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

Media Advisory: To contact Lawrence Scahill, M.S.N., Ph.D., call Holly Korschun at 404-727-3990 or email hkorsch@emory.edu. To contact editorial author Bryan H. King, M.D., M.B.A., call Leila Gray at 206-685-0381 or email leilag@uw.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.2015.3150 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.2628

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

Media Advisory: To contact Mintu P. Turakhia, M.D., M.A.S., email Michael Hill-Jackson at Michael.Hill-Jackson@va.gov.

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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

Media Advisory: To contact Anny H. Xiang, Ph.D., email Al Martinez at albert.martinez@kp.org or Sandra Hernandez-Millett at sandra.d.hernandez-millett@kp.org.

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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

Media Advisory: To contact Andrew B. Cohen, M.D., D.Phil., email Ziba Kashef at ziba.kashef@yale.edu.

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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.

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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

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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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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MARCH 17, 2015

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Study Raises Concerns About Reporting of Noninferiority Trials

An examination of the reporting of noninferiority clinical trials raises questions about the adequacy of their registration and results reporting within publicly accessible trial registries, according to a study in the March 17 issue of JAMA.

Noninferiority clinical trials are designed to determine whether an intervention is not inferior to a comparator by more than a prespecified difference (known as the noninferiority margin). Selection of an appropriate margin is fundamental to noninferiority trial validity, yet a point of frequent ambiguity. Given the increasing use of noninferiority trial designs, maintaining high standards for conduct and reporting is a priority, according to background information in the article.

Joseph S. Ross, M.D., M.H.S., of the Yale University School of Medicine, New Haven, Conn., and colleagues examined registration records and results of noninferiority clinical trials posted on ClinicalTrials.gov, as well as their corresponding publications, for information about the noninferiority margin and statistical analyses. Because ClinicalTrials.gov does not require registration of noninferiority-specific information, the authors searched MEDLINE for noninferiority trials published between January 2012 and June 2014, then selected publications reporting primary analyses of noninferiority trials indexed with a Clinical Trials.gov identifier. The researchers recorded details on trial design (including specification and justification of the noninferiority margin) and results (including reporting of noninferiority statistical analyses) from both ClinicalTrials.gov and corresponding publications.

The authors identified and characterized 344 unique trials registered on ClinicalTrials.gov, published in 338 articles (6 described multiple trials) that reported primary results of noninferiority trials. All publications described noninferiority designs and nearly all (98.8 percent) provided noninferiority margins. However, any justification for choosing margins was provided for only 28 percent. On ClinicalTrials.gov, approximately one­quarter described noninferiority designs, among which 15 (4.4 percent of total) specified noninferiority margins.

Nearly all publications reported noninferiority analyses and results (99.4 percent). On ClinicalTrials.gov, 38 percent had posted summary results, among which 76 (22 percent of total) reported that noninferiority analyses were performed and provided appropriate confidence intervals or P values to interpret results.

“Our findings raise concerns about the adequacy of noninferiority trial registration and results reporting within publicly accessible trial registries and highlight the need for continued efforts to improve its quality,” the authors write.

They add that even though ClinicalTrials.gov does not provide specific registration data elements for specifying noninferiority trial designs, it does provide specific elements for reporting noninferiority results. “Nevertheless, modifications may improve reporting and temper the possibility of post hoc distortion of design and margins, facilitating transparency and accountability for noninferiority trial conduct.”

(doi:10.1001/jama.2015.1697; 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 17, 2015

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Longer Duration Antiplatelet Therapy Following Coronary Stent Placement Does Not Reduce Risk of Adverse Events

An additional 18 months of dual antiplatelet therapy among patients who received a bare metal coronary stent did not result in significant differences in rates of stent thrombosis (formation of a blood clot), major adverse cardiac and cerebrovascular events, or moderate or severe bleeding, compared to patients who received placebo, according to a study in the March 17 issue of JAMA. The authors note that limitations in sample size may make definitive conclusions regarding these findings difficult.

Current clinical practice guidelines recommend a minimum of only 1 month of dual antiplatelet therapy (DAPT) after bare metal stent (BMS) placement following elective percutaneous coronary intervention (PCI; a procedure used to open narrowed coronary arteries, such as stent placement), compared with 6 to 12 months for drug-eluting stents (DES). Although randomized trial results showed a reduction in stent thrombosis and non­stent-related heart attack with thienopyridine therapy (a class of antiplatelet agents) beyond 12 months after DES placement, few trials have assessed optimal duration of DAPT after BMS, according to background information in the article.

Dean J. Kereiakes, M.D., of the Christ Hospital Heart and Vascular Center, Cincinnati, and Laura Mauri, M.D., M.Sc., of the Harvard Clinical Research Institute and Brigham and Women’s Hospital, Boston, and colleagues randomly assigned 11,648 patients who received a bare metal stent (n = 1,687;) or drug eluting stent (n = 9,961), were treated with aspirin and who completed 12 months of DAPT without bleeding or ischemic events to continued thienopyridine or placebo at months 12 through 30.

Among the patients treated with BMS who were randomized to continued thienopyridine vs placebo, rates of stent thrombosis were 0.5 percent vs 1.11 percent; rates of major adverse cardiac and cerebrovascular events (MACCE; composite of death, heart attack, or stroke) were 4.04 percent vs 4.69 percent; and rates of moderate/severe bleeding were 2.03 percent vs 0.90 percent, respectively.

Among all 11,648 randomized patients (both BMS and DES), stent thrombosis rates were 0.41 percent vs 1.32 percent; rates of MACCE were 4.29 percent vs 5.74 percent, and rates of moderate/severe bleeding were 2.45 percent vs 1.47 percent.

The results comparing continued thienopyridine vs placebo in the cohort treated with DES were previously reported and demonstrated significant reductions in stent thrombosis and MACCE.

The authors write that fewer patients treated with BMS were enrolled and randomized because of the prevailing use of DES in clinical practice. “The BMS subset may have been underpowered to identify such differences [in adverse events], and further trials are suggested.”

(doi:10.1001/jama.2015.1671; 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 17, 2015

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Early Imaging for Back Pain in Older Adults Not Associated With Better Outcomes

Older adults who had spine imaging within 6 weeks of a new primary care visit for back pain had pain and disability over the following year that was not different from similar patients who did not undergo early imaging, according to a study in the March 17 issue of JAMA.

When to image older adults with back pain remains controversial. Many guidelines recommend that older adults undergo early imaging because of the higher prevalence of serious underlying conditions.  However, there is not strong evidence to support this recommendation. Adverse consequences of early imaging are more substantial in an older population because the prevalence of incidental findings on spine imaging increases with age, which may lead to a cascade of subsequent interventions that increase costs without benefits, according to background information in the article.

Jeffrey G. Jarvik, M.D., M.P.H., of the University of Washington, Seattle, and colleagues compared function and pain at the 12-month follow-up visit among older adults who received early imaging (within 6 weeks) with those who did not. The study included 5,239 patients (65 years or older) with a new primary care visit for back pain in three U.S. health care systems, who did not have radiculopathy (a condition affecting the spinal nerve roots and spinal nerves). Diagnostic imaging (plain films, computed tomography [CT], magnetic resonance imaging [MRI]) was of the lumbar or thoracic spine.

Among the patients studied, 1,174 had early radiographs and 349 had early MRI/CT. At 12 months, neither the early radiograph group nor the early MRI/CT group differed significantly from controls on measures of back or leg pain–related disability.

In contrast, there were marked differences in 1-year resource use and costs. Estimated monetary differences in 1-year total payments (payer and patient contributions) were $1,380 higher for patients with early radiographs and $1,430 higher for patients with early MRI/CTs.

“Among older adults with a new primary care visit for back pain, early imaging was not associated with better 1-year outcomes. The value of early diagnostic imaging in older adults for back pain without radiculopathy is uncertain.”

(doi:10.1001/jama.2015.1871; 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 17, 2015

Media Advisory: To contact Joann G. Elmore, M.D., M.P.H., email Susan Gregg at sghanson@uw.edu. To contact editorial author Nancy E. Davidson, M.D., email Courtney McCrimmon at mccrimmoncp@upmc.edu.

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Study Examines Diagnostic Accuracy of Pathologists Interpreting Breast Biopsies

In a study in which pathologists provided diagnostic interpretation of breast biopsy slides, overall agreement between the individual pathologists’ interpretations and that of an expert consensus panel was 75 percent, with the highest level of concordance for invasive breast cancer and lower levels of concordance for ductal carcinoma in situ and atypical hyperplasia, according to a study in the March 17 issue of JAMA.

Approximately 1.6 million women in the United States have breast biopsies each year. The accuracy of pathologists’ diagnoses is an important and inadequately studied area. Although nearly one-quarter of biopsies demonstrate invasive breast cancer, the majority are categorized by pathologists according to a diagnostic spectrum ranging from benign to pre-invasive disease. Breast lesions with atypia or ductal carcinoma in situ (DCIS; abnormal breast cells that have not spread outside the duct into the normal surrounding breast tissue) are associated with significantly higher risks of subsequent invasive carcinoma, and women with these findings may require additional surveillance, prevention, or treatment to reduce their risks. The incidence of atypical ductal hyperplasia (atypia; a benign lesion of the breast that indicates an increased risk of breast cancer) and DCIS breast lesions has increased over the past 3 decades as a result of widespread mammography screening. Misclassification of breast lesions may contribute to either overtreatment or undertreatment, according to background information in the article.

Joann G. Elmore, M.D., M.P.H., of the University of Washington, Seattle, and colleagues examined the extent of diagnostic disagreement among pathologists compared with a consensus panel reference diagnosis. The study included 115 pathologists who interpret breast biopsies in clinical practices in 8 U.S. states. Participants independently interpreted slides between November 2011and May 2014 from test sets of 60 breast biopsies (240 total cases, 1 slide per case), including 23 cases of invasive breast cancer, 73 DCIS, 72 with atypical hyperplasia (atypia), and 72 benign cases without atypia. Participants were blinded to the interpretations of other study pathologists and the three consensus panel members, who were experienced pathologists internationally recognized for research and continuing medical education on diagnostic breast pathology. Among the consensus panel members, unanimous agreement of their independent diagnoses was 75 percent, and concordance with the consensus-derived reference diagnoses was 90 percent.

For all the cases, the participants provided 6,900 total individual interpretations for comparison with the consensus-derived reference diagnoses. Participating pathologists agreed with the consensus panel diagnosis for 75 percent of the interpretations. The overall concordance rate for the invasive breast cancer cases was 96 percent. The participants agreed with the consensus-derived reference diagnosis on less than half of the atypia cases, with a concordance rate of 48 percent. The overall concordance rate for benign without atypia was 87 percent; for DCIS, it was 84 percent.

Although overinterpretation of DCIS as invasive carcinoma occurred in only 3 percent, overinterpretation of atypia was noted in 17 percent and overinterpretation of benign without atypia was noted in 13 percent. Underinterpretation of invasive breast cancer was noted in 4 percent, whereas underinterpretation of DCIS was noted in 13 percent and underinterpretation of atypia was noted in 35 percent.

Disagreement with the consensus-derived reference diagnosis was significantly more frequent when breast biopsies were interpreted by pathologists with lower weekly case volume, from non-academic settings, or smaller practices; and from women with dense breast tissue on mammography (vs low density), although the absolute differences in rates according to these factors were generally small.

“The variability of pathology interpretations is relevant to concerns about overdiagnosis of atypia and DCIS. When a biopsy is overinterpreted (e.g., interpreted as DCIS by a pathologist when the consensus-derived reference diagnosis is atypia), a woman may undergo unnecessary surgery, radiation, or hormonal therapy. In addition, overinterpretation of atypia in a biopsy with otherwise benign findings can result in unnecessary heightened surveillance, clinical intervention, costs, and anxiety,” the researchers write. “Given our findings, clinicians and patients may want to obtain a formal second opinion for breast atypia prior to initiating more intensive surveillance or risk reduction using chemoprevention or surgery.”

The authors conclude that further research is needed to understand the relationship of these findings with patient management.

(doi:10.1001/jama.2015.1405; 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: Expertise vs Evidence in Assessment of Breast Biopsies – An Atypical Science

“An undesirable short-term outcome from the study by Elmore et al will undoubtedly be heightened anxiety among women who undergo breast biopsy and concern among their physicians about the accuracy of the pathologic diagnosis,” write Nancy E. Davidson, M.D., of the University of Pittsburgh Cancer Institute and UPMC CancerCenter, Pittsburgh, and David L. Rimm, M.D., Ph.D., of the Yale University School of Medicine, New Haven, Conn., in an accompanying editorial.

“However, this study confirms that the majority of diagnoses, especially at either end of the spectrum from benign to invasive cancer, are readily and accurately made by practicing pathologists. It also identifies areas of uncertainty that must be addressed, providing a framework for process improvement in the pathology and scientific communities, especially in the diagnosis of atypia. The study supports the value of a second opinion in cases of ambiguity. Indeed, it is axiomatic [unquestionable] that an abnormal breast biopsy is certainly a cause for concern but does not constitute a medical emergency. Extra time and care devoted to confirmation of the histologic diagnosis and a thoughtful discussion of the treatment options are imperative.”

“Importantly, breast pathology is a biological continuum from normal to invasive cancer whereas prescription of treatment requires categorization into specific diagnoses. The goal should be to match emerging biological understanding about breast carcinogenesis with opportunities for tailored treatment in an era of ever more precise, evidence-based medicine.”

(doi:10.1001/jama.2015.1945; 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 17, 2015

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Effect of Aspirin, NSAIDs on Colorectal Cancer Risk May Differ, According to Genetic Variations

Among approximately 19,000 individuals, the use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with an overall lower risk of colorectal cancer, although this association differed according to certain genetic variations, according to a study in the March 17 issue of JAMA.

Considerable evidence demonstrates that use of aspirin and other NSAIDs is associated with a lower risk of colorectal cancer. However, the mechanisms behind this association are not well understood. Routine use of aspirin, NSAIDs, or both for prevention of cancer is not currently recommended because of uncertainty about the risk-benefit profile. Understanding the relationship between genetic markers and use of aspirin and NSAIDs, also known as gene by environment interactions, can help to identify population subgroups defined by genetic background that may benefit most from use of these agents to prevent cancer, according to background information in the article.

Andrew T. Chan, M.D., M.P.H., of Massachusetts General Hospital, Boston, Li Hsu, Ph.D., of the Fred Hutchinson Cancer Research Center, Seattle, and colleagues conducted a genome-wide analysis of gene by environment interactions between regular use of aspirin, NSAIDs, or both and single-nucleotide polymorphisms (SNPs; genetic variations) in relation to risk of colorectal cancer.  The researchers used data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia, and Germany and included colorectal cancer case patients (n = 8,634) and matched controls (n = 8,553) ascertained between 1976 and 2011. Participants were all of European descent.

An analysis of the overall data indicated that regular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer compared with nonregular use. But among individuals with two less common genotypes of rs16973225 (AC or CC, 9 percent of participants), no association was found between regular use and risk of colorectal cancer. And among participants with two rare genotypes of rs2965667 (TA or AA, 4 percent of participants), aspirin and/or NSAID use was associated with a higher risk of colorectal cancer.

In this genome-wide investigation of gene by environment interactions, “use of aspirin, NSAIDs, or both was associated with lower risk of colorectal cancer, and the association of these medications with colorectal cancer risk differed according to genetic variation at 2 SNPs at chromosomes 12 and 15. Validation of these findings in additional populations may facilitate targeted colorectal cancer prevention strategies,” the authors write.

(doi:10.1001/jama.2015.1815; 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: Aspirin and NSAID Chemoprevention, Gene-Environment Interactions, and Risk of Colorectal Cancer

“In the not-too-distant future it will be possible to affordably and efficiently conduct genetic testing in healthy individuals to more accurately define benefits and risks of interventions intended to decrease risk of disease,” writes Richard C. Wender, M.D., of the American Cancer Society, Atlanta, in an accompanying editorial.

“It will be important for primary care clinicians to understand genetic risk and to have informed, clear, literacy-adjusted, culturally competent discussions with their patients about how to use this information; otherwise, the goal of using genetic information to enhance decision making about prevention will remain elusive. Research needs to test different approaches to translating this complex information into practical methods to share information and improve clinical decisions. The ability to translate genetic profiling into tailored preventive care plans for individuals is still years away, but with the study by Nan et al, the road, arduous as it may be, is more clearly illuminated.”

(doi:10.1001/jama.2015.1032; 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: 1:45 P.M. (ET) SUNDAY, MARCH 15, 2015

Media Advisory: To contact Yong Huo, M.D., email huoyong@263.net.cn. To contact editorial co-author Meir Stampfer, M.D., Dr.P.H., email Todd Datz at tdatz@hsph.harvard.edu.

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Folic Acid Supplementation Among Adults with Hypertension Reduces Risk of Stroke

In a study that included more than 20,000 adults in China with high blood pressure but without a history of stroke or heart attack, the combined use of the hypertension medication enalapril and folic acid, compared with enalapril alone, significantly reduced the risk of first stroke, according to a study appearing in JAMA. The study is being released to coincide with its presentation at the American College of Cardiology Annual Scientific Session.

Stroke is the leading cause of death in China and second leading cause of death in the world. Primary prevention (prevention prior to a first episode) is particularly important because about 77 percent of strokes are first events.  Uncertainty remains regarding the efficacy of folic acid therapy for primary prevention of stroke because of limited and inconsistent data, according to background information in the article.

Yong Huo, M.D., of Peking University First Hospital, Beijing, China, and colleagues had 20,702 adults with hypertension without history of stroke or heart attack randomly assigned to receive daily treatment with a single-pill combination containing enalapril (10 mg) and folic acid (0.8 mg; n = 10,348), or a tablet containing enalapril alone (10 mg; n = 10,354). The trial was conducted from May 2008 to August 2013 in 32 communities in Jiangsu and Anhui provinces in China. Participants were tested for variations in the MTHFR C677T gene (CC, CT, and TT genotypes) that may affect folate levels.

During a median treatment duration of 4.5 years, first stroke occurred in 282 participants (2.7 percent) in the enalapril-folic acid group compared with 355 participants (3.4 percent) in the enalapril group, representing an absolute risk reduction of 0.7 percent and a relative risk reduction of 21 percent. Analyses also showed significant reductions among participants in the enalapril-folic acid group in the risk of ischemic stroke (2.2 percent vs 2.8 percent) and composite cardiovascular events (cardiovascular death, heart attack and stroke) (3.1 percent vs 3.9 percent).

There was no significant difference between groups in the risk of hemorrhagic stroke, heart attack, or all-cause death, or in the frequencies of adverse events.

The authors write that this trial (China Stroke Primary Prevention Trial; CSPPT), with data on individual baseline folate levels and MTHFR genotypes, has provided convincing evidence that baseline folate level is an important determinant of efficacy of folic acid therapy in stroke prevention. “The CSPPT is the first large-scale randomized trial to test the hypothesis using individual measures of baseline folate levels. In this population without folic acid fortification, we observed considerable individual variation in plasma folate levels and clearly showed that the beneficial effect appeared to be more pronounced in participants with lower folate levels.”

“We speculate that even in countries with folic acid fortification and widespread use of folic acid supplements such as in the United States and Canada, there may still be room to further reduce stroke incidence using more targeted folic acid therapy—in particular, among those with the TT genotype and low or moderate folate levels.”

(doi:10.1001/jama.2015.2274; 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: Folate Supplements for Stroke Prevention

“The trial by Huo et al has important implications for stroke prevention worldwide,” write Meir Stampfer, M.D., Dr.P.H., and Walter Willett, M.D., Dr.P.H., of the Harvard T. H. Chan School of Public Health and Channing Division of Network Medicine, Boston, in an accompanying editorial.

“Although the trial participants all had hypertension, there is little reason to doubt that the results would apply to normotensive persons, although the absolute effect would be smaller. It is possible to debate the ethics of whether a replication trial should be performed, especially because folic acid supplementation (or fortification) is safe and inexpensive, and carries other benefits. Large segments of the world’s population, potentially billions of people, including those living in northern China, Bangladesh, and Scandinavia, have low levels of folate.”

“Individuals with the TT genotype might particularly benefit, although it seems unlikely that genotyping for that purpose would be cost-effective. Also, some persons in the United States on the low end of the distribution of folate intake may benefit; effects in this subgroup would not have been detected in previous trials. Ideally, adequate folate levels would be achieved from food sources such as vegetables (especially dark green leafy vegetables), fruits and fruit juices, nuts, beans, and peas. However, for many populations, achieving adequate levels from diet alone is difficult because of expense or availability. This study seems to support fortification programs where feasible, and supplementation should be considered where fortification will take more time to implement.”

(doi:10.1001/jama.2015.1961; 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) MONDAY, MARCH 16, 2015

Media Advisory: To contact Yaling Han, M.D., Ph.D., email hanyaling@263.net. To contact editorial co-author David P. Faxon, M.D., email Haley Bridger at HBRIDGER@partners.org.

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For Heart Attack Patients Undergoing Procedure Such as Stent Placement, Anticoagulant Bivalirudin May Improve Outcomes Compared to Heparin

Among patients who experienced a heart attack and underwent a percutaneous coronary intervention (PCI; a procedure used to open narrowed coronary arteries, such as stent placement), the use of the anticoagulant bivalirudin following the procedure resulted in a decrease in adverse clinical events, primarily due to a reduction in bleeding events, compared with heparin alone or heparin plus the antiplatelet agent tirofiban, according to a study appearing in JAMA.

Antithrombotic therapy is essential to prevent adverse ischemic events, especially stent thrombosis (formation of a blood clot) and the occurrence of a subsequent heart attack during and after primary PCI in patients who had a heart attack (acute myocardial infarction; AMI). The benefits of antithrombotic (anticlotting) agents must be weighed against their risk of hemorrhagic (bleeding) complications, which have been associated with subsequent death. Anticoagulation during primary PCI is most commonly achieved with heparin or with bivalirudin. Because of mixed results in trials involving these drugs, the safety and efficacy of bivalirudin in patients with AMI undergoing PCI is still uncertain, especially compared with heparin alone, according to background information in the article.

Yaling Han, M.D., Ph.D., of the General Hospital of Shenyang Military Region, Shenyang Liaoning Province, China, and colleagues randomly assigned 2,194 patients with AMI undergoing primary PCI at 82 centers in China to receive bivalirudin with a post-PCI infusion (n = 735), heparin alone (n = 729), or heparin plus tirofiban with a post-PCI infusion (n = 730).

Net adverse clinical events at 30 days (a composite of major adverse cardiac or cerebral events [all-cause death, subsequent heart attack, ischemia-driven target vessel revascularization, or stroke] or bleeding) occurred in 8.8 percent of patients treated with bivalirudin, compared with 13.2 percent of patients treated with heparin, and 17 percent of patients treated with heparin plus tirofiban.

Bleeding at 30 days was reduced by bivalirudin compared with heparin and heparin plus tirofiban (4.1 percent vs 7.5 percent vs 12.3 percent, respectively). Bivalirudin also reduced bleeding requiring medical intervention.

There were no statistically significant differences between treatments in the 30-day rates of major adverse cardiac or cerebral events, stent thrombosis, acquired thrombocytopenia (decrease in platelets in the blood), or in acute (<24-hour) stent thrombosis. At the 1-year follow-up, the results remained similar.

“In this multicenter randomized trial [the BRIGHT trial], by reducing bleeding with comparable rates of major adverse cardiac or cerebral events and stent thrombosis, bivalirudin significantly reduced 30-day and 1-year rates of net adverse clinical events compared with both heparin alone and heparin plus tirofiban in patients with AMI undergoing primary PCI. The reduction in net adverse clinical events was consistent across multiple subgroups,” the authors write.

(doi:10.1001/jama.2015.2323; 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: Can BRIGHT Restore The Glow of Bivalirudin?

Patients undergoing PCI should have a tailored approach with regards to their antithrombotic regimen, write Matthew A. Cavender, M.D., M.P.H., and David P. Faxon, M.D., of Brigham and Women’s Hospital, Harvard Medical School, Boston, in an accompanying editorial.

“Patients in whom the risk of bleeding is high such as women, patients with renal dysfunction, or patients for whom femoral access is needed may benefit from an antithrombotic regimen that decreases the risk of bleeding. In contrast, patients at high risk of thrombotic complications may benefit from regimens that reduce the risk of thrombosis while conceding that the risk of bleeding may increase. Understanding how to optimize outcomes for each individual patient remains the ultimate goal—a goal that is only achieved with the help of more studies like BRIGHT.”

(doi:10.1001/jama.2015.2345; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Cavender reports consulting fees from AstraZeneca and Merck. Dr. Faxon did not report any conflicts of interest.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, MARCH 10, 2015

Media Advisory: To contact Amar Rangan, F.R.C.S. (Tr. & Orth.), email amar.rangan@stees.nhs.uk.

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No Significant Difference in Outcomes Found for Surgical vs Non-Surgical Treatment of Displaced Fracture of Upper Arm

Among patients with a displaced fracture in the upper arm near the shoulder (proximal humeral), there was no significant difference between surgical treatment and nonsurgical treatment in patient-reported outcomes over two years following the fracture, results that do not support the trend of increased surgery for patients with this type of fracture, according to a study in the March 10 issue of JAMA.

Proximal humeral fractures account for 5 percent to 6 percent of all adult fractures; an estimated 706,000 occurred worldwide in 2000. The majority occur in people older than 65 years, and the age-specific incidence of these fractures is increasing. Approximately half of these fractures are displaced, the majority of which involve the surgical neck (located on the upper portion of the humerus). Surgical treatment is being increasingly used, contributing to increased treatment costs for upper limb fractures. A review of results from randomized clinical trials found insufficient evidence to conclude whether surgical intervention produces consistently better outcomes than nonsurgical treatment, according to background information in the article.

Amar Rangan, F.R.C.S. (Tr. & Orth.), of James Cook University Hospital, Middlesbrough, England, and colleagues randomly assigned 250 patients (average age, 66 years) who sustained a displaced fracture of the proximal humerus involving the surgical neck to surgical treatment (fracture fixation or humeral head replacement) or nonsurgical treatment (sling immobilization). Standardized outpatient and community-based rehabilitation was provided to both groups. Patients were followed up for 2 years and 215 had complete follow-up data. The data for 231 patients (114 in surgical group and 117 in nonsurgical group) were included in the primary analysis.

The researchers found that there were no statistically or clinically significant differences between surgical and non-surgical treatment either overall or at individual time points (at 6, 12, and 24 months) for the Oxford Shoulder Score (OSS), a shoulder-specific outcome measure that provides a total score based on the patient’s subjective assessment of pain and function. In addition, there were no clinically or significant differences on measures of health-related quality of life, complications related to surgery or shoulder fracture, complications requiring secondary surgery or treatment, and death.

Ten medical complications (2 cardiovascular events, 2 respiratory events, 2 gastrointestinal events, and 4 others) occurred in the surgical group during the postoperative hospital stay.

“These results do not support the trend of increased surgery for patients with displaced fractures of the proximal humerus,” the authors conclude.

(doi:10.1001/jama.2015.1629; 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 10, 2015

Media Advisory: To contact John J. P. Kastelein, M.D., Ph.D., email j.j.kastelein@amc.nl. To contact editorial co-author David Preiss, M.D., Ph.D., email david.preiss@glasgow.ac.uk.

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Lower Prevalence of Diabetes Found Among Patients With Inherited High Cholesterol Disorder

The prevalence of type 2 diabetes among 25,000 patients with familial hypercholesterolemia (a genetic disorder characterized by high low-density lipoprotein [LDL] cholesterol levels) was significantly lower than among unaffected relatives, with the prevalence varying by the type of gene mutation, according to a study in the March 10 issue of JAMA.

Statins have been associated with increased risk for diabetes, but the cause for this is not clear. One theory is that statins increase expression of LDL receptors and increase cholesterol uptake into cells including the pancreas, which could cause pancreatic dysfunction. Familial hypercholesterolemia causes decreased LDL transport into cells. Researchers have hypothesized that with familial hypercholesterolemia, decreased pancreatic LDL transport would lessen cell death and ultimately lead to lower rates of diabetes.

John J. P. Kastelein, M.D., Ph.D., of the Academic Medical Centre, Amsterdam, the Netherlands, and colleagues assessed the prevalence of type 2 diabetes between patients with familial hypercholesterolemia and their unaffected relatives. The study included all individuals (n = 63,320) who underwent DNA testing for familial hypercholesterolemia in the national Dutch screening program between 1994 and 2014.

The prevalence of type 2 diabetes was 1.75 percent in familial hypercholesterolemia patients (n = 440/25,137) vs 2.93 percent in unaffected relatives (n = 1,119/38,183), with adjusted figures indicating that patients with familial hypercholesterolemia had a 51 percent lower odds of having type 2 diabetes. Prevalence varied by the type of gene mutation. The researchers observed an inverse dose-response relationship between the severity of the familial hypercholesterolemia causing mutation and prevalence of type 2 diabetes.

“The small absolute difference in prevalence of type 2 diabetes between patients with familial hypercholesterolemia and unaffected relatives will not have a major influence on individual risk for type 2 diabetes. However, the substantial relative difference of 50 percent, together with previous findings, might suggest an effect of intracellular cholesterol metabolism on pancreatic beta cell function. Nevertheless, a plethora of pathways contribute to development of type 2 diabetes, and therefore, the mechanism we discuss here can only be 1 part of the pathogenesis of this highly complex disease,” the authors write.

“If these findings are confirmed in longitudinal studies, they might provide support for development of new approaches to the prevention and treatment of type 2 diabetes by improving function and survival of pancreatic beta cells.”

(doi:10.1001/jama.2015.1206; 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: Does the LDL Receptor Play a Role in the Risk of Developing Type 2 Diabetes?

David Preiss, M.D., Ph.D., and Naveed Sattar, M.D., Ph.D., of the University of Glasgow, United Kingdom, comment on the findings of this study in an accompanying editorial.

“What are the implications of these findings? This report adds to the growing literature of a complex interplay between lipids, glycemia, and adiposity, in which statins and other lipid-modifying agents appear to affect diabetes risk. The study also provides mechanistic insight into the potential roles of the LDL receptor and intracellular cholesterol accumulation. From a clinical perspective, the findings should allay any concerns about the potential diabetogenic effect of statins when treating patients with familial hypercholesterolemia from childhood or young adulthood given that these patients appear to be at a low risk for diabetes.”

“The study by Besseling et al contributes important evidence to strengthen the previously observed relationship between statin therapy and diabetes risk. However, this does not, and should not, alter guidance regarding the use of these important medications in patients at elevated cardiovascular risk given the clear overall benefit of statin therapy.”

(doi:10.1001/jama.2015.1275; 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 10, 2015

Media Advisory: To contact David R. Holmes Jr., M.D., email Traci Klein at Klein.Traci@mayo.edu.

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Study Examines Outcomes for Patients One Year After Transcatheter Aortic Valve Replacement

In an analysis of outcomes of about 12,000 patients who underwent transcatheter aortic valve replacement, death rate after one year was nearly one in four; of those alive at 12 months, almost half had not been rehospitalized and approximately 25 percent had only one hospitalization, according to a study in the March 10 issue of JAMA.

Following U.S. Food and Drug Administration approval in 2011, transcatheter aortic valve replacement (TAVR) has been used with increasing frequency for the treatment of severe aortic stenosis in patients who have high risks with conventional surgical AVR. TAVR, a less invasive procedure than open heart-valve surgery, involves replacing the aortic valve using a catheter inserted in the patient’s groin. Introducing new medical devices into routine practice raises concerns because patients and outcomes may differ from those in clinical trials, according to background information in the article.

David R. Holmes Jr., M.D., of Mayo Clinic, Rochester, Minn., and colleagues examined 1-year outcomes for TAVR patients who had 30-day outcomes previously reported. Data from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapies Registry were linked with patient-specific Centers for Medicare & Medicaid Services administrative claims data. The authors identified 12,182 patients with linked CMS data that underwent TAVR procedures at 299 U.S. hospitals from November 2011 through June 2013; the end of the follow-up period was June 30, 2014.

The median age of patients was 84 years and 52 percent were women. Following the TAVR procedure, 60 percent were discharged to home and the 30-day mortality rate was 7.0 percent. By 1 year, the overall mortality rate was 24 percent, the stroke rate was 4.1 percent, and the rate of the composite outcome of mortality and stroke was 26 percent. In addition, 47 percent of patients who remained alive at 12 months had not been rehospitalized, 24 percent were rehospitalized once and 12.5 percent were rehospitalized twice. Readmission for a composite of stroke, heart failure, or repeat aortic valve intervention occurred in 19 percent of patients.

Characteristics significantly associated with 1-year mortality included advanced age, male sex, end-stage renal disease and severe chronic obstructive pulmonary disease. Compared with men, women had a higher risk of stroke.

The authors note that the rate of l-year mortality reported with this registry is similar to that in other comprehensive reports. “Although this study includes only patients considered to have high risks with AVR, the majority of this mortality does not represent periprocedural complications, as 30-day mortality was only 7.0 percent. As such, this makes it imperative to focus on better prediction of the overall risks and benefits of the procedure, particularly given the existing comorbidities of the group of patients being considered for TAVR.”

They add that it may be possible to identify patients who may not benefit from this procedure and who should be counseled accordingly.

“Although 3 randomized trials and multiple single-center and multicenter registry studies have been published, the profile and longer-term outcomes of U.S. TAVR cases in routine clinical practice remains limited,” the researchers write. “These findings should be helpful in discussions with patients undergoing TAVR.”

(doi:10.1001/jama.2015.1474; 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 10, 2015

Media Advisory: To contact Hallie C. Prescott, M.D., M.Sc., email Kara Gavin at kegavin@med.umich.edu.

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Hospital Readmissions Following Severe Sepsis Often Preventable

In an analysis of about 2,600 hospitalizations for severe sepsis, readmissions within 90 days were common, and approximately 40 percent occurred for diagnoses that could potentially be prevented or treated early to avoid hospitalization, according to a study in the March 10 issue of JAMA.

Patients are frequently rehospitalized within 90 days after having severe sepsis. Little is known, however, about the reasons for readmission and whether they can be reduced. Hallie C. Prescott, M.D., M.Sc., of the University of Michigan, Ann Arbor, and colleagues examined the most common readmission diagnoses after hospitalization for severe sepsis, the extent to which readmissions may be potentially preventable by posthospitalization ambulatory care, and whether the pattern of readmission diagnoses differs compared with that of other acute medical conditions.

The study included participants in the nationally representative U.S. Health and Retirement Study, a sample of households with adults 50 years of age or older, that is linked to Medicare claims (1998-2010). For the analysis, the researchers identified 2,617 hospitalizations for severe sepsis, which were matched to hospitalizations for other acute medical conditions. To gauge what proportion of rehospitalizations may be potentially preventable, ambulatory care sensitive conditions (ACSCs) were measured, which are diagnoses for which effective outpatient care may reduce hospitalization rates.

There were 1,115 severe sepsis survivors (42.6 percent) rehospitalized within 90 days. The 10 most common readmission diagnoses following severe sepsis included several ACSCs (e.g., heart failure, pneumonia, chronic obstructive pulmonary disease exacerbation, and urinary tract infection). Collectively, ACSCs accounted for 22 percent of 90-day readmissions.

Readmissions for a primary diagnosis of infection (sepsis, pneumonia, urinary tract, and skin or soft tissue infection) occurred in 12 percent of severe sepsis survivors compared with 8.0 percent of matched acute medical conditions. Readmissions for ACSCs were more common after severe sepsis (22 percent) vs matched  acute conditions (19 percent) and accounted for a greater proportion of all 90-day readmissions (42 percent vs 37 percent, respectively).

“The high prevalence and concentration of specific diagnoses during the early postdischarge period suggest that further study is warranted of the feasibility and potential benefit of postdischarge interventions tailored to patients’ personalized risk for a limited number of common conditions,” the authors write.

(doi:10.1001/jama.2015.1410; 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) THURSDAY, MARCH 5, 2015

Media Advisory: To contact Mark J. Mulligan, M.D., email Vincent Dollard at vdollar@emory.edu. To contact editorial author Thomas W. Geisbert, Ph.D., email Raul Reyes at rareyes@utmb.edu.

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Researchers Examine Effect of Experimental Ebola Vaccine After High-Risk Exposure

A physician who received an experimental Ebola vaccine after experiencing a needle stick while working in an Ebola treatment unit in Sierra Leone did not develop Ebola virus infection, and there was strong Ebola-specific immune responses after the vaccination, although because of its limited use to date, the effectiveness and safety of the vaccine is not certain, according to a study appearing in JAMA.

On September 26, 2014, a 44-year-old physician from the United States caring for patients in an Ebola treatment unit in Sierra Leone experienced an accidental needle stick, which was estimated to pose a significant risk of infection. Given the concern about potentially lethal Ebola virus disease, the patient was offered, and provided his consent for, postexposure vaccination with an experimental vaccine, VSVΔG-ZEBOV (which has entered a clinical trial for the prevention of Ebola in West Africa). Forty-three hours after exposure, the patient boarded a jet for medical evacuation to the United States and received the vaccine intramuscularly.

Mark J. Mulligan, M.D., of Emory University, Atlanta, and colleagues assessed the patient’s response to the vaccine. The patient developed malaise, nausea and fever 12 hours after the vaccination while on the transport jet. A physical exam in the U.S. approximately 14 hours postvaccination (performed at the National Institutes of Health Special Clinical Studies Unit) indicated the patient was in mild to moderate distress from fever, nausea, malaise, myalgia (muscle pain), and chills. On day 2, the fever declined; however, severe symptoms continued along with mild nausea and arthralgia (joint pain). On days 3 through 5, the patient experienced resolution of symptoms and laboratory abnormalities. By day 7, he was completely asymptomatic.

Blood tests detected Ebola virus glycoprotein-specific antibodies and strong Ebola-specific adaptive immune responses. “The clinical syndrome and laboratory evidence were consistent with vaccination response and no evidence of Ebola virus infection was detected,” the authors write.

“In the current patient, a self-limited, moderate to severe clinical syndrome began at 12 hours postvaccination. Future decision making about using this experimental vaccine for postexposure vaccination will need to balance the risks of harm from the vaccine or possible Ebola infection (both were unknowns at the time of the patient’s exposure) against the possible benefit of vaccination (also unknown at the time of the patient’s treatment).”

“Neither the safety nor the efficacy of the VSVΔG-ZEBOV vaccine for postexposure protection can be learned from this single case, but the clinical and laboratory parameters are informative at a time when there is a need to garner all information available on Ebola vaccines.”

(doi:10.1001/jama.2015.1995; 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: Emergency Treatment for Exposure to Ebola Virus

Thomas W. Geisbert, Ph.D., of the University of Texas Medical Branch, Galveston, writes in an accompanying editorial that the most effective way to prevent and control outbreaks and to protect high-risk personnel, including medical staff and laboratory workers, is through the use of preventive vaccines along with use of appropriate personal protective equipment.

“Historically, there has been a small global market for developing an Ebola virus vaccine and there was no financial interest for large pharmaceutical companies to become involved. The current epidemic has spurred substantial scientific activity to develop vaccines.”

“Although it is not possible to know with absolute certainty whether the first-generation VSVΔG-ZEBOV vaccine used to treat the potential high-risk exposure had any influence on survival of the exposed patient in the report by Lai et al, this incident serves as an example of how important it is to have safe and effective countermeasures available in sufficient quantities that can be rapidly deployed for emergency use for both medical workers and affected populations.”

(doi:10.1001/jama.2015. 2057; 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 3, 2015

Media Advisory: To contact Hari R. Mallidi, M.D., email Julia Parsons at Julia.parsons@bcm.edu.

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Study Examines Outcomes of Lung Transplantations Since Implementation of Need-Based Allocation System

Since implementation of a medical need-based allocation system of donor lungs in 2005, double-lung transplantation has been associated with better graft survival than single-lung transplantation in patients with idiopathic pulmonary fibrosis (IPF); at 5 years, there has been no survival difference between single- and double-lung transplant recipients in patients with chronic obstructive pulmonary disease (COPD), according to a study in the March 3 issue of JAMA.

Before 2005, lung transplant allocation in the United States was based on accumulated time on the lung transplant waiting list after matching for ABO blood type. In response to increasing wait times, the U.S. Department of Health and Human Services mandated the development of an allocation system based on medical need instead of waiting time. The resulting system—the Lung Allocation Score (LAS) organ allocation algorithm—was implemented in May 2005. A patient’s LAS is based on risk factors associated with either wait list or post-transplantation mortality. The use of the LAS has brought with it a change in the demographics of single- and double-lung transplant recipients; what effect this may have on post-transplantation outcomes has not been assessed, according to background information in the article.

Hari R. Mallidi, M.D., of the Baylor College of Medicine, Houston, and colleagues reviewed data from the United Network for Organ Sharing thoracic registry to summarize the contemporary demographics and outcomes in adults with IPF or COPD who underwent single- or double­ lung transplantation in the United States between May 2005 and December 2012.

Since May 2005, the researchers identified 4,134 patients with IPF (of whom 2,010 underwent single-lung and 2,124 underwent double-lung transplantation) and 3,174 patients with COPD, of whom 1,299 underwent single-lung and 1,875 underwent double-lung transplantation. The median follow-up time was 23.5 months. Of the patients with IPF, 33.4 percent died and 2.8 percent underwent retransplantation; of the patients with COPD, 34.0 percent died and 1.9 percent underwent retransplantation. Further analysis indicated that double-lung transplants were associated with better graft survival in patients with IPF (adjusted median survival, 65.2 months vs 50.4 months) but not in patients with COPD (adjusted median survival, 67.7 months vs 64.0 months).

“The interaction between diagnosis (COPD or IPF) and treatment type (single- and double-lung transplantation) was significant, supporting the finding that the benefit of double-lung transplantation may differ by diagnosis. Like­wise, prognostic models designed to account for the time­varying effect of double-lung transplantation (compared with single-lung transplantation) showed that double-lung transplantation was significantly associated with graft survival among patients with IPF but not among patients with COPD,” the authors write.

Other variables associated with graft failure included age, excessively high or low body mass index, worse functional status, poor 6-minute walk test performance, pulmonary hypertension (in patients with COPD), and donor age. Variables associated with graft survival included undergoing transplantation at a high-performing center, undergoing transplantation at a moderate- or high­ volume transplant center, receiving a locally allocated organ, and donor-recipient race match (in patients with IPF).

(doi:10.1001/jama.2015.1175; 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 3, 2015

Media Advisory: To contact Julie M. Zito, Ph.D., email Karen Robinson at karobinson@umaryland.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.2015.0763

Most States Have Implemented Prior Authorization Policies for Atypical Antipsychotic Prescribing To Children

With a concern about inappropriate prescribing of antipsychotic medications to children, 31 states have implemented prior authorization policies for atypical antipsychotic prescribing, mostly within the past 5 years, and with most states applying their policies to children younger than 7 years of age, according to a study in the March 3 issue of JAMA.

Over the past two decades, antipsychotic prescribing to youth, almost exclusively comprising atypical antipsychotic medications, was estimated to have increased from 0.16 percent in 1993- 1998 to 1.07 percent in 2005-2009 in office-based physician visits. Antipsychotic use is also 5-fold greater in Medicaid-insured youth than in privately insured youth, and occurs mostly for indications not approved by the U.S. Food and Drug Administration (FDA). In light of antipsychotic treatment-emergent cardiometabolic adverse events, several government reports called for efforts to improve pediatric psychotropic medication oversight in state Medicaid agencies. Such efforts have included age­restricted prior authorization policies, which require clinicians to obtain preapproval from Medicaid agencies to prescribe atypical antipsychotics to children younger than a certain age as a condition for coverage, according to background information in the article.

Julie M. Zito, Ph.D., of the University of Maryland, Baltimore, and colleagues reviewed antipsychotic-related Medicaid prior authorization policies for youth (<18 years) in 50 states plus the District of Columbia between June 2013 and August 2014 and characterized these policies according to age­restriction criteria and whether a peer review process was present. A subset of prior authorization policies, classified as “peer review”, brings clinical expertise into the review process by requiring contracted clinicians (peer reviewers) to adjudicate antipsychotic prescriptions for children.

The researchers found that 31 states have implemented prior authorization policies for atypical antipsychotic prescribing to children, mostly within the past 5 years. Most states apply their policies to children younger than 5, 6, or 7 years of age. Only 7 states (Alabama, Kentucky, Maryland, Nevada, North Carolina, Pennsylvania, Tennessee) apply their policies to Medicaid-insured youth up to age 18 years. Seven other states (California, Colorado, Georgia, Mississippi, Nebraska, New York, Washington) have age-restriction criteria that vary by drug entity.

Of the 31 states, 15 have incorporated a peer review process, wherein the adjudication process usually involves a psychiatrist or other physician specialty. The programs without a peer review process use automated systems or non­physician manual reviews for adjudication.

“The findings may inform pediatric research to assess the effect of these policies on atypical antipsychotic use to ensure clinical appropriateness and to minimize unintended consequences,” the authors write.

They add that potential unintended consequences of these restrictive policies include inadequate treatment, substitution of potentially inappropriate, off-label psychotropic medication classes such as anticonvulsant mood stabilizers and antidepressants, and administrative burden on prescribers.

“Additionally, Medicaid oversight programs should be concerned not only with unnecessary antipsychotic use, but also should ensure adherence to appropriate cardiometabolic monitoring practices at baseline and during antipsychotic treatment, and support access to alternative evidence-based nonpharmacological treatments.”

(doi:10.1001/jama.2015.0763; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This study was funded by the U.S. Food and Drug Administration (FDA). Mr. Schmid was supported in part by a fellowship administered by the Oak Ridge Institute for Science and Education and funded by the U.S. FDA. 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, MARCH 3, 2015

Media Advisory: To contact Sebastiano Filetti, M.D., email sebastiano.filetti@uniroma1.it. To contact editorial co-author Anne R. Cappola, M.D., Sc.M., email Holly Auer at holly.auer@uphs.upenn.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.0956

This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.0836

Long-Term Follow-up of Benign Thyroid Nodules Shows Favorable Prognosis

After five years of follow-up, a majority of asymptomatic, benign thyroid nodules exhibited no significant change in size, or actually decreased in size, and diagnoses of thyroid cancer were rare, according to a study in the March 3 issue of JAMA.

Detection of asymptomatic thyroid nodules has increased, largely from improved detection of small incidentally discovered nodules. Consensus is lacking regarding the optimal follow-up of cytologically (analysis of aspirated cells) proven benign lesions and sonographically (an imaging technique using ultrasonic waves) nonsuspicious nodules. Current guidelines recommend serial ultrasound examinations and repeat cytology exam if significant growth in the nodule is observed. However, little is known about the actual frequency and magnitude of nodule growth, and there is no reliable method for identifying patients likely to experience growth. The assumption that growing nodules increase a patient’s risk of malignancy has been untested, according to background information in the article.

Sebastiano Filetti, M.D., of the Universita di Roma Sapienza, Rome, and colleagues studied the frequency, magnitude, and factors associated with changes in thyroid nodule size. The study involved 992 patients with 1 to 4 asymptomatic, sonographically or cytologically benign thyroid nodules. Patients were recruited from 8 hospital-based thyroid-disease referral centers in Italy between 2006 and 2008. Data collected during the first 5 years of follow-up, through January 2013, were analyzed.

Nodule growth occurred in 153 patients (15.4 percent). One hundred seventy-four of the 1,567 original nodules (11.1 percent) increased in size. Nodule growth was associated with presence of multiple nodules. In 184 individuals (18.5 percent), nodules shrank. Thyroid cancer was diagnosed in 5 original nodules (0.3 percent), only 2 of which had grown. New nodules developed in 93 patients (9.3 percent), with detection of one cancer.

“One of the goals of surveillance is the prompt detection and treatment of thyroid cancers that arise during follow-up or have been missed on the initial assessment. In the population we studied, these events were rare,” the authors write.

“Only 2 of the 5 diagnoses of cancer in an established nodule were preceded by significant growth of the cancerous nodule. These data suggest that the American Thyroid Association’s recommendation for indication for repeat cytology should be revised. Clinical and sonographic findings should probably play larger roles in the decision-making process.”

(doi:10.1001/jama.2015.0956; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The study was funded by research grants from the Umberto Di Mario Foundation, Banca d’ltalia, and the Italian Thyroid Cancer Observatory Foundation. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Improving the Long-term Management of Benign Thyroid Nodules

In an accompanying editorial, Anne R. Cappola, M.D., Sc.M., and Susan J. Mandel, M.D., M.P.H., of the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, (Dr. Cappola is also an Associate Editor, JAMA), write that this study has four important implications for the follow-up of thyroid nodules.

“First, these prospective data provide reassurance about the validity of a benign cytology result obtained by ultrasound-guided fine-needle aspiration and confirm a very low false-negative rate, at 1.1 percent. Second, the practice of routine sonographic surveillance with repeat fine-needle aspiration for growth, as recommended by published guidelines, is not the most efficient strategy to detect the very small number of missed cancers among previously sampled cytologically benign nodules. The one-size-fits-all approach simply does not work. Instead, surveillance strategies should be individualized based on a nodule’s sonographic appearance.”

“Third, many nodules detected on ultrasound are small (i.e., < 1 cm) and not sonographically suspicious. In fact, fifty-four percent of nodules followed up in this study were initially classified as benign not through fine-needle aspiration but because they were smaller than 1 cm and lacked suspicious sonographic features. How reliable is the absence of these features at predicting benign disease? The answer is excellent. … Fourth, although 69 percent of nodules remained stable in size, size increase was not a harbinger of malignancy, especially if the nodule had no sonographically suspicious features. Benign nodules grow and Durante et al provide insights about predicting when growth is most likely to occur, e.g., in multinodular glands, larger nodule size, and younger patients.”

“Thyroid nodules are pervasive, whereas thyroid cancer is not. The findings from Durante et al represent an important step in improving the efficiency and mitigating the expense of follow-up for the vast majority of thyroid nodules that are either cytologically or sonographically benign.”

(doi:10.1001/jama.2015.0836; 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, MARCH 3, 2015

Media Advisory: To contact Axel Maurice-Szamburski, M.D., email amszamburski@gmail.com.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.1108

Findings Question Benefit of Administering Sedatives Before Surgery for Patients Receiving General Anesthesia

Although sedatives are often administered before surgery, a randomized trial finds that among patients undergoing elective surgery under general anesthesia, receiving the sedative lorazepam before surgery, compared with placebo or no premedication, did not improve the self-reported patient experience the day after surgery, but was associated with longer time till removal off a breathing tube (extubation) and a lower rate of early cognitive recovery, according to a study in the March 3 issue of JAMA.

Patients scheduled for surgery may experience considerable stress and anxiety. Benzodiazepine (a class of sedatives) premedication is frequently used to reduce anxiety but also causes amnesia, drowsiness, and cognitive impairment. Treating anxiety is not necessarily associated with a better perioperative (before and after surgery) experience for the patient. More needs to be known about the efficacy of preoperative anxiety treatment to better counsel patients to make informed decisions, according to background information in the article.

Axel Maurice-Szamburski, M.D., of the Hôpital de la Timone Adulte, Marseille, France, and colleagues randomly assigned 1,062 adult patients (younger than 70 years of age) who had been scheduled for various elective surgeries under general anesthesia at 5 French teaching hospitals to receive either 2.5 mg of lorazepam (approximately two hours before being transferred to the operating room), placebo, or no premedication. The perioperative patient experience was assessed 24 hours after surgery with a questionnaire.

The researchers found that premedication with lorazepam did not improve a measure of overall patient satisfaction compared with no premedication or placebo. Of the most anxious patients, no significant differences were found for overall patient satisfaction between the groups.

The time to extubation was significantly longer in the lorazepam group (17 minutes) than in the no premedication (12 minutes) and placebo (13 minutes) groups. Forty minutes after the end of anesthesia, the rate of patients scoring as recovered regarding cognition was significantly lower in the lorazepam group (51 percent) than in the no pre­medication group (71 percent) and the placebo group (64 percent). On postoperative day 1, the number of patients with amnesia during the perioperative period was higher in the lorazepam group than in the other groups.

“Compared with placebo, lorazepam did reduce patient anxiety upon arrival to the operating room. Because there was no overall benefit from preoperative anxiety treatment, it is possible that anxiety arising upon arrival to the operating room does not influence overall patient satisfaction,” the authors write.

“The findings suggest a lack of benefit with routine use of lorazepam as sedative pre-medication in patients undergoing general anesthesia.”

(doi:10.1001/jama.2015.1108; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by a grant from the French Institutional Clinical Hospital Research Program, Ministry 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, MARCH 3, 2015

Media Advisory: To contact Vicky Stergiopoulos, M.D., or Stephen W. Hwang, M.D., email Leslie Shepherd at ShepherdL@smh.ca. To contact editorial author Mitchell H. Katz, M.D., email Michael Wilson at micwilson@dhs.lacounty.gov.

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.2015.1163

This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.1277

Intervention Results in More Stable Housing for Homeless Adults, But Does Not Improve Health-Related Quality of Life

A program that included scattered-site supportive housing using rent supplements and case management services led to more stable housing for homeless adults with mental illness in four cities in Canada, compared with usual access to existing housing and community services, but the intervention did not result in significant improvements in health-related quality of life, according to a study in the March 3 issue of JAMA.

Homelessness affects large numbers of people in many countries and is associated with enormous personal and societal costs. One-year prevalence estimates indicate there were at least 150,000 homeless people in Canada in 2009 and 1.5 million in the United States in 2012. Large numbers of homeless adults have mental illness, with or without substance use disorders. Although the intervention Assertive Community Treatment (ACT) provides support via a resource-intensive interdisciplinary team (including a psychiatrist and nurses) and small case­loads, Intensive Case Management (ICM) is a less-intensive intervention in which individual case managers broker necessary services to other supports in the community. Intensive Case Management may be an appropriate and less-costly treatment option for homeless individuals not requiring ACT service intensity, according to background information in the article.

Vicky Stergiopoulos, M.D., and Stephen W. Hwang, M.D., of St. Michael’s Hospital, Toronto, and colleagues conducted a study in which 1,198 homeless adults with mental illnesses (recruited in Vancouver, Winnipeg, Toronto, and Montreal) were randomly assigned to the intervention group (n = 689) or usual care group (n = 509), and followed up for 24 months. The intervention consisted of scattered-site housing (using rent supplements) and off-site ICM services. The usual care group had access to existing housing and support services in their communities.

The researchers found that during the 24 months following randomization, the percentage of days stably housed was higher among the intervention group than the usual care group: Site A, 63 percent vs 30 percent; Site B, 73 percent vs 24 percent; Site C, 74 percent vs 39 percent; and Site D, 77 percent vs 32 percent.

On a measure of quality of life, assessed by a health questionnaire, the average change of the score from baseline to 24 months was not statistically different between intervention or usual care participants. Additional analyses suggested significant gains in condition-specific quality of life among the intervention group compared with the usual care group, such as for measures of living situation and safety.

“Our findings highlight that scattered-site housing with ICM services is effective in reducing homelessness among a broader spectrum of the homeless population who may have a severe mental illness but do not require ACT support, best reserved for a smaller group of homeless adults with high needs for mental health and other support services,” the authors write.

(doi:10.1001/jama.2015.1163; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This research has been made possible through a financial contribution from Health Canada. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Housing as a Remedy for Chronic Homelessness

Mitchell H. Katz, M.D., of the County of Los Angeles, Department of Health Services, Los Angeles, comments on this topic in an accompanying editorial.

“Clinicians who provide care for homeless persons are aware that they can order a variety of reimbursable tests and treatments for them, except the one intervention that most likely would make all the difference—supportive housing. There are many conditions medicine cannot cure; chronic homelessness does not need to be one of them.”

“More than half a million persons are homeless in the United States on a given night. The study by Stergiopoulos et al suggests that there is a solution to what has been a difficult and emotionally distressing problem in the United States, Canada, and around the world.”

(doi:10.1001/jama.2015.1277; 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) MONDAY, FEBRUARY 23, 2015

Media Advisory: To contact Mark S. Sulkowski, M.D., email Ekaterina Pesheva at Epeshev1@jhmi.edu. To contact Shyam Kottilil, M.D., Ph.D., email Nora Grannell at NGrannell@ihv.umaryland.edu. To contact editorial author Camilla S. Graham, M.D., M.P.H., email Jerry Berger at jberger@bidmc.harvard.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.2015.1328. This link to the 2^nd study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.1373. This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.1111

Two Studies Show Promising Results in Treating Hepatitis C in Patients Co-Infected with HIV

With there being a need for interferon-free treatment because of potential toxicities for patients with hepatitis C virus (HCV) and human immunodeficiency virus 1 (HIV-1), two studies appearing in JAMA using interferon-free drug regimens resulted in high rates of sustained virologic response, which is a lack of detectable HCV RNA at least 12 weeks after completion of treatment.

Hepatitis C virus and HIV-1 co-infections are common because of similar routes of transmission, including injection drug use, blood transfusion, or sexual contact. Since the advent of effective antiretroviral therapy, liver-related disease has emerged as a leading cause of illness and death in HCV/HIV-1 co-infected patients, who are at greater risk for progression to liver cirrhosis and hepatitis or liver-related death than individuals with HCV and not HIV-1.

Interferon-based treatments for HCV infection have significant toxicities, limiting their use; a significant unmet need exists for a highly efficacious, interferon-free treatment. Mark S. Sulkowski, M.D., of Johns Hopkins University, Baltimore, and colleagues assessed the three oral direct-acting antiviral (3D) regimen of ombitasvir, paritaprevir (co-dosed with ritonavir [paritaprevir/r]), dasabuvir, and ribavirin in 63 HCV genotype 1-infected adults with HIV-1 co-infection, including patients with cirrhosis, randomly assigned to either 12 or 24 weeks of treatment. The patients had not received prior HCV treatment or had history of prior treatment failure with peginterferon plus ribavirin therapy. The study was conducted at 17 sites in the United States and Puerto Rico between September 2013 and August 2014.

Plasma HCV RNA suppression was rapid in patients receiving 3D plus ribavirin; 58 of 63 patients (92 percent) had an HCV RNA below the lower limit of quantitation at treatment week 2; after 12 or 24 weeks of treatment with 3D plus ribavirin, 29 of 31 patients (94 percent) and 29 of 32 patients (91 percent) achieved SVR12 (sustained virologic response at posttreatment week 12), respectively; the difference between treatment groups was not statistically significant.

The most common treatment-emergent adverse events were fatigue (48 percent), insomnia (19 percent), nausea (18 percent), and headache (16 percent).Adverse events were generally mild, with none reported as serious or leading to discontinuation of treatment.

“In this open-label, randomized uncontrolled study, treatment with the all-oral, interferon-free 3D-plus-ribavirin regimen resulted in high SVR rates among patients co-infected with HCV genotype 1 and HIV-1 whether treated for 12 or 24 weeks. Further phase 3 studies of this regimen are warranted in co­infected patients,” the authors write.

(doi:10.1001/jama.2015.1328; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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In another study, Shyam Kottilil, M.D., Ph.D., of the University of Maryland School of Medicine and the Institute of Human Virology, Baltimore, and colleagues evaluated the rates of SVR following a treatment regimen of the antiviral agents ledipasvir and sofosbuvir in 50 patients co-infected with HCV genotype 1 and HIV who were never before treated for HCV. The patients, who did not have cirrhosis, were prescribed a fixed-dose combination of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily for 12 weeks. The study was conducted from June 2013 to September 2014 at the Clinical Research Center of the National Institutes of Health.

Forty-nine of 50 participants (98 percent) achieved sustained viral response 12 weeks after the end of treatment. One patient experienced relapse at week 4 following treatment; further analysis indicated a genetic mutation associated with resistance to inhibitors such as ledipasvir.

The most common adverse events were nasal congestion (16 percent of patients) and myalgia (14 percent; pain in the muscles or within muscle tissue). There were no discontinuations or serious adverse events attributable to the study drug.

“In this open-label, uncontrolled, pilot study enrolling patients co-infected with HCV genotype 1 and HIV, administration of an oral combination of ledipasvir and sofosbuvir for 12 weeks was associated with high rates of SVR after treatment completion. Larger studies that also include patients with cirrhosis and lower CD4 T-cell counts are required to understand if the results of this study generalize to all patients co-infected with HCV and HIV,” the authors write.

“These results show for the first time, to our knowledge, that an interferon- and ribavirin-free therapy is associated with high SVR rates in patients co-infected with HCV and HIV.”

(doi:10.1001/jama.2015.1373; 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: Hepatitis C and HIV Co-infection

Camilla S. Graham, M.D., M.P.H., of the Beth Israel Deaconess Medical Center, Boston, comments on the findings of these studies in an accompanying editorial.

“Liver disease represents the second leading cause of death in persons infected with HIV. The high SVR rates in these 2 studies suggest that future barriers to prevention of unnecessary deaths due to HCV may be related to failures of the health care system. Clinicians who care for patients with HIV infection are already skilled at selecting regimens, managing drug­drug interactions, optimizing adherence, and providing harm reduction counseling. These skills are exactly what is needed to treat patients with hepatitis C and to ensure that the successes seen in research trials are replicated in clinical practice.”

“Many clinicians also have experience advocating for their patients, and this skill may be as valuable now as it was in the early days of HIV. With the current concern about the high price of these regimens, it is critical that the patients who are living with hepatitis C and the value of treating this disease remain front and center.”

(doi:10.1001/jama.2015.1111; 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.

Previous Related Content From JAMA: Sofosbuvir and Ribavirin for Hepatitis C in Patients With HIV Co-infection (July 23/30, 2014); available at this link: https://ja.ma/1ESyOWw

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

Media Advisory: To contact Hagen B. Huttner, M.D., email hagen.huttner@uk-erlangen.de.

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.2015.0846

Findings May Help With the Management of Anticoagulant-Related Bleeding Within the Brain

Among patients with oral anticoagulation-associated intracerebral hemorrhage (bleeding within the brain), reversal of international normalized ratio (INR; a measure used to determine the clotting tendency of blood while on medication) below a certain level within 4 hours and systolic blood pressure less than 160 mm Hg at 4 hours were associated with lower rates of hematoma (a localized swelling filled with blood) enlargement, and resumption of anticoagulant therapy was associated with a lower risk of ischemic events without increased bleeding complications, according to a study in the February 24 issue of JAMA.

The prevalence of cardiovascular diseases requiring long-term oral anticoagulation (OAC) is increasing. The most significant complication of OAC is intracerebral hemorrhage (ICH). Among all types of stroke, there is a substantial lack of data about how to manage OAC-ICH. Two of the most pressing unsettled questions are how to prevent hematoma enlargement and how to manage anticoagulation in the long-term. Consensus exists that elevated INR levels should be reversed to minimize hematoma enlargement, yet mode of reversal, timing, and extent of INR reversal are unclear. Valid data on safety and clinical benefit of OAC resumption are missing and remain to be established, according to background information in the article.

Hagen B. Huttner, M.D., of the University of Erlangen-Nuremberg, Erlangen, Germany, and colleagues conducted a study to assess the association of anticoagulation reversal and blood pressure (BP) with hematoma enlargement and the effects of OAC resumption. The study, conducted at 19 German tertiary care centers (2006-2012), included 1,176 individuals for analysis of long-term functional outcome, 853 for analysis of hematoma enlargement, and 719 for analysis of OAC resumption.

Hemorrhage enlargement occurred in 307 of 853 patients (36.0 percent). Reduced rates of hematoma enlargement were associated with reversal of INR levels <1.3 within 4 hours after admission (43/217 [19.8 percent]) vs INR of ≥ 1.3 (264/636 [41.5 percent]) and systolic BP <160 mm Hg at 4 hours (167/504 [33.1 percent]) vs ≥ 160 mm Hg (98/187 [52.4 percent]).The combination of INR reversal <1.3 within 4 hours and systolic BP of <160 mm Hg at 4 hours was associated with lower rates of hematoma enlargement (18.1 percent vs 44.2 percent not achieving these values) and lower rates of in-hospital death (13.5 percent vs 20.7 percent).

OAC was resumed in 172 of 719 survivors (23.9 percent). OAC resumption showed fewer ischemic complications (5.2 percent vs no OAC, 15.0 percent) and not significantly different hemorrhagic complications (8.1 percent vs no OAC, 6.6 percent).

“The study represents the largest cohort of patients with OAC­ICH to date and reports 2 clinically valuable associations. First, rates of hematoma enlargement were decreased in patients with INR values reversed below 1.3 within 4 hours of admission and systolic blood pressures of less than 160 mm Hg at 4 hours. Second, rates of ischemic events were decreased among patients who restarted OAC without increased rates of bleeding complications,” the authors write.

“These retrospective findings require replication and assessment in prospective studies.”

(doi:10.1001/jama.2015.0846; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This work was supported by a research grant from the Johannes and Frieda Marohn Foundation, University of Erlangen, Germany. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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

Media Advisory: To contact Ping Yang M.D., Ph.D., email Joe Dangor at dangor.yusuf@mayo.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.2015.413

Study Suggests Need for More Sensitive Lung Cancer Screening Criteria

An analysis of lung cancer incidence and screening found a decline in the proportion of patients with lung cancer meeting high-risk screening criteria, suggesting that an increasing number of patients with lung cancer would not have been candidates for screening, according to a study in the February 24 issue of JAMA.

Lung cancer screening using low-dose computed tomography is recommended for high-risk individuals by professional associations, including the U.S. Preventive Services Task Force (USPSTF). Ping Yang M.D., Ph.D., of the Mayo Clinic, Rochester, Minn., and colleagues conducted a study to examine the trends in the proportion of patients with lung cancer meeting the USPSTF screening criteria.

The study population included all Olmsted County, Minn., residents older than 20 years from 1984 through 2011, comprising approximately 140,000 people, of whom 83 percent were non-Hispanic white and socioeconomically similar to the general Midwestern U.S. population. All pathologically confirmed incident cases of primary lung cancer were identified using the Rochester Epidemiology Project database. Trends in lung cancer incidence rates were determined based on census data adjusted for the age and sex distribution of the U.S. population in 2000. The proportion of cases meeting USPSTF screening criteria were identified. The criteria included asymptomatic adults 55 to 80 years of age, having a 30 pack-year (a measure of cigarette consumption equivalent to smoking one pack a day for a year) smoking history, and currently smoking or having quit within the past 15 years.

There were 1,351 patients with a new diagnosis of primary lung cancer between 1984 and 2011. The proportion of patients with lung cancer who smoked more than 30 pack-years declined, and the proportion of former smokers, especially those who quit smoking more than 15 years ago, increased. The researchers found there was a decline in the relative proportion of patients with lung cancer meeting the USPSTF criteria overall, from 57 percent in 1984-1990 to 43 percent in 2005-2011. The proportion of patients who would have been eligible under the criteria decreased among women from 52 percent to 37 percent, and from 60 percent to 50 percent among men.

“Our findings may reflect a temporal change in smoking patterns in which the proportion of adults with a 30 pack-year smoking history and having quit within 15 years declined,” the authors write.

“The decline in the proportion of patients meeting USPSTF high-risk criteria indicates that an increasing number of patients with lung cancer would not have been candidates for screening. More sensitive screening criteria may need to be identified while balancing the potential harm from computed tomography.”

(doi:10.1001/jama.2015.413; 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, a grant from the National Institute on Aging, and funding from the Mayo Clinic Foundation. 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, FEBRUARY 24, 2015

Media Advisory: To contact William E. Evans, Pharm.D., email media@stjude.org. To contact editorial author Howard L. McLeod, Pharm.D., email Kim Polacek at Kim.Polacek@Moffitt.org.

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.2015.0894. This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.1086.

Gene Variant Associated With Increased Risk and Severity of Nerve Disorder Linked to Widely-Prescribed Cancer Drug

Children with acute lymphoblastic leukemia who had a certain gene variant experienced a higher incidence and severity of peripheral neuropathy after receiving treatment with the cancer drug vincristine, according to a study in the February 24 issue of JAMA.

Cancer remains the leading cause of death by disease in U.S. children despite major advances in the last 20 years. Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and as cure rates have surpassed 85 percent, it becomes increasingly important to lessen the toxicities of treatment that adversely affect quality of life and longevity. Vincristine is one of the most widely used and effective anticancer agents for treating leukemias in both adults and children. The dose-limiting toxic effect of vincristine is peripheral neuropathy (damage to the nerves), characterized by neuropathic (nerve) pain and impaired manual dexterity, balance, and altered gait. Currently, there are no reliable means of identifying patients at high risk of vincristine­induced neuropathy nor strategies to reduce this drug toxicity, according to background information in the article.

William E. Evans, Pharm.D., of St. Jude Children’s Research Hospital, Memphis, and colleagues performed a genome-wide association study to determine whether there are genetic variants associated with vincristine-induced neuropathy. The study included patients in 1 of 2 prospective clinical trials for childhood ALL that included treatment with 36 to 39 doses of vincristine. Genetic analysis and vincristine-induced peripheral neuropathy were assessed in 321 patients from whom DNA was available: 222 patients (median age, 6.0 years) enrolled in 1994-1998 in a St. Jude Children’s Research Hospital cohort; and 99 patients (median age, 11.4 years) enrolled in 2007-2010 in a Children’s Oncology Group (COG) cohort.

Grade 2 (moderate) to 4 (life threatening) vincristine-induced neuropathy during therapy occurred in 28.8 percent of patients (64/222) in the St. Jude cohort and in 22.2 percent (22/99) in the COG cohort. The researchers found that an inherited variant in the gene CEP72 was associated with a higher incidence and severity of vincristine-related peripheral neuropathy in children with ALL. Among patients with the gene variant, 28 of 50 (56 percent) developed at least 1 episode of grade 2 to 4 neuropathy, compared with 21 percent (58/271) of other patients.

“If replicated in additional populations, this finding may provide a basis for safer dosing of this widely prescribed anticancer agent,” the authors write.

(doi:10.1001/jama.2015.0894; 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: Precision Medicine to Improve the Risk and Benefit of Cancer Care

“The study by Diouf et al has many key elements; genome-wide discovery in patients from well-conducted clinical trials, replication in a multicenter cohort, statistical robustness, and laboratory correlative findings that contribute biologic plausibility,” writes Howard L. McLeod, Pharm.D., of the Moffitt Cancer Center, Tampa, Fla., in an accompanying editorial.

“However, vincristine remains a component of the most widely accepted treatment regimens for childhood ALL, although there is variation in both dose and intensity. It is not clear that vincristine can be removed from the treatment options for a child with CEP72 variants, although this study suggests that the resulting increase in leukemia cellular sensitivity makes vincristine dose reductions possible without compromising antileukemic effect.”

“However, there is value in the association of CEP72 with vincristine-induced peripheral neuropathy (VIPN). The ability to objectively ascribe a degree of heightened VIPN risk will allow for greater transparency in discussions of risk and benefits of therapy with patients and their family members. This also may lead to developmental therapeutic approaches to modulate CEP72 function as either primary prevention or treatment of chronic VIPN. This study also represents an initial robust effort to generate predictors for adverse drug reactions in cancer care.”

(doi:10.1001/jama.2015.1086; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. McLeod reports stock options for Cancer Genetics Inc.

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

Media Advisory: To contact Anne-Marie Schjerning Olsen, M.D., Ph.D., email aols0073@geh.regionh.dk. To contact editorial co-author David J. Moliterno, M.D., email Kristi Lopez at Kristi.lopez@uky.edu.

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Taking NSAIDs With Anti-Clotting Medications Following Heart Attack Associated With Increased Risk of Bleeding, Cardiovascular Events

Among patients receiving antithrombotic therapy (to prevent the formation of blood clots) after a heart attack, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with an increased risk of bleeding and events such as heart attack, stroke or cardiovascular death, even after short-term treatment, according to a study in the February 24 issue of JAMA.

Guidelines recommend that all patients with myocardial infarction (MI; heart attack) should be prescribed dual antithrombotic therapy (aspirin and clopidogrel) for up to 12 months and one agent thereafter. Although bleeding risks associated with antithrombotic agents are increased by NSAIDs, certain NSAID agents (e.g., ibuprofen) may also impede the antithrombotic effects of aspirin and may increase risk of cardiovascular events. These risks are of considerable public health concern, given the widespread use of NSAIDs, according to background information in the article.

Anne-Marie Schjerning Olsen, M.D., Ph.D., of Copenhagen University Hospital Gentofte, Hellerup, Denmark, and colleagues examined the risk of bleeding and cardiovascular events among patients with prior MI taking antithrombotic drugs and for whom NSAID therapy was then prescribed. The researchers used nationwide administrative registries in Denmark (2002-2011) and included patients 30 years or older admitted with first-time MI and alive 30 days after hospital discharge. Subsequent treatment with aspirin, clopidogrel, or other oral anticoagulants and their combinations, as well as ongoing concomitant (accompanying) NSAID use was determined.

The study included 61,971 patients (average age, 68 years); of these, 34 percent filled at least 1 NSAID prescription. The number of deaths during a median follow-up of 3.5 years was 18,105 (29.2 percent). A total of 5,288 bleeding events (8.5 percent) and 18,568 cardiovascular events (30.0 percent) occurred. Analysis indicated that there was about twice the risk of bleeding with NSAID treatment compared with no NSAID treatment, and the cardiovascular risk was also increased. An increased risk of bleeding and cardiovascular events was evident with accompanying use of NSAIDs, regardless of antithrombotic treatment, types of NSAIDs, or duration of use.

“There was no safe therapeutic window for concomitant NSAID use, because even short-term (0-3 days) treatment was associated with increased risk of bleeding compared with no NSAID use. Confirming previous studies and despite increased bleeding complications, NSAIDs were not associated with decreased cardiovascular risk,” the authors write.

“More research is needed to confirm these findings; however, physicians should exercise appropriate caution when prescribing NSAIDs for patients who have recently experienced MI.”

(doi:10.1001/jama.2015.0809; 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: Potential Hazards of Adding Nonsteroidal Anti-inflammatory Drugs to Antithrombotic Therapy After Myocardial Infarction

In an accompanying editorial, Charles L. Campbell, M.D., of the University of Tennessee-Chattanooga, and David J. Moliterno, M.D., of the University of Kentucky, Lexington, comment on the findings of this study.

“The cumulative evidence available is an important reminder that the while NSAIDs can be helpful and at times necessary medications for satisfactory quality of life, use of these medications among patients with a history of a recent MI is likely to be associated with clinically meaningful bleeding and ischemic risks. Because the present study tracked only prescription NSAID use, it is plausible that an even greater health care effect might occur in many countries, such as the United States, where NSAIDs are widely available as over-the-counter medications and physicians may be unaware whether their patients are taking NSAIDs.”

(doi:10.1001/jama.2015.0567; 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, FEBRUARY 17, 2015

Media Advisory: To contact Pramod K. Mistry, M.D., Ph.D., F.R.C.P., email Ziba Kashef at ziba.kashef@yale.edu.

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Drug Improves Measures of Genetic Disease That Affects Liver, Spleen

Among previously untreated adults with Gaucher disease type 1, a genetic disease in which there is improper metabolism due to a defect in an enzyme, treatment with the drug eliglustat resulted in significant improvements in liver and spleen size hemoglobin level, and platelet count, according to a study in the February 17 issue of JAMA.

Gaucher disease type 1 is characterized by enlargement of the spleen and liver, anemia, low blood platelets, chronic bone pain, and the failure to grow properly.  Untreated Gaucher disease type 1 is a chronic and progressive disorder associated with disability, reduced life expectancy, and, in some patients, life-threatening complications. The current standard of care is enzyme replacement therapy, which requires lifelong intravenous infusions every other week. A safe, effective oral therapy is needed, according to background information in the article.

Pramod K. Mistry, M.D., Ph.D., F.R.C.P., of the Yale University School of Medicine, New Haven, Conn., and colleagues randomly assigned 40 untreated adults with Gaucher disease type 1 to receive eliglustat (twice daily; n = 20) or placebo (n = 20) for 9 months. Eliglustat is a novel oral medication, which showed favorable results for patients with this disease in a phase 2 trial. This phase 3 trial was conducted at 18 sites in 12 countries.

The researchers found that administration of eliglustat resulted in a reduction in spleen volume of approximately 30 percent compared with placebo, as well as improvements in hemoglobin level, decreased liver volume (-6.6 percent), and increased platelet count (41 percent).  No serious adverse events occurred.  No patient discontinued treatment over the course of the 9-month study because of a treatment-emergent adverse event.

The authors add that more definitive conclusions about clinical efficacy and utility will require comparison with the standard treatment of enzyme replacement therapy as well as longer-term follow-up.

(doi:10.1001/jama.2015.459; Available pre-embargo to the media at https://media.jamanetwork.com)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, FEBRUARY 17, 2015

Media Advisory: To contact Ollie Jay, Ph.D., email Michelle Blowes at michelle.blowes@sydney.edu.au.

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Study Shows Beneficial Effect of Electric Fans in Extreme Heat and Humidity

Although some public health organizations advise against the use of electric fans in severe heat, a new study published in the February 17 issue of JAMA demonstrated that electric fans prevent heat-related elevations in heart rate and core body temperature.

One review of previous research concluded “no evidence currently exists supporting or refuting the use of electric fans during heat waves” for mortality and illness. However, public health guidance typically warns against fan use in hot weather, with some research suggesting that fan use could potentially accelerate body heating, according to background information in the article.

Ollie Jay, Ph.D., of the University of Sydney, New South Wales, Australia, and colleagues examined the effect of fan use at temperatures and humidities that can no longer be physiologically tolerated without rapid increases in heart rate and core body temperature. Sweat evaporation declines with increasing humidity, so in more humid environments fans may not prevent heat­induced elevations in cardiovascular and thermal (core temperature) strain.

Wearing shorts and t-shirts, eight healthy males (average age, 23 years) sat in a chamber maintained at temperatures equal to (36°C; 97°F) or exceeding (42°C; 108°F), the limits currently recommended for fan use. Each temperature was tested with and without an 18-inch fan facing the participant (from about 3 feet). After a 20-minute baseline period, relative humidity was increased in 15 equal steps from 25 percent to 95 percent at 97°F and from 20 percent to 70 percent at 108°F. Heart rate and core temperature of the study participants were measured throughout.

The researchers found that the electric fans prevented heat-related elevations in heart and core temperature up to approximately 80 percent relative humidity at 97°F and 50 percent relative humidity at 108°F. “Thus, contrary to existing guidance, fans may be effective cooling devices for those without air conditioning during hot and humid periods,” the authors write. “Advice to the public to stop using fans during heat waves may need to be reevaluated.”

The authors note that only young participants were assessed, so similar results would need to be derived for other populations (e.g., elderly with illnesses) and those with diminished sweat production.

(doi:10.1001/jama.2015.153; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: This research was supported by a discovery grant from the Natural Sciences and Engineering Research Council of Canada. 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, FEBRUARY 17, 2015

Media Advisory: To contact Karolina Szummer, M.D., Ph.D., email karolina.szummer@karolinska.se.

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Anticoagulant Fondaparinux Associated With Lower Risk of Bleeding and Death Following Heart Attack Compared to Heparin

Patients who experienced a certain type of heart attack who received the anticoagulant fondaparinux had a lower risk of major bleeding events and death both in the hospital and after six months compared to patients who received low-molecular-weight heparin (LMWH), although both groups had similar rates of subsequent heart attack or stroke, according to a study in the February 17 issue of JAMA.

Reducing bleeding events in patients receiving antithrombotic therapy is important since bleeding events are associated with increased mortality. Fondaparinux was associated with reduced major bleeding events and improved survival compared with LMWH (a class of anticoagulant medications) in a large randomized clinical trial involving patients with non-ST-segment elevation myocardial infarction (NSTEMI; a certain pattern on an electrocardiogram following a heart attack). Large-scale experience of the use of fondaparinux vs LMWH outside of a clinical trial setting has been lacking, according to background information in the article.

Karolina Szummer, M.D., Ph.D., of the Karolinska Institutet, Stockholm, Sweden, and colleagues analyzed data from a Swedish registry that included 40,616 patients with NSTEMI who received in-hospital treatment with fondaparinux or LMWH between September 2006 through June 2010, with follow-up through December 2010.

Overall, 14,791 patients (36.4 percent) received fondaparinux and 25,825 (63.6 percent) received LMWH. The absolute rate of severe in-hospital bleeding events was lower in the fondaparinux group than the LMWH group (1.1 percent vs 1.8 percent), as was in-hospital mortality (2.7 percent vs 4.0 percent). The differences in major bleeding events and mortality between the two treatments were similar at 30 and 180 days.

The rate of recurrent heart attack in the fondaparinux group was 9.0 percent vs 9.5 percent in the LMWH group at 30 days and was 14.2 percent vs 15.8 percent at 180 days. The rate of stroke was low in both groups.

The results were similar in patients with varying degrees of kidney function and in the subgroup of patients with NSTEMI who had undergone early percutaneous coronary intervention (a procedure used to open narrowed coronary arteries, such as stent placement).

“A randomized clinical trial is often needed to provide definite evidence and an estimate of the treatment effect in a specific, selected, well-defined target patient population. However, the effect of implementing the same treatment in clinical practice might differ and should therefore be investigated in observational cohorts and, preferably, in continuous registries with complete coverage of nonselected patients with an indication for the studied treatment. Outside of a trial setting, the treatment is given to a much more heterogeneous patient population and the treating centers and physicians are less selected. Thus, the balance between benefit and risk can differ between a randomized clinical trial and experience in a nontrial, routine clinical care setting. Therefore, experiences from clinical practice provide important complementary information,” the authors write.

(doi:10.1001/jama.2015.517; 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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