with incidences in countries with poor access to health care and low community and physician awareness of diabetes, and is much higher than incidences reported in Canada or the United Kingdom.

“Some of the factors associated with DKA at diagnosis are potentially modifiable. For example, the association with family history suggests the importance of awareness of diabetic symptoms. However, economic factors are more difficult to modify. Increasing incidence of DKA correlated temporally with an increase in Colorado child poverty prevalence from 10 percent in 2000 to 18 percent in 2012. The recent increase of DKA incidence among youth with private insurance may be related to proliferation of high-deductible health plans.”

“To our knowledge, this is the only report of increasing incidence of DKA in the developed world. Further research on the reasons for the increase and interventions to decrease the incidence are warranted.”

(doi:10.1001/jama.2015.1414; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases and by funding from the Children’s Diabetes Foundation in Denver. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 21, 2015

Media Advisory: To contact Marina Cavazzana, M.D., Ph.D., email m.cavazzana@nck.aphp.fr. To contact editorial author Harry L. Malech, M.D., email the NIAID Office of Communications at niaidnews@niaid.nih.gov.

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Study Shows Feasibility of Using Gene Therapy to Treat Rare Immunodeficiency Syndrome

In a small study that included seven children and teens with Wiskott-Aldrich syndrome, a rare immunodeficiency disorder, use of gene therapy resulted in clinical improvement in infectious complications, severe eczema, and symptoms of autoimmunity, according to a study in the April 21 issue of JAMA, a theme issue on child health.

Wiskott-Aldrich syndrome (WAS) is caused by loss-of-function mutations in the WAS gene. The condition is characterized by thrombocytopenia (low platelet count), eczema, and recurring infections. In the absence of definitive treatment, patients with classic WAS generally do not survive beyond their second or third decade of life. Partially human leucocyte antigen (HLA) antigen-matched allogeneic (donated from another individual) hematopoietic stem cell (HSC) transplantation is often curative, but is associated with a high incidence of complications. Gene therapy based on transplantation of autologous (from the same individual) gene­corrected HSCs may be an effective and potentially safer alternative. This procedure involves the removal and treatment of the patient’s own blood stem cells, and their return to the patient by intravenous injection.

Marina Cavazzana, M.D., Ph.D., of Necker Children’s Hospital, Paris, France, and colleagues assessed the outcomes and safety of autologous HSC gene therapy in patients with Wiskott-Aldrich syndrome. Gene-corrected autologous HSCs were infused in 7 patients (age range, 0.8-15.5 years) with severe Wiskott-Aldrich syndrome lacking HLA antigen-matched related or unrelated HSC donors. Patients were enrolled in France and England and treated between December 2010 and January 2014. Follow-up of patients in this intermediate analysis ranged from 9 to 42 months.

Among 6 of the 7 patients, there was clinical improvement after gene therapy, which was well tolerated. One patient died of preexisting, treatment-refractory infectious disease. In the 6 surviving patients, the infectious complications resolved after gene therapy, and prophylactic (preventative) antibiotic therapy was successfully discontinued in 3 cases. Severe eczema resolved in all affected patients, as did signs and symptoms of autoimmunity.

No severe bleeding episodes were recorded after treatment, and at last follow-up, all 6 surviving patients were free of blood product support. Hospitalization days were reduced from a median of 25 days during the 2 years before treatment to a median of 0 days during the 2 years after treatment.

The authors note that the interpretation of the results of this type of study is constrained by the small number of patients. “We therefore cannot draw conclusions on long-term outcomes and safety. Further follow-up of these patients and those reported in a similar study last year, together with additional clinical trials of this therapy, are therefore necessary.”

(doi:10.1001/jama.2015.3253; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was sponsored by Genethon, Evry, France. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: An Emerging Era of Clinical Benefit From Gene Therapy

In an accompanying editorial, Harry L. Malech, M.D., of the National Institutes of Health, Bethesda, Md., and Hans D. Ochs, M.D., of the University of Washington and Seattle Children’s Research Institute, Seattle, write that this study provides strong evidence that this type of gene therapy achieves substantial restoration of immune function associated with prolonged clinical benefit to patients with severe Wiskott­Aldrich syndrome.

They add that the impressive clinical response seen in the study was achieved in the context of a long line of research by many groups of investigators striving toward the goal of clinically beneficial gene therapy. “Taken together, the available evidence demonstrates substantial sustained clinical benefit following gene therapy for certain diseases.”

“At a time when many are championing personalized medicine, no advance is as representative of that fundamental biological approach as gene therapy.”

(doi:10.1001/jama.2015.2055; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 14, 2015

Media Advisory: To contact Joanna Chikwe, M.D., email Lauren Woods at Lauren.Woods@mountsinai.org.

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No Long-Term Survival Difference Found Between Types of Mitral Valve Replacements

In a comparison of mechanical prosthetic vs bioprosthetic mitral valves among patients 50 to 69 years of age undergoing mitral valve replacement, there was no significant difference in survival at 15 years, although there were differences in risk of reoperation, bleeding and stroke, according to a study in the April 14 issue of JAMA.

In patients with severe, symptomatic mitral valve disease unsuitable for surgical repair, mitral valve replacement reduces symptoms and improves survival.  Bioprosthetic valves (made primarily with tissue) are recommended in patients older than 70 years, in whom the likelihood of needing reoperation because of valve degeneration is low. In nonelderly patients requiring valve replacement, deciding between bioprosthetic and mechanical prosthetic valves is challenging because long-term survival and other outcomes have not been well defined, according to background information in the article.

Joanna Chikwe, M.D., of the Icahn School of Medicine at Mount Sinai, New York, and colleagues compared long-term survival, stroke, reoperation, and bleeding events after bioprosthetic vs mechanical prosthetic mitral valve replacement among 3,433 patients (age 50-69 years) who underwent mitral valve replacement in New York State hospitals from 1997-2007. Propensity score matching for 19 baseline characteristics yielded 664 patient pairs. Follow-up ended November 2013; median duration was 8.2 years.

The researchers found there was no difference in long-term survival between the mechanical prosthetic and bioprosthetic mitral valve replacement: 15-year survival was 57.5 percent vs. 59.9 percent, respectively. The cumulative incidence of stroke at l5 years after mitral valve replacement was significantly higher in the mechanical prosthesis group (14.0 percent) compared with the bioprosthesis group (6.8 percent), as was the cumulative incidence of bleeding events (14.9 percent vs. 9.0 percent).

The cumulative incidence of mitral valve reoperation at 15 years was significantly lower in the mechanical prosthesis group (5.0 percent) compared with the bioprosthesis group (11.1 percent).

“Consensus guidelines have increasingly emphasized patient preference in preoperative decision making. Quality-of-life surveys indicate that many patients view the distant possibility of reoperation as a reasonable trade-off for freedom from lifelong anticoagulation, reduced quality of life, and poorer perceived health status associated with mechanical prosthetic valves,” the researchers write. “Our data strongly suggest that the incremental risks of stroke and bleeding associated with mechanical prosthetic valve replacement should also be a major consideration in any discussion of prosthesis choice.”

The authors note that even though these findings suggest bioprosthetic mitral valve replacement may be a reasonable alternative to mechanical prosthetic valve replacement in patients aged 50 to 69 years, the 15-year follow-up was insufficient to fully assess lifetime risks, particularly of reoperation.

(doi:10.1001/jama.2015.3164; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 14, 2015

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Study Identifies Factors Linked to Greater Adherence to Use of Anticoagulant

Among patients with atrial fibrillation who filled prescriptions for the anticoagulant dabigatran at Veterans Health Administration sites, there was variability in patient medication adherence across sites, with appropriate patient selection and pharmacist-led monitoring associated with greater adherence to the medication, according to a study in the April 14 issue of JAMA.

Atrial fibrillation is the most common cardiac arrhythmia, affecting more than 3 million patients and necessitating treatment with oral anticoagulation in moderate- to high-risk patients to reduce stroke risk. Warfarin was the only treatment available until the recent introduction of target-specific oral anticoagulants (TSOACs), including dabigatran. Unlike warfarin, for which periodic laboratory testing is required, TSOACs do not require routine testing to evaluate anticoagulation effect. A previous study reported that suboptimal adherence to dabigatran was associated with increased risk of stroke and death, according to background information in the article.

Mintu P. Turakhia, M.D., M.A.S., of the VA Palo Alto Health Care System and Stanford University School of Medicine, and colleagues examined site-level variation in patient adherence to dabigatran and modifiable site-level practices associated with improved adherence in the Veterans Health Administration (VHA). The study included 67 VHA sites with 20 or more patients filling dabigatran prescriptions between 2010 and 2012 for nonvalvular atrial fibrillation (4,863 total patients; median, 51 patients per site), and also included 47 pharmacists from 41 eligible sites.

The median proportion of patients adherent to dabigatran was 74 percent, with variation in patient adherence across VHA sites. The authors write that the principal finding of their study was that appropriate patient selection was associated with better dabigatran adherence. Similarly, pharmacist-led monitoring (such as determining how medication was taken and stored, frequency of missed doses with timely laboratory testing) was associated with higher adherence with a progressive increase in adherence with longer duration of monitoring. In addition, pharmacist collaboration with clinicians for patients who were nonadherent was associated with higher adherence rates.

“These findings suggest that such site-level practices provide modifiable targets to improve patient adherence to dabigatran as opposed to patient characteristics that frequently cannot be modified.”

“Our results highlight the importance of selecting patients and monitoring strategies to translate the efficacy of TSOACs in randomized trials to clinical practice. Prior studies have described variation in patient performance on warfarin across sites further highlighting the importance of management strategies in improving patient performance to anticoagulants,” the researchers write. They add that the higher adherence rates associated with provision of dedicated monitoring even for a short time is potentially due to consistent contact made with patients.

(doi:10.1001/jama.2015.2761; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 14, 2015

Media Advisory: To contact Vincent Liu, M.D., M.S., email Maureen McInaney (Maureen.Mcinaney@kp.org) or Ann Wallace (Ann.M.Wallace@kp.org). To contact editorial co-author David Blumenthal, M.D., M.P.P., email Mary Mahon at mm@cmwf.org.

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Increase Seen in Data Breaches of Health Information

Between 2010 and 2013, data breaches of protected health information reported by HIPAA-covered entities increased and involved approximately 29 million records, with most data breaches resulting from overt criminal activity, according to a study in the April 14 issue of JAMA.

Reports of data breaches have increased during the past decade. Compared with other industries, these breaches are estimated to be the most costly in health care; however, few studies have detailed their characteristics and scope. Vincent Liu, M.D., M.S., of the Kaiser Permanente Division of Research, Oakland, Calif., and colleagues evaluated an online database maintained by the U.S. Department of Health and Human Services describing data breaches of unencrypted protected health information (i.e., individually identifiable information) reported by entities (health plans and clinicians) covered under the Health Insurance Portability and Accountability Act (HIPAA). The researchers included breaches affecting 500 individuals or more reported as occurring from 2010 through 2013, accounting for 82 percent of all reports.

The authors identified 949 breaches affecting 29.1 million records. Six breaches involved more than 1 million records each and the number of reported breaches increased over time (from 214 in 2010 to 265 in 2013). Breaches were reported in every state, the District of Columbia, and Puerto Rico. Five states (California, Texas, Florida, New York, and Illinois) accounted for 34 percent of all breaches. However, when adjusted by population estimates, the states with the highest adjusted number of breaches and affected records varied.

Most breaches occurred via electronic media (67 percent), frequently involving laptop computers or portable electronic devices (33 percent). Most breaches also occurred via theft (58 percent). The combined frequency of breaches resulting from hacking and unauthorized access or disclosure increased during the study period (12 percent in 2010 to 27 percent in 2013). Breaches involved external vendors in 29 percent of reports.

The authors note that the study was limited to breaches that were already recognized, reported, and affecting at least 500 individuals. “Therefore, our study likely underestimated the true number of health care data breaches occurring each year.”

“Given the rapid expansion in electronic health record deployment since 2012, as well as the expected increase in cloud­based services provided by vendors supporting predictive analytics, personal health records, health-related sensors, and gene sequencing technology, the frequency and scope of electronic health care data breaches are likely to increase. Strategies to mitigate the risk and effect of these data breaches will be essential to ensure the well-being of patients, clinicians, and health care systems.”

(doi:10.1001/jama.2015.2252; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Dr. Liu was supported by the Permanente Medical Group and a grant from the National Institutes of Health. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Keeping Personal Health Information Safe

In an accompanying editorial, David Blumenthal, M.D., M.P.P., of The Commonwealth Fund, New York, and Deven McGraw, J.D., L.L.M., M.P.H., of Manatt Phelps & Phillips LLP, Washington, D.C., write that “if patients have concerns that their digitized personal health information will be compromised, they will resist sharing it via electronic means, thus reducing its value in their own care and its availability for research and performance measurement.”

“Concerned patients may also withhold sensitive information about issues such as mental health, substance abuse, human immunodeficiency virus status, and genetic predispositions. Surveys suggest this may already be happening to some degree. Loss of trust in an electronic health information system could seriously undermine efforts to improve health and health care in the United States.”

“The stakes associated with the privacy and security of personal health information are huge. Threats to the safety of health care data need much more focused attention than they have received in the past from both public and private stakeholders.”

(doi:10.1001/jama.2015.2746; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 14, 2015

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Intrauterine Exposure to Maternal Gestational Diabetes Associated With Increased Risk of Autism

Among a group of more than 320,000 children, intrauterine exposure to gestational diabetes mellitus diagnosed by 26 weeks’ gestation was associated with risk of autism spectrum disorders (ASDs), according to a study in the April 14 issue of JAMA. Maternal pre-existing type 2 diabetes was not significantly associated with risk of ASD in offspring.

Exposure of fetuses to maternal hyperglycemia may have long-lasting effects on organ development and function. Previous studies have revealed long-term risks of obesity and related metabolic disorders in offspring of women who had diabetes prior to pregnancy as well as women with hyperglycemia first detected during pregnancy (gestational diabetes mellitus [GDM]). Whether such exposure can disrupt fetal brain development and heighten risk of neurobehavioral developmental disorders in offspring is less clear, according to background information in the article.

Anny H. Xiang, Ph.D., of Kaiser Permanente Southern California, Pasadena, Calif., and colleagues analyzed data from a single health care system to assess the association between maternal diabetes, both known prior to pregnancy and diagnosed during pregnancy, and the risk of ASD in children. The study included 322,323 children born from 1995-2009 at Kaiser Permanente Southern California (KPSC) hospitals. Children were tracked from birth until the first of the following: date of clinical diagnosis of ASD, last date of continuous KPSC health plan membership, death due to any cause, or December 31, 2012.

Of the children included in the study, 6,496 (2.0 percent) were exposed to pre-existing type 2 diabetes, 25,035 (7.8 percent) were exposed to GDM, and 290,792 (90.2 percent) were unexposed. Following birth (median of 5.5 years), 3,388 children were diagnosed as having ASD (115 exposed to pre-existing type 2 diabetes, 130 exposed to GDM at 26 weeks or less, 180 exposed to GDM at more than 26 weeks, and 2,963 unexposed). After adjustment for various factors, including maternal age, household income, race/ethnicity, and sex of the child, GDM diagnosed by 26 weeks was significantly associated with risk of ASD in offspring, but maternal pre-existing type 2 diabetes was not.

The increased ASD risk was independent of maternal smoking, prepregnancy body mass index, and gestational weight gain. Antidiabetic medication use was not independently associated with ASD risk in offspring.

The authors write that potential biological mechanisms linking intrauterine hyperglycemia and ASD risk in offspring may include multiple pathways, such as hypoxia (a lower-than-normal concentration of oxygen in the blood) in the fetus, oxidative stress in cord blood and placental tissue, chronic inflammation, and epigenetics (something that affects a cell, organ or individual without directly affecting its DNA).

(doi:10.1001/jama.2015.2707; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by Kaiser Permanente Southern California Direct Community Benefit Funds. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 7, 2015

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Default Surrogate Consent Statutes May Differ With Wishes of Patients

Among a sample of veterans in Connecticut, a substantial number had individuals listed as next of kin who were not nuclear family members, according to a study in the April 7 issue of JAMA. State default consent statutes do not universally recognize such persons as decision makers for incapacitated patients.

For patients who lose capacity and have no legally appointed surrogate decision maker, most states have laws that specify a hierarchy of persons who may serve as surrogate decision makers by default. A patient’s spouse is usually given priority, followed by adult children, parents, and siblings (members of the nuclear family). Even though an increasing number of adults are unmarried and live alone, state default surrogate consent statutes vary in their recognition of important relationships beyond the nuclear family, such as friends, more distant relatives, and intimate relationships outside marriage. Little has been known about how often patients identify a person who is not a nuclear family member as their next of kin, according to background information in the article.

Andrew B. Cohen, M.D., D.Phil., of the Yale University School of Medicine, New Haven, Conn., and colleagues reviewed the next-of-kin relationships for patients receiving care at Connecticut Veterans Health Administration (VHA) facilities from 2003-2013. Patients receiving care at VHA facilities are asked for information about their next of kin, which is entered into the electronic record along with a description of the relationship between the patient and next of kin.

From 2003-2013, 134,241 veterans received care at Connecticut VHA facilities, of whom 109,803 were included in the analysis. For most patients (93 percent), the next of kin was a nuclear family member. For 7.1 percent of the patients, a person outside the patient’s nuclear family was listed as next of kin. There were 3,190 patients (2.9 percent) with a more distant relative and 4.2 percent for whom the individual was not a blood or legal relative. This was most often a friend or an intimate relationship outside marriage (e.g., “common law spouse,” “live-in soul mate,” and “same-sex partner”). Veterans younger than 65 years were more likely than those 65 years or older (9.2 percent vs 6.0 percent) to have a next of kin who was not a nuclear family member.

Even though some patients use advance directives to identify decision makers who differ from their next of kin, completion rates remain low.

“Clinicians may be uncertain about whether a next of kin outside the nuclear family may make decisions for an incapacitated person, particularly when difficult choices arise during life-limiting illness. Such uncertainty may interfere with timely clinical care. In some circumstances, a guardian must be appointed, which is a slow and costly process,” the authors write.

If the finding that a substantial number of veterans have a next- of-kin relationship outside the nuclear family is confirmed in other populations, “states should consider adopting uniform default consent statutes, and these statutes should be broad and inclusive to reflect the evolving social ties in the United States.”

(doi:10.1001/jama.2015.2409; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, APRIL 7, 2015

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Risk of Breast and Ovarian Cancer May Differ By Type of BRCA1, BRCA2 Mutation

In a study that involved more than 31,000 women who are carriers of disease-associated mutations in the BRCA1 or BRCA2 genes, researchers identified mutations that were associated with significantly different risks of breast and ovarian cancers, findings that may have implications for risk assessment and cancer prevention decision making among carriers of these mutations, according to a study in the April 7 issue of JAMA.

Women who have inherited mutations in BRCA1 or BRCA2 (BRCA1/2) have an increased risk of breast and ovarian cancers. Little has been known about how cancer risks differ by BRCA1/2 mutation type, according to background information in the article.

Timothy R. Rebbeck, Ph.D., of the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and colleagues evaluated whether BRCA1 and BRCA2 mutation type or location is associated with variation in breast and ovarian cancer risk. The study included 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 33 countries.

Among BRCA1 mutation carriers, 9,052 women (46 percent) were diagnosed with breast cancer, 2,317 (12 percent) with ovarian cancer, 1,041 (5 percent) with breast and ovarian cancer, and 7,171 (37 percent) without cancer. Among BRCA2 mutation carriers, 6,180 women (52 percent) were diagnosed with breast cancer, 682 (6 percent) with ovarian cancer, 272 (2 percent) with breast and ovarian cancer, and 4,766 (40 percent) without cancer. Analysis of the data indicated that the risk of breast and ovarian cancer varied by the type and location of BRCA1/2 mutations.

“This study is the first step in defining differences in risk associated with location and type of BRCA1 and BRCA2 mutations. Pending additional mechanistic insights into the observed associations, knowledge of mutation-specific risks could provide important information for clinical risk assessment among BRCA1/2 mutation carriers, but further systematic studies will be required to determine the absolute cancer risks associated with different mutations,” the authors write.

“It is yet to be determined what level of absolute risk change will influence decision making among carriers of BRCA1/2 mutations. Additional research will be required to better understand what level of risk difference will change decision making and standards of care, such as preventive surgery, for carriers of BRCA1 and BRCA2 mutations.”

(doi:10.1001/jama.2014.5985; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MARCH 24, 2015

Media Advisory: To contact Osama O. Zaidat, M.D., M.S., email Maureen Mack at mmack@mcw.edu. To contact editorial co-author Colin P. Derdeyn, M.D., email Judy Martin at martinju@wustl.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.1693

This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.1276

Use of Stent, Compared to Medications, Increases Risk of Stroke in Patients With Narrowed Artery Within the Brain

Among patients with symptomatic intracranial arterial stenosis (narrowing of an artery inside the brain), the use of a balloon-expandable stent compared with medical therapy (clopidogrel and aspirin) resulted in an increased of stroke or transient ischemic attack (TIA), according to a study in the March 24/31 issue of JAMA.

Intracranial arterial stenosis is a common cause of stroke worldwide. The recurrent stroke risk with severe symptomatic intracranial stenosis may be as high as 23 percent at 1 year, despite medical therapy, according to background information in the article.

Osama O. Zaidat, M.D., M.S., of the Medical College of Wisconsin/Froedtert Hospital, Milwaukee, and colleagues randomly assigned 112 patients with symptomatic intracranial stenosis (narrowing of 70 percent or greater) to receive a balloon-expandable stent plus medical therapy (stent group; n = 59) or medical therapy alone (medical group; n = 53). Medical therapy consisted of clopidogrel (75 mg daily) for the first 3 months after enrollment and aspirin (81-325 mg daily) for the study duration. This international trial (VISSIT) enrolled patients from 27 sites (January 2009-June 2012) with last follow-up in May 2013. Enrollment was halted by the sponsor after negative results from another trial prompted an early analysis of outcomes, which suggested futility after 112 patients of a planned sample size of 250 were enrolled.

The 30-day safety end point of any stroke within 30 days or hard TIA (defined as a transient episode of neurological dysfunction caused by focal brain or retinal ischemia lasting at least 10 minutes but resolving within 24 hours) within 2 to 30 days was 9.4 percent (5/53) in the medical group and 24.1 percent (14/58) in the stent group. Ischemic stroke was observed in 3 patients (5.7 percent) in the medical group and in 10 patients (17.2 percent) in the stent group. Intracranial hemorrhage occurred in 5 patients (8.6 percent) in the stent group and in 0 in the medical group. The 1-year outcome of stroke or hard TIA occurred in more patients in the stent group (36.2 percent) vs the medical group (15.1 percent).

Thirty day all-cause death was 3 of 58 patients (5.2 percent) in the stent group and 0 in the medical group. A measure of disability worsened in more patients in the stent group than in the medical group.

“These findings do not support the use of a balloon-expandable stent for patients with intracranial arterial stenosis,” the authors conclude.

(doi:10.1001/jama.2015.1693; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The trial was initiated and funded by Micrus Endovascular. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Endovascular Therapy for Atherosclerotic Intracranial Arterial Stenosis – Back to the Drawing Board

Marc I. Chimowitz, M.B.Ch.B., of the Medical University of South Carolina, Charleston, and Colin P. Derdeyn, M.D., of the Washington University School of Medicine, St. Louis, comment in an accompanying editorial.

“For endovascular therapy (e.g., angioplasty alone or new stents) to have any role, multicenter pilot studies will be required to establish the safety and potential efficacy of these devices in carefully defined patient populations. Given the disappointing performance of intracranial stenting in both VISSIT and SAMMPRIS [a trial with similar results], it is difficult to foresee how these necessary steps will happen anytime soon.”

(doi:10.1001/jama.2015.1276; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MARCH 24, 2015

Media Advisory: To contact Ulrike Muench, Ph.D., R.N., email Scott Maier at Scott.Maier@ucsf.edu.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.1487

Pay Gap Between Male and Female RNs Has Not Narrowed

An analysis of the trends in salaries of registered nurses (RNs) in the United States from 1988 through 2013 finds that male RNs outearned female RNs across settings, specialties, and positions, with no narrowing of the pay gap over time, according to a study in the March 24/31 issue of JAMA.

Fifty years after the Equal Pay Act, the male-female salary gap has narrowed in many occupations. Yet pay inequality persists for certain occupations, including medicine and nursing. Studies have documented higher salaries for male registered nurses, although analyses have not considered employment factors that could explain salary differences and have not been based on recent data, according to background information in the article.

Ulrike Muench, Ph.D., R.N., of the University of California, San Francisco, and colleagues examined salaries of males and females in nursing over time using nationally representative data from the last 6 (1988-2008) quadrennial National Sample Survey of Registered Nurses (NSSRN; discontinued in 2008) and data from the American Community Survey (ACS; 2001-2013).

The NSSRN sample included 87,903 RNs, of whom 7 percent were men; the ACS sample included 205,825 RNs, of whom 7 percent were men. Both surveys showed that male RN salaries were higher than female RN salaries during every year. No significant changes in female vs male salary were found over time. Analysis estimated an overall adjusted earnings difference of $5,148.

The salary gap was $7,678 for ambulatory care and $3,873for hospital settings. The gap was present in all specialties except orthopedics, ranging from $3,792 for chronic care to $6,034 for cardiology. Salary differences also existed by position (such as for middle management, nurse anesthetists).

“The roles of RNs are expanding with implementation of the Affordable Care Act and emphasis on team-based care delivery. A salary gap by gender is especially important in nursing because this profession is the largest in health care and is predominantly female, affecting approximately 2.5 million women. These results may motivate nurse employers, including physicians, to examine their pay structures and act to eliminate inequities,” the authors write.

(doi:10.1001/jama.2015.1487; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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