EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 6, 2016

Media Advisory: To contact Joel G. Ray, M.D., M.Sc., F.R.C.P.C., call Maria Feldman at 416-864-5047 or email feldmanm@smh.ca.

To place an electronic embedded link to this study and editorial in your story  These links will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.12126

In an analysis that included more than 1.4 million births, exposure to magnetic resonance imaging (MRI) during the first trimester of pregnancy compared with nonexposure was not associated with increased risk of harm to the fetus or in early childhood, although gadolinium MRI at any time during pregnancy was associated with an increased risk of a broad set of rheumatological, inflammatory, or skin conditions and, possibly, for stillbirth or neonatal death, according to a study appearing in the September 6 issue of JAMA.

Concern has been expressed about the safety of MRI exposure in the first trimester of pregnancy due to the heating of sensitive tissues by radiofrequency fields and exposure to the loud acoustic environment. When indicated, MRI’s diagnostic accuracy is improved with gadolinium, an intravenous contrast medium. Fetal safety of MRI during the first trimester of pregnancy or with gadolinium enhancement at any time of pregnancy is unknown.

With the use of universal health care databases in the province of Ontario, Joel G. Ray, M.D., M.Sc., F.R.C.P.C., of St. Michael’s Hospital and the Institute for Clinical Evaluative Sciences, Toronto, and colleagues identified all births of more than 20 weeks from 2003-2015 to evaluate the long-term safety after exposure to MRI in the first trimester of pregnancy or to gadolinium at any time during pregnancy.

The study included 1,424,105 deliveries. In pregnancies that lasted a minimum of 21 gestational weeks, 1 in 250 had an MRI in pregnancy, including 1 in 1,200 in the first trimester and 1 in 3,000 with gadolinium contrast. Maternal MRI in the first trimester was not associated with a higher risk of stillbirth or neonatal death, congenital anomalies, neoplasm, or hearing loss.

Exposure to gadolinium-enhanced MRI at any gestation was not associated with a greater risk of congenital anomalies. Although a nephrogenic systemic fibrosis-like outcome was extremely rare, gadolinium-enhanced MRI was associated with an increased risk for a non-specific outcome of any rheumatological, inflammatory or infiltrative skin condition up to age 4 years, and for stillbirth or neonatal death, although there were just 7 events in the gadolinium MRI group.

“The current findings inform published recommendations about the safety of MRI in the first trimester of pregnancy,” the authors write. “Until further studies are done, these findings suggest that gadolinium contrast should be avoided during pregnancy.”

(doi:10.1001/jama.2016. 12126; the study is available pre-embargo to the media at the For the Media website)

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, SEPTEMBER 6, 2016

Media Advisory: To contact the U.S. Preventive Services Task Force, email the Media Coordinator at Newsroom@USPSTF.net or call 202-572-2044.

To place an electronic embedded link to this report in your story  This link will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11046

The U.S. Preventive Services Task Force (USPSTF) recommends screening for latent tuberculosis infection in populations at increased risk. People who are considered at increased risk include people who were born in or have lived in countries where tuberculosis is highly prevalent, or who have lived in group settings where exposure to tuberculosis is more likely, such as homeless shelters or correctional facilities. The report appears in the September 6 issue of JAMA.

This is a B recommendation, indicating that there is high certainty that the net benefit is moderate, or there is moderate certainty that the net benefit is moderate to substantial.

In the United States, tuberculosis remains an important preventable disease, including active tuberculosis infection, which may be infectious, and latent infection (LTBI), which is asymptomatic and not infectious but can later reactivate and progress to active disease. The precise prevalence rate of LTBI in the United States is difficult to determine; however, based on 2011-2012 National Health and Nutrition Examination Survey data, estimated prevalence is 4.7 percent to 5.0 percent. An effective strategy for reducing the transmission, illness and death of active disease is the identification and treatment of LTBI to prevent progression to active disease. To issue a current recommendation on screening for LTBI, the USPSTF reviewed the evidence on screening for LTBI in asymptomatic adults seen in primary care, including evidence dating from the inception of searched databases.

The USPSTF is an independent, volunteer panel of experts that makes recommendations about the effectiveness of specific preventive care services such as screenings, counseling services, and preventive medications.

Detection

The USPSTF found adequate evidence that accurate screening tests are available to detect LTBI. Screening tests include the Mantoux tuberculin skin test (TST) and interferon-gamma release assays (IGRAs); both are moderately sensitive and highly specific.

Benefits of Early Detection and Treatment

The USPSTF found no studies that evaluated the direct benefits of screening for LTBI. The USPSTF found adequate evidence that treatment of LTBI with regimens recommended by the Centers for Disease Control and Prevention (CDC) decreases progression to active tuberculosis; the magnitude of this benefit is moderate.

Harms of Early Detection and Treatment

The USPSTF found no direct evidence on the harms of screening for LTBI. The USPSTF found adequate evidence that the magnitude of harms of treatment of LTBI with CDC-recommended regimens is small. The primary harm of treatment is hepatotoxicity.

Summary

The USPSTF found adequate evidence that accurate screening tests for LTBI are available, treatment of LTBI provides a moderate health benefit in preventing progression to active disease, and the harms of screening and treatment are small. The USPSTF has moderate certainty that screening for LTBI in persons at increased risk for infection provides a moderate net benefit.

(doi:10.1001/jama.2016.11046; the full report is available pre-embargo to the media at the For the Media website)

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

Note: More information about the U.S. Preventive Services Task Force, its process, and its recommendations can be found on the newsroom page of its website.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 6, 2016

Media Advisory: To contact Craig G. Crandall, Ph.D., call Cathy Frisinger at 214-648-7228 or email Cathy.Frisinger@UTSouthwestern.edu.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.10550

In a study appearing in the September 6 issue of JAMA, Craig G. Crandall, Ph.D., of the University of Texas Southwestern Medical Center, Dallas, and colleagues examined whether electric fan use would delay elevations in heart rate and core temperature of elderly adults exposed to extreme heat and humidity.

Research has indicated that electric fan use delays elevations in heart rate and core temperature of young adults exposed to 108°F. However, it remains unknown if fans are effective in vulnerable populations, such as the elderly who display altered cardiovascular and thermoregulatory responses during heat exposure. This study included 3 men and 6 women volunteers (average age, 68 years). Wearing shorts (men) or shorts and a sports bra (women), participants sat in a chamber maintained at 108°F. After 30 minutes at a relative humidity of 30 percent, relative humidity was increased 2 percent every 5 minutes to 70 percent (100 minutes total). On separate randomly assigned days, participants performed the protocol with or without a 16-in fan facing them from about 3 feet. No fluid intake was allowed during the protocol. Measurements taken included heart rate, core temperature and sweat loss.

The researchers found that fan use resulted in greater heart rate and core temperature. “Although differences were small, their cumulative effect may become clinically important with fan use during more prolonged heat exposure. Fan use elevates sweat loss in young adults. This was not observed in elderly adults, suggesting that age-related impairments in sweating capacity possibly limit the effectiveness of electric fans. Overall, this preliminary study indicates that electric fans may be detrimental for attenuating cardiovascular and thermal strain of elderly adults during heat waves.”

(doi:10.1001/jama.2016.10550; the study is available pre-embargo to the media at the For the Media website)

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, SEPTEMBER 6, 2016

Media Advisory: To contact Sophie Dupuis-Girod, M.D., Ph.D., email sophie.dupuis-girod@chu-lyon.fr. To contact Kevin J. Whitehead, M.D., email Julie Kiefer at julie.kiefer@hsc.utah.edu.

To place an electronic embedded link to these studies in your story  These links will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11387  http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11724

Two studies appearing in the September 6 issue of JAMA examine the effectiveness of nasal sprays to reduce the frequency and duration of nosebleeds caused by hereditary hemorrhagic telangiectasia (HHT), an inherited condition characterized by abnormal blood vessels which are delicate and prone to bleeding.

Epistaxis (nosebleed) are the most frequent and disabling manifestation of HHT. These epistaxis episodes can be severe and life threatening. There is currently no medical or surgical treatment available to cure the nosebleeds definitively. Sophie Dupuis-Girod, M.D., Ph.D., of the Hopital Femme-Mere-Enfants, Bron, France and colleagues evaluated the efficacy of 3 different doses of the drug bevacizumab administered as a nasal spray. Bevacizumab is a monoclonal antibody that slows the growth of new bloods vessels. In this phase 2/3 clinical trial, 80 patients with HHT and a history of nosebleeds were randomly assigned to received placebo or one of three doses of bevacizumab nasal spray (3 doses 14 days apart for a total treatment duration of 4 weeks).

The researchers found that average monthly epistaxis duration measured at 3 months was not significantly different in the patients receiving bevacizumab in comparison with the placebo group or between the bevacizumab groups. Toxicity was low and no severe adverse events were reported. Treatment with bevacizumab had no measurable effect on secondary outcomes including number of epistaxis episodes, quality of life, number of red blood cell transfusions, or hemoglobin and ferritin levels.

The study was terminated prior to phase 3 for treatment futility after interim analysis on the recommendations of an independent data monitoring committee.

(doi:10.1001/jama.2016.11387; the study is available pre-embargo to the media at the For the Media website)

Editor’s Note: This work was financed by the Hospices Civils de Lyon grant supported by the National Research Program and by the patients’ association (Association Pour la Maladie de Rendu-Osler). All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were re­ported.

In another study, Kevin J. Whitehead, M.D., of the University of Utah, Salt Lake City, and colleagues examined whether therapy with any of 3 drugs would be effective in reducing HHT-related epistaxis.

Based on published data and anecdotal experience, 3 agents with theoretically differing mechanisms of action were selected: bevacizumab, estriol, or tranexamic acid. The study included 121 patients with HHT who had experienced HHT-related epistaxis. Patients were randomly assigned to receive twice-daily nose sprays for 12 weeks with either of the agents or placebo.

The researchers found that drug therapy did not significantly reduce epistaxis frequency. After 12 weeks of treatment, the median weekly number of bleeding episodes was 7 for patients in the bevacizumab group, 8 for the estriol group, 7.5 for the tranexamic acid group, and 8 for the placebo group. No drug treatment was significantly different from placebo for epistaxis duration. There were no significant differences between groups for hemoglobin level, ferritin level, treatment failure, need for transfusion, or emergency department visits.

No serious adverse effects were seen in the study.

(doi:10.1001/jama.2016.11724; the study is available pre-embargo to the media at the For the Media website)

Editor’s Note: The North American Study of Epistaxis in HHT trial was funded by Cure HHT, a nonprofit patient organization supporting the HHT community. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 2:30 A.M. (ET) TUESDAY, AUGUST 30, 2016

Media Advisory: To contact Marlous Hall, Ph.D., email m.s.hall@leeds.ac.uk.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.10766

Among nearly 400,000 patients hospitalized with a certain type of heart attack in England and Wales between 2003 and 2013, improvement in survival was significantly associated with use of an invasive coronary strategy (such as coronary angiography) and not entirely related to a decline in baseline clinical risk or increased use of pharmacological therapies, according to a study published online by JAMA. The study is being released to coincide with its presentation at the European Society of Cardiology Congress 2016.

There has been a global decline in the rates of death following acute coronary syndrome (conditions such as heart attack or unstable angina); however, the extent to which this is due to use of guideline-indicated treatments for management of non-ST-elevation myocardial infarction (NSTEMI; a type of heart attack with certain findings on an electrocardiogram) is not known. Marlous Hall, Ph.D., of the University of Leeds, Leeds, England, and colleagues analyzed data on 389,057 patients with NSTEMI in 247 hospitals in England and Wales. Among these patients, there were 113,586 deaths (29 percent). From 2003-2004 to 2012-2013, proportions with intermediate to high clinical risk (patient factors such as cardiac arrest, elevated enzyme levels, systolic blood pressure, heart rate) decreased (87 percent vs 82 percent); proportions with lowest risk increased (4.2 percent vs 7.6 percent). The prevalence of diabetes, hypertension, cerebrovascular disease, chronic obstructive pulmonary disease, chronic renal failure, previous invasive coronary strategy, and current or ex-smoking status increased. Unadjusted all-cause mortality rates at 180 days decreased from 10.8 percent to 7.6 percent.

Analysis indicated that improvements in survival were associated with use of an invasive coronary strategy (defined as coronary angiography, percutaneous coronary intervention [procedure such as stent placement], coronary artery bypass graft surgery), which was associated with a relative decrease in mortality of 46 percent. A reduction in baseline acute coronary syndrome risk, increase in comorbidities, and use of guideline-indicated pharmacological therapies did not fully explain improvement in survival.

The authors note that these findings should not be interpreted to indicate that medical therapies have no role in management of NSTEMI. In this study group, aspirin, P2Y₁₂ inhibitors, beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and statins each had a significant association with improved survival.

(doi:10.1001/jama.2016.10766; the study is available pre-embargo to the media at the For the Media website)

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

Note: Available pre-embargo at the For The Media website is an accompanying editorial, “Management of Non-ST-Elevation Myocardial Infarction,” by Erin A. Bohula, M.D., D.Phil., and Elliott M. Antman, M.D., of Brigham and Women’s Hospital, Harvard Medical School, Boston.

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For more information, contact JAMA Network Media Relations at 312-464-JAMA (5262) or email mediarelations@jamanetwork.org.

EMBARGOED FOR RELEASE: 3 A.M. (ET) MONDAY, AUGUST 29, 2016

Media Advisory: To contact John P. Greenwood, Ph.D., email j.greenwood@leeds.ac.uk.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.12680

In a study published online by JAMA, John P. Greenwood, Ph.D., of the University of Leeds, Leeds, United Kingdom, and colleagues examined whether among patients with suspected coronary heart disease (CHD), cardiovascular magnetic resonance (CMR)-guided care is superior to National Institute for Health and Care Excellence (NICE) guidelines-directed care and myocardial perfusion scintigraphy (MPS)-guided care in reducing unnecessary angiography. The study is being released to coincide with its presentation at the European Society of Cardiology Congress 2016.

Coronary heart disease is a leading cause of death and disability worldwide. Several methods are available to diagnose CHD, risk-stratify patients, and determine the need for revascularization. Despite the widespread availability and recommendations for noninvasive imaging in international guidelines, invasive coronary angiography is commonly used in patients with suspected CHD. Evidence from large populations presenting with chest pain has confirmed that the majority will not have significant obstructive coronary disease. Avoiding unnecessary angiography should reduce patient risk and provide significant financial savings.

In this study, 1,202 symptomatic patients from 6 UK hospitals with suspected CHD were randomly assigned to management according to UK NICE guidelines (n = 240) or to guided care based on the results of CMR (n = 481) or MPS (n = 481) testing. Among the patients, the number with invasive coronary angiography after 12 months was 102 in the NICE guidelines group (43 percent), 85 in the CMR group (18 percent); and 78 in the MPS group (16 percent). The researchers found that a CMR-guided strategy significantly reduced study-defined unnecessary angiography compared with NICE guidelines-guided care, but was not significantly different from an MPS-guided strategy.

Between the 3 strategies, there was no difference in major adverse cardiovascular event rates at 12 months or disease detection (positive angiography) rates.

(doi:10.1001/jama.2016.12680; the study is available pre-embargo to the media at the For the Media website)

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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For more information, contact JAMA Network Media Relations at 312-464-JAMA (5262) or email mediarelations@jamanetwork.org.

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 23, 2016

Media Advisory: To contact Aaron S. Kesselheim, M.D., J.D., M.P.H., call Elaine St. Peter at 617-525-6375 or email estpeter@partners.org.

To place an electronic embedded link to this study and editorial in your story  These links will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11237

High prescription drug prices are attributable to several causes, including the approach the U.S. has taken to granting government-protected monopolies to drug manufacturers, and the restriction of price negotiation at a level not observed in other industrialized nations, according to a study appearing in the August 23/30 issue of JAMA.

The increasing cost of prescription drugs in the United States has become a source of growing concern for patients, prescribers, payers, and policy makers. Aaron S. Kesselheim, M.D., J.D., M.P.H., of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues reviewed the peer-reviewed medical and health policy literature from January 2005 to July 2016 for articles addressing the sources of drug prices in the United States, the justifications and consequences of high prices, and possible solutions.

The authors write that per capita prescription drug spending in the United States exceeds that in all other countries, largely driven by brand-name drug prices that have been increasing in recent years at rates far beyond the consumer price index. In 2013, per capita spending on prescription drugs was $858 compared with an average of $400 for 19 other industrialized nations. In the United States, prescription medications now comprise an estimated 17 percent of overall personal health care services.

Drug prices are higher in the United States than in the rest of the industrialized world because, unlike that in nearly every other advanced nation, the U.S. health care system allows manufacturers to set their own price for a given product. In contrast, in countries with national health insurance systems, a delegated body negotiates drug prices or rejects coverage of products if the price demanded by the manufacturer is excessive in light of the benefit provided; manufacturers may then decide to offer the drug at a lower price.

The most important factor that allows manufacturers to set high drug prices is market exclusivity, protected by monopoly rights awarded upon Food and Drug Administration approval and by patents. The availability of generic drugs after this exclusivity period is the main means of reducing prices in the United States, but access to them may be delayed by numerous business and legal strategies. The primary counterweight against excessive pricing during market exclusivity is the negotiating power of the payer, which is currently constrained by several factors, including the requirement that most government drug payment plans cover nearly all products. Another key contributor to drug spending is physician prescribing choices when comparable alternatives are available at different costs. Although prices are often justified by the high cost of drug development, there is no evidence of an association between research and development costs and prices; rather, prescription drugs are priced in the United States primarily on the basis of what the market will bear.

The researchers write that the most realistic short-term strategies to address high prices include enforcing more stringent requirements for the award and extension of exclusivity rights; enhancing competition by ensuring timely generic drug availability; providing greater opportunities for meaningful price negotiation by governmental payers; generating more evidence about comparative cost-effectiveness of therapeutic alternatives; and more effectively educating patients, prescribers, payers, and policy makers about these choices.

“There is little evidence that such policies would hamper innovation, and they could even drive the development of more valuable new therapies rather than rewarding the persistence of older ones. Medications are the most common health care intervention and can have a major benefit on the health of individuals, as well as of populations, but unnecessarily high prices limit the ability of patients and health care systems to benefit fully from these vital products.”

(doi:10.1001/jama.2016.11237; the study is available pre-embargo to the media at the For the Media website)

Editor’s Note: This work was funded by a grant from the Laura and John Arnold Foundation. Additional support was provided by the Engelberg Foundation. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 23, 2016

Media Advisory: To contact Brenda Reiss-Brennan, Ph.D., A.P.R.N., email Daron Cowley at daron.cowley@imail.org. To contact editorial author Thomas L. Schwenk, M.D., call Anne McMillin at 775-682-9254 or email amcmillin@med.unr.edu.

To place an electronic embedded link to this study and editorial in your story  These links will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11232  http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11031

Among adults enrolled in an integrated health care system, receipt of primary care at integrated team-based care practices compared with traditional practice management practices was associated with higher rates of some measures of quality of care, lower rates for some measures of acute care utilization, and lower actual payments received by the delivery system, according to a study appearing in the August 23/30 issue of JAMA.

Limited evidence is available to support the utility of medical home and accountable care integration with mental health and primary care teams. Brenda Reiss-Brennan, Ph.D., A.P.R.N., of Intermountain Healthcare, Salt Lake City, and colleagues assessed the association of integrating physical and mental health over time in team-based care (TBC) practices with patient outcomes and costs. The study included adult patients who received primary care at 113 Intermountain Healthcare Medical Group primary care practices from 2003 through 2005 and had yearly encounters with Intermountain Healthcare through 2013, including some patients who received care in both TBC and traditional practice management (TPM) practices.

Of the 113 practices observed over the study period (2010- 2013), 102 practices were classified annually as TBC (n = 27) or TPM (n = 75). The analysis included 113,452 patients (average age, 56 years; women, 59 percent). The researchers found that patients treated in TBC practices compared with those treated in TPM practices had higher rates of active depression screening (46 percent for TBC vs 24 percent for TPM), adherence to a diabetes care bundle (25 percent for TBC vs 20 percent for TPM), and documentation of self-care plans (48 percent for TBC vs 8.7 percent for TPM), lower proportion of patients with controlled hypertension (85 percent for TBC vs 98 percent for TPM), and no significant differences in documentation of advanced directives (9.6 percent for TBC vs 9.9 percent for TPM).

Rates of health care utilization were lower for TBC patients compared with TPM patients for emergency department visits, hospital admissions, ambulatory care sensitive visits and admissions, and primary care physician encounters, with no significant difference in visits to urgent care facilities and visits to specialty care physicians.

Payments to the delivery system were lower in the TBC group vs the TPM group ($3,401 for TBC vs $3,516 for TPM) and were less than investment costs of the TBC program.

“The study suggests the value of coordinated team relationships within a delivery system emphasizing the integration of physical and mental health care,” the authors write.

(doi:10.1001/jama.2016.11232; the study is available pre-embargo to the media at the For the Media website)

Editor’s Note: This research was supported by Intermountain Healthcare’s Medical Group, Primary Care Clinical Program, Institute for Healthcare Leadership, Office of Research, and Office of Population Health. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Integrated Behavioral and Primary Care – What Is the Real Cost?

“This study has several important implications. Integrated TBC is clearly superior to TPM for patients with complex mental illness and chronic medical disease, consistent with the increasing recognition that this type of care is best applied to higher-risk patients with substantial disease burden,” writes Thomas L. Schwenk, M.D., of the University of Nevada, Reno, in an accompanying editorial.

“However, practicing in an integrated, value- and outcomes­ based model but continuing to be reimbursed in a traditional, volume-based system is costly. The investigators note that the investment cost of the program was lower than the reduction in reimbursement, but both are, in fact, a reduction in the bottom line for practices large and small, and therein lies the most important implication of this study.”

“The results of the study by Reiss-Brennan et al document the value of an integrated model of mental health and chronic disease care that likely can only be provided to patients who receive their care in large, integrated health systems. The most significant consequence, however unintended, of outcomes-based medical care and value-based reimbursement may be a profound change in the fundamental structure of the U.S. health care delivery system.”

(doi:10.1001/jama.2016.11031; the study is available pre-embargo to the media at the For the Media website)

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, AUGUST 23, 2016

Media Advisory: To contact Michael Levin, F.R.C.P.C.H., email m.levin@imperial.ac.uk. To contact Octavio Ramilo, M.D., call Gina Bericchia at 614-355-0495 or email MediaRelations@NationwideChildrens.org. To contact Howard Bauchner, M.D., email mediarelations@jamanetwork.org.

To place an electronic embedded link to these studies and editorial in your story  These links will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11236

http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.9207  http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11137

Two studies appearing in the August 23/30 issue of JAMA examine the use of genetic tests to help rule out a serious bacterial infection in infants with fever, and also to determine if an infection is bacterial or viral in children with fever.

In one study, Michael Levin, F.R.C.P.C.H., of Imperial College London, and colleagues investigated whether bacterial infection can be distinguished from other causes of fever in children by the pattern of host genes activated or suppressed in blood in response to the infection and whether a subset of these genes could be identified as the basis for a diagnostic test.

The majority of febrile (with fever) children have self-resolving viral infection, but a small proportion have life-threatening bacterial infections. Because clinical features do not reliably distinguish bacterial from viral infection, many children worldwide receive unnecessary antibiotic treatment, while bacterial infection is missed in others. A number of studies have suggested that specific infections can be identified by the pattern of host genes activated during the inflammatory response.

This study included febrile children presenting to participating hospitals in the United Kingdom, Spain, the Netherlands, and the United States between 2009-2013, and placed in a discovery group or validation group. Each group was classified after microbiological investigation as having definite bacterial infection, definite viral infection, or indeterminate infection. RNA expression signatures (determined with a blood sample) distinguishing definite bacterial from viral infection were identified in the discovery group and diagnostic performance assessed in the validation group. Additional validation was undertaken in separate studies of children with meningococcal disease (n = 24) and inflammatory diseases (n = 48) and on published gene expression datasets.

The discovery group of 240 children (median age, 19 months) included 52 with definite bacterial infection, of whom 36 (69 percent) required intensive care, and 92 with definite viral infection, of whom 32 (35 percent) required intensive care. Ninety-six children had indeterminate infection. The researchers identified a host whole blood RNA transcriptomic signature that distinguished bacterial from viral infection with 2 gene transcripts. The signature also distinguished bacterial infection from childhood inflammatory diseases, systemic lupus erythematosus, juvenile idiopathic arthritis, and discriminated bacterial from viral infection in published adult studies. Of the children in the indeterminate groups, 46 percent were classified as having bacterial infection, although 95 percent received antibiotic treatment.

The authors write that a major challenge in using transcriptomic signatures for diagnosis is the translation of multitranscript signatures into clinical tests suitable for use in hospital laboratories or at the bedside. “The disease risk score signature, distinguishing viral from bacterial infections with only 2 transcripts, has potential to be translated into a clinically applicable test using current technology such as polymerase chain reaction. Furthermore, new methods for rapid detection of nucleic acids … have potential for low­ cost, rapid analysis of multitranscript signatures.”

“This study provides preliminary data regarding test accuracy of a 2-transcript host RNA signature discriminating bacterial from viral infection in febrile children. Further studies are needed in diverse groups of patients to assess accuracy and clinical utility of this test in different clinical settings.”

(doi:10.1001/jama.2016.11236; the study is available pre-embargo to the media at the For the Media website)

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

In another study, Octavio Ramilo, M.D., of Nationwide Children’s Hospital, Columbus, Ohio, and colleagues examined whether RNA biosignatures can distinguish febrile infants age 60 days or younger with and without serious bacterial infections.

Young febrile infants are at substantial risk of serious bacterial infections; however, the current culture-based diagnosis has limitations. The lack of an optimal management strategy has led to substantial variation in the care for this vulnerable population, unnecessarily exposing many infants to potential harm. A genomic approach based on analysis of the host response to infection has been investigated as an alternative. Microbial pathogens induce specific host responses or “RNA biosignatures” that can be identified using microarray analyses of blood leukocytes (white cells).

This study involved a sample of febrile infants 60 days or younger evaluated for fever in 22 emergency departments from December 2008 to December 2010 who underwent laboratory evaluations including blood cultures. A random sample of infants with and without bacterial infections was selected for RNA biosignature analysis. Afebrile healthy infants served as controls. Blood samples were collected for cultures and RNA biosignatures. Bioinformatics tools were applied to define RNA biosignatures to classify febrile infants by infection type.

Of 1,883 febrile infants (median age, 37 days), RNA biosignatures were measured in 279 randomly selected infants (89 with bacterial infections—including 32 with bacteremia and 15 with urinary tract infections—and 190 without bacterial infections), and 19 afebrile healthy infants. Sixty-six classifier genes were identified that distinguished infants with and without bacterial infections in the test set. Ten classifier genes distinguished infants with bacteremia from those without bacterial infections in the test set.

“In this preliminary study, RNA biosignatures were defined to distinguish febrile infants aged 60 days or younger with vs without bacterial infections. Further research with larger populations is needed to refine and validate the estimates of test accuracy and to assess the clinical utility of RNA biosignatures in practice,” the authors write.

“As technology advances, RNA biosignatures may prove to be an alternative and accurate method to identify infants with bacterial infections. This would help clinicians target evaluation and therapy when they are needed and avoid invasive procedures, antibiotics, and hospitalizations when they are not.”

(doi:10.1001/jama.2016.9207; the study is available pre-embargo to the media at the For the Media website)

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

Editorial: Genetics and the Evaluation of the Febrile Child

“The results of these 2 preliminary studies represent promissory notes. Clearly, RNA sequencing and other techniques for RNA quantitation are in the early days of development and evaluation for clinical applications,” writes Howard Bauchner, M.D., Editor in Chief, JAMA, Chicago, in an accompanying editorial.

“The substantial decline in the prevalence of serious bacterial infection, following the introduction of conjugate vaccines, has made clinical decision making more difficult—the needle has become much smaller, and the haystack much larger, particularly in young infants. However, if the promises of findings reported in the studies by Mahajan and colleagues and Herberg and colleagues are fulfilled by replication and refinement in other rigorous investigations, it may be possible that such advances will further reduce morbidity, mortality, and costs associated with caring for febrile children. The day when a parent of a febrile child may do a laboratory test at home, call a physician, and mutually decide if that child should be seen for evaluation may soon be here.”

(doi:10.1001/jama.2016.11137; the editorial is available pre-embargo to the media at the For the Media website)

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, AUGUST 23, 2016

Media Advisory: To contact Jason D. Wright, M.D., email Karin Eskenazi at ket2116@cumc.columbia.edu.

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In a study appearing in the August 23/30 issue of JAMA, Jason D. Wright, M.D., of the Columbia University College of Physicians and Surgeons, New York, and colleagues examined trends in the route of hysterectomy (abdominal, minimally invasive, or vaginal), use of electric power morcellators (a procedure in which the uterus is fragmented into smaller pieces, and may result in the spread of undetected malignancies), and prevalence of abnormal pathology before and after a Food and Drug Administration (FDA) warning.

Concern about the safety of electric power morcellation for gynecologic surgery led the FDA to issue a safety communication in April 2014 discouraging use of the devices and, in November 2014, to recommend against use of morcellation in perimenopausal and postmenopausal women. Concern has been raised that these actions may result in performance of a greater number of hysterectomies via laparotomy (surgical incision into the abdominal wall), with an increased risk of complications.

The study included women age 18 to 95 years who underwent hysterectomy from 2013 to the first quarter of 2015 recorded in the Perspective database, which includes more than 500 hospitals across the United States and approximately 15 percent of hospitalized patients. Outcomes were compared before and after the FDA’s alert in April 2014.

The researchers identified 203,520 women, including 117,653 women (58 percent) who underwent minimally invasive hysterectomy. Among women who underwent minimally invasive hysterectomy, power morcellation was used in 13.5 percent in Q1 2013, peaked at 13.7 percent by Q4 2013, and declined to 2.8 percent by Q1 2015. The overall complication rate was unchanged over time. Complications declined for abdominal hysterectomy, attributable to a decline in intraoperative complications, but were stable for minimally invasive hysterectomy and vaginal hysterectomy. The prevalence of uterine cancer, endometrial hyperplasia, other gynecologic cancers, and uterine tumors of indeterminate behavior in women who underwent morcellation were unchanged.

“The FDA warnings might result in a lower prevalence of cancer among women who underwent morcellation due to greater scrutiny on patient selection. However, the high rate of abnormal pathology after the warnings highlights the difficulty in the preoperative detection of uterine pathology. Continued caution is needed to limit the inadvertent morcellation of uterine pathology,” the authors write.

(doi:10.1001/jama.2016.9432; the study is available pre-embargo to the media at the For the Media website)

Editor’s Note: This article was funded by grants from the National Cancer Institute. 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, AUGUST 16, 2016

Media Advisory: To contact Paul D. Miller, M.D., call 303-925-4514 or email millerccbr@aol.com. To contact editorial co-author Anne R. Cappola, M.D., Sc.M., email Abbey Anderson at Abbey.Anderson@uphs.upenn.edu.

To place an electronic embedded link to this study and editorial in your story  These links will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11136  http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11032

Among postmenopausal women with osteoporosis at risk of fracture, daily injection of the drug abaloparatide for 18 months significantly reduced the risk of new vertebral and nonvertebral fractures compared with placebo, according to a study appearing in the August 16 issue of JAMA.

Osteoporosis is associated with substantial social, economic, and public health burdens. Based on 2010 U.S. Census data, a study estimated the prevalence of osteoporosis among women 50 to 69 years of age at 3.4 million. It has been estimated that the lifetime risk of osteoporotic fracture for a 60-year-old woman is 44 percent. Additional therapies are needed for prevention of osteoporotic fractures. As a result of its mechanism of action, it has been hypothesized that the drug abaloparatide, a synthetic peptide, would have a more pronounced anabolic (i.e., bone growing) action on bone compared with the osteoporosis drug teriparatide.

Paul D. Miller, M.D., of the Colorado Center for Bone Research, Lakewood, Colo., and colleagues randomly assigned postmenopausal women with osteoporosis to receive daily injections for 18 months of placebo (n = 821); abaloparatide (n = 824); or teriparatide (n = 818). The trial was conducted at 28 sites in 10 countries.

Among 2,463 women (average age, 69 years), 1,901 completed the study. New vertebral fractures occurred less frequently in the active treatment groups vs placebo: in 0.58 percent (n = 4) of participants in the abaloparatide group; in 0.84 percent (n = 6) of participants in the teriparatide group; and in 4.22 percent (n = 30) of those in the placebo group. The estimated event rate for nonvertebral fracture was lower with abaloparatide vs placebo: 2.7 percent in the abaloparatide group; 3.3 percent in the teriparatide group; and 4.7 percent in the placebo group.

Bone mineral density (BMD) increases were greater with abaloparatide than placebo. Incidence of hypercalcemia (the presence of abnormally high levels of calcium in the blood) was lower with abaloparatide (3.4 percent) vs teriparatide (6.4 percent). Overall, there were no differences in serious adverse events between the treatment groups.

“Further research is needed to understand the clinical importance of risk difference, the risks and benefits of abaloparatide treatment, and the efficacy of abaloparatide vs other osteoporosis treatments,” the authors write.

(doi:10.1001/jama.2016.11136; the study is available pre-embargo to the media at the For the Media website)

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

Editorial: Osteoporosis Therapy in Postmenopausal Women With High Risk of Fracture

“Ultimately, which therapy is selected for osteoporosis treatment may be less important than identifying and initiating an approved treatment,” write Anne R. Cappola, M.D., Sc.M., of the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and Associate Editor, JAMA, and Dolores M. Shoback, M.D., of the University of California, San Francisco, in an accompanying editorial.

“The bar is high for any preventive treatment—in the efforts to prevent a fracture that may or may not ever occur, prescribers do not want to prescribe a therapy that causes a new problem. The way forward for fracture prevention involves not only the development of better therapies to prevent fracture and easier delivery systems but also improved adoption of existing osteoporosis therapies for patients with prior fractures and minimization of adverse effects, particularly those associated with long-term use.”

(doi:10.1001/jama.2016.11032; the editorial is available pre-embargo to the media at the For the Media website)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 16, 2016

Media Advisory: To contact Imran S. Haque, Ph.D., call Andrew Padgett at 415-318-4301 or email Press@counsyl.com. To contact editorial author Wayne W. Grody, M.D., Ph.D., call Elaine Schmidt at 310- 267-8323 or email eschmidt@mednet.ucla.edu.

To place an electronic embedded link to this study and editorial in your story  These links will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.11139  http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.10888

In an analysis that included nearly 350,000 adults of diverse racial and ethnic background, expanded carrier screening for up to 94 severe or profound conditions may increase the detection of carrier status for a variety of potentially serious genetic conditions compared with current recommendations from professional societies, according to a study appearing in the August 16 issue of JAMA.

Genetic testing of prospective parents to detect carriers of specific inherited recessive diseases is part of routine obstetrical practice. Current recommendations by professional organizations are to test for a limited number of individual diseases in part based on self-reported racial/ethnic background. Advances in genetic testing now allow for rapid expanded carrier screening for a large number of conditions. These advances could facilitate screening for an expanded number of conditions independent of racial/ethnic background.

Imran S. Haque, Ph.D., of Counsyl, South San Francisco, and colleagues analyzed results from expanded carrier screening in reproductive-aged individuals without known indication for specific genetic testing, primarily from the United States. Tests were offered by clinicians providing reproductive care. Individuals were tested for carrier status for up to 94 conditions. Risk was defined as the probability that a hypothetical fetus created from a random pairing of individuals (within or across 15 self-reported racial/ethnic categories) would be homozygous (possessing two identical forms of a particular gene, one inherited from each parent) or compound heterozygous (the presence of two different mutant alleles at a particular gene locus) for 2 mutations presumed to cause severe or profound disease. Severe conditions were defined as those that if left untreated cause intellectual disability or a substantially shortened lifespan; profound conditions were those causing both.

The study included 346,790 individuals. Among major U.S. racial/ethnic categories, the calculated frequency of fetuses potentially affected by a profound or severe condition ranged from 95 per 100,000 for Hispanic couples to 392 per 100,000 for Ashkenazi Jewish couples. In most racial/ethnic categories, expanded carrier screening modeled more hypothetical fetuses at risk for severe or profound conditions than did screening based on current professional guidelines. For Northern European couples, the 2 professional guidelines-based screening panels (American College of Medical Genetics and Genomics [ACMG], the American Congress of Obstetricians and Gynecologists [ACOG]), modeled 55 hypothetical fetuses affected per 100,000 and the expanded carrier screening modeled 159 fetuses per 100,000.

Overall, relative to expanded carrier screening, guideline-based screening ranged from identification of 6 percent of hypothetical fetuses affected for East Asian couples to 87 percent for African or African American couples.

“The findings showed that an expanded testing panel identified more hypothetical fetuses at risk for severe or profound phenotypes than did testing based on current screening guidelines. This was not only because expanded carrier screening included additional disorders but also because guideline-based testing was based in part on self-identified racial/ethnic categories. The data further suggested that the guidelines recommended by the ACOG and the ACMG at the time of the study did not perform equally between racial/ethnic categories, resulting in differing residual risk among different racial/ethnic categories,” the authors write.

“Even though current guidelines target a number of diseases prevalent in those of European descent (such as cystic fibrosis), they do not identify risk for other conditions that may be important to diverse populations. Expanded carrier screening revealed that many non-European racial/ethnic categories have a risk of a profound or severe genetic disease that may not be detected by the guidelines in place at the time of this analysis.”

The researchers write that “before assertions regarding the clinical utility of broadly testing for these variants can be made with certainty, additional data are needed from unselected diverse populations on the phenotypic spectrum and for the health consequences of pathogenic variants associated with rare conditions.”

(doi:10.1001/jama.2016.11139; the study is available pre-embargo to the media at the For the Media website)

Editor’s Note: This study was funded by Counsyl, a laboratory providing expanded carrier screening. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Where to Draw the Boundaries for Prenatal Carrier Screening

“The study by Haque and colleagues is an important contribution in the evolving field of prenatal testing. It provides a wealth of data on the frequency of genetic variants that can be detected in individuals of childbearing age from a diversity of racial/ethnic backgrounds,” writes Wayne W. Grody, M.D., Ph.D., of the UCLA Medical Center, Los Angeles, in an accompanying editorial.

“The large number of silent but potentially damaging sequence variants in every human genome went unnoticed until the last few years when high-throughput DNA sequencing technology became widely available. However, just because these variants can now be detected, there needs to be convincing evidence before they all are tested for and possibly acted upon. Pregnant couples have many other concerns (genetic, obstetric, and psychosocial) of substantially higher and more certain risk to occupy their attention.”

(doi:10.1001/jama.2016.10888; the editorial is available pre-embargo to the media at the For the Media website)

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, AUGUST 16, 2016

Media Advisory: To contact Kirsten Bibbins-Domingo, Ph.D., M.D., M.A.S., email Scott Maier at Scott.Maier@ucsf.edu.

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Although the recently FDA approved cholesterol-lowering drugs, PCSK9 inhibitors, could substantially reduce heart attacks, strokes, and cardiovascular deaths, they would not be cost-effective for use in patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease, with annual drug prices needing to be reduced by more than two-thirds to meet a generally acceptable threshold for cost-effectiveness, according to a study appearing in the August 16 issue of JAMA.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were approved by the U.S. Food and Drug Administration (FDA) for use in patients with heterozygous familial hypercholesterolemia (FH; a disorder caused primarily by mutations in the low-density lipoprotein [LDL] receptor gene that causes severe elevations in levels of LDL-cholesterol [C], resulting in early atherosclerotic lesions) or pre-existing atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of LDL-C despite maximally tolerated doses of statins. If clinical benefits seen in short-term trials are sustained in the longer term, PCSK9 inhibitors could become an important option for patients at high risk of ASCVD, potentially lowering health care costs through preventing ASCVD events. However, with an average U.S. price in 2015 of more than $14,000 per patient per year, their cost-effectiveness and effect on national health care spending are uncertain.

Kirsten Bibbins-Domingo, Ph.D., M.D., M.A.S., of the University of California, San Francisco, and colleagues used the Cardiovascular Disease Policy Model, an established simulation model of ASCVD in the U.S. population, to evaluate cost-effectiveness of PCSK9 inhibitors or the cholesterol drug ezetimibe in heterozygous FH or ASCVD. The model incorporated 2015 annual PCSK9 inhibitor costs of $14,350 (based on average wholesale acquisition costs of evolocumab and alirocumab).

Adding PCSK9 inhibitors to statins in heterozygous FH was estimated to prevent 316,300 major adverse cardiovascular events (MACE; cardiovascular death, nonfatal heart attack, or stroke) at a cost of $503,000 per quality-adjusted life-year (QALY) gained compared with adding ezetimibe to statins. In ASCVD, adding PCSK9 inhibitors to statins was estimated to prevent 4.3 million MACE compared with adding ezetimibe at $414,000 per QALY. Reducing annual drug costs to $4,536 per patient or less would be needed for PCSK9 inhibitors to be cost-effective at less than $100,000 per QALY.

At 2015 prices, PCSK9 inhibitor use in all eligible patients was estimated to reduce cardiovascular care costs by $29 billion over 5 years, but drug costs increased by an estimated $592 billion (a 38 percent increase over 2015 prescription drug expenditures), and was estimated to increase annual U.S. health care expenditures by about $120 billion (a 4 percent increase from the $2.8 trillion dollars in total U.S. health care spending in 2015).

The authors write that the high cost of PCSK9 inhibitors is uniquely challenging. “This is because PCSK9 inhibitors are meant to be lifelong therapy not only for the relatively small number of patients with FH but also for a large and growing population with ASCVD. As a result, the potential increase in health care expenditures at current or even moderately discounted prices could be staggering, despite cost savings from averted ASCVD events.”

“In the face of limited health care resources, payers must consider the potential trade-off between paying for new drug treatments like PCSK9 inhibitors and investing in interventions known to improve access, physician prescription rates, and patient adherence to statin therapy among those at high ASCVD risk.”

(doi:10.1001/jama.2016.11004; the study is available pre-embargo to the media at the For the Media website)

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, AUGUST 16, 2016

Media Advisory: To contact Susan L. Mitchell, M.D., M.P.H., call Courtney Howe at 617-363-8267 or email CourtneyHowe@hsl.harvard.edu.

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In a study appearing in the August 16 issue of JAMA, Susan L. Mitchell, M.D., M.P.H., of Hebrew SeniorLife Institute for Aging Research, Harvard Medical School, Boston, and colleagues examined feeding tube insertion rates from 2000-2014 among U.S. nursing home residents with advanced dementia.

Over the last 2 decades, research has failed to demonstrate benefits of tube feeding in patients with advanced dementia. Expert opinion and position statements by national organizations increasingly advocate against this practice. For this study, data were derived from federally mandated Minimum Data Set assessments completed quarterly, as required, on all residents in U.S. nursing homes between January 1, 2000, and October 31, 2015. Residents who met certain study criteria were included in the analysis.

Between 2000 and 2014, 71,251 residents with advanced dementia and recent dependence for eating were identified with the following characteristics: average age, 84 years; women, 76 percent; white, 86 percent; black, 9.5 percent; and prior stroke, 14 percent. These characteristics were similar across years. The proportion of residents receiving feeding tubes over the next 12 months declined from 12 percent in 2000 to 6 percent in 2014. Insertion rates declined between 2000 and 2014 among white residents (8.6 percent to 3.1 percent) and black residents (38 percent to 18 percent). However, black residents were more likely to get tube fed in 2000 and 2014 than white residents.

“The proportion of U.S. nursing home residents with advanced dementia and eating dependency receiving feeding tubes decreased by approximately 50 percent between 2000 and 2014,” the authors write. “Feeding tube use decreased across racial groups, but remained relatively higher among black residents, consistent with prior research.”

“To ensure the message from existing evidence and expert recommendations is disseminated and disparities are reduced, fiscal and regulatory policies are needed that discourage tube feeding and promote a palliative approach to feeding problems in patients with advanced dementia.”

(doi:10.1001/jama.2016.9374; the study is available pre-embargo to the media at the For the Media website)

Editor’s Note: This work was supported by grants from the National Institutes of Health. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 9, 2016

Media Advisory: To contact the U.S. Preventive Services Task Force, email the Media Coordinator at Newsroom@USPSTF.net or call 202-572-2044.

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The U.S. Preventive Services Task Force (USPSTF) has concluded that the current evidence is insufficient to assess the balance of benefits and harms of screening for lipid disorders in children and adolescents 20 years or younger. The report appears in the August 9 issue of JAMA.

This is an I statement, indicating that the evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined.

Elevations in levels of total, low-density lipoprotein (LDL), and non-high-density lipoprotein cholesterol (non-HDL-C); lower levels of high-density lipoprotein cholesterol; and, to a lesser extent, elevated triglyceride levels are associated with risk of cardiovascular disease in adults. Recent estimates from the National Health and Nutrition Examination Survey (NHANES) indicate that 7.8 percent of children age 8 to 17 years have elevated levels of total cholesterol (TC) and 7.4 percent of adolescents age 12 to 19 years have elevated LDL-C. The rationale for screening for lipid disorders in children and adolescents is that early identification and treatment of elevated levels of LDL-C could delay the atherosclerotic process and thereby reduce the incidence of premature ischemic cardiovascular events in adults.

To update its 2007 recommendation, the USPSTF reviewed the evidence on screening for lipid disorders in children and adolescents 20 years or younger—1 review focused on screening for heterozygous familial hypercholesterolemia (a disorder caused primarily by mutations in the LDL receptor gene that causes severe elevations in levels of LDL-C, resulting in early atherosclerotic lesions), and 1 review focused on screening for multifactorial dyslipidemia (defined by elevated levels of LDL-C or TC that are not attributable to familial hypercholesterolemia).

The USPSTF is an independent, volunteer panel of experts that makes recommendations about the effectiveness of specific preventive care services such as screenings, counseling services, and preventive medications.

Detection

The USPSTF found inadequate evidence on the quantitative difference in diagnostic yield between universal and selective screening for familial hypercholesterolemia or multifactorial dyslipidemia.

Benefits of Early Detection and Treatment

The USPSTF found inadequate direct evidence on the benefits of screening for familial hypercholesterolemia or multifactorial dyslipidemia.

— Familial Hypercholesterolemia: The USPSTF found adequate evidence from short-term trials (2 years or less) that pharmacotherapy interventions result in substantial reductions in levels of LDL-C and TC in children with familial hypercholesterolemia. The USPSTF found inadequate evidence to address whether treatment with short-term pharmacotherapy leads directly to a reduced incidence of premature cardiovascular disease (e.g., heart attack or stroke). The USPSTF found inadequate evidence on the association between changes in intermediate lipid outcomes or noninvasive measures of atherosclerosis in children and adolescents and incidence of or mortality from relevant adult health outcomes.

— Multifactorial Dyslipidemia: The USPSTF found inadequate evidence on the benefits of lifestyle modification or pharmacotherapy interventions in children and adolescents with multifactorial dyslipidemia to improve intermediate lipid outcomes or atherosclerosis markers or to reduce incidence of premature cardiovascular disease.

Harms of Early Detection and Treatment

The USPSTF found inadequate evidence to assess the harms of screening for familial hypercholesterolemia or multifactorial dyslipidemia. The USPSTF found inadequate evidence to assess the long-term harms of treatment of familial hypercholesterolemia in children or adolescents. Long-term evidence on the treatment of familial hypercholesterolemia was limited to 1 study of statins. Short-term statin use was generally well tolerated in children and adolescents with familial hypercholesterolemia, with transient adverse effects (such as elevated liver enzyme levels). The USPSTF also found inadequate evidence to assess the harms of treatment of multifactorial dyslipidemia in children or adolescents.

Summary

Evidence on the quantitative difference in diagnostic yield between universal and selective screening approaches, the effectiveness and harms of long-term treatment and the harms of screening, and the association between changes in intermediate outcomes and improvements in adult cardiovascular health outcomes are limited. Therefore, the USPSTF concludes that the balance of benefits and harms cannot be determined.

(doi:10.1001/jama.2016.9852; the full report is available pre-embargo to the media at the For the Media website)

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

Note: More information about the U.S. Preventive Services Task Force, its process, and its recommendations can be found on the newsroom page of its website.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 9, 2016

Media Advisory: To contact Axel Linke, M.D., email Axel.Linke@medizin.uni-leipzig.de. To contact editorial co-author Steven R. Messe, M.D., email Lee-Ann Donegan at Leeann.Donegan@uphs.upenn.edu.

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Among patients with severe aortic stenosis (narrowing of the aortic valve) undergoing transcatheter aortic valve implantation, the use of a cerebral protection device (a filter that captures debris [tissue and plaque] dislodged during the procedure) reduced the number and volume of brain lesions, according to a study appearing in the August 9 issue of JAMA.

Although the clinical outcomes of transcatheter aortic valve implantation (TAVI; replacement of the aortic valve, delivered via a blood vessel with a catheter) have improved considerably during the last decade, stroke, which is associated with a 3-fold increase in mortality following TAVI, remains an important concern. Adding to this concern is the observation that ischemic lesions are found in as many as 80 percent of TAVI patients. Numerous devices have been developed to protect the brain from injury caused by embolic debris during TAVI, although clear evidence of the efficacy of any embolic protection device in TAVI is still missing.

Axel Linke, M.D., of the University of Leipzig, Germany, and colleagues randomly assigned 100 higher-risk patients with severe aortic stenosis to undergo TAVI with a cerebral protection device (n = 50; filter group) or without a cerebral protection device (n = 50; control group). Brain magnetic resonance imaging (MRI) was performed at study entry, 2 days, and 7 days after TAVI.

The researchers found that the number of new brain lesions 2 days after TAVI was lower in the filter group (4) than in the control group (10). New lesion volume after TAVI was lower in the filter group (242 mm³) vs in the control group (527 mm³).

Regarding adverse events, 1 patient in the control group died prior to the 30-day visit. Life-threatening hemorrhages occurred in 1 patient in the filter group and 1 in the control group. Major vascular complications occurred in 5 patients in the filter group and 6 patients in the control group. One patient in the filter group and 5 in the control group had acute kidney injury, and 3 patients in the filter group had a thoracotomy (surgical incision into the chest wall).

“Larger studies are needed to assess the effect of cerebral protection device use on neurological and cognitive function after TAVI and to devise methods that will provide more complete coverage of the brain to prevent new lesions,” the authors write.

(doi:10.1001/jama.2016.10302; the study is available pre-embargo to the media at the For the Media website)

Editor’s Note: The Leipzig Heart Center received a grant from Claret Medical and Medtronic. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Improving Outcomes From Transcatheter Aortic Valve Implantation

The results from this trial demonstrates 2 important points, write Steven R. Messe, M.D., of the University of Pennsylvania, Philadelphia, and Michael J. Mack, M.D., of the Heart Hospital Baylor Plano, Plano, Texas, in an accompanying editorial.

“First, as other studies have noted, emboli to the brain that cause infarction detected on MRI are very common with TAVI. In this trial, acute lesions on MRI were present in virtually all patients enrolled, although the vast majority of these lesions were quite small. Second, use of an embolic protection device can successfully reduce cerebral infarct number and volume. Whether that reduction translates to a meaningful improvement in clinical outcomes will require more study, but the findings represent a compelling and encouraging start.”

(doi:10.1001/jama.2016.10316; the editorial is available pre-embargo to the media at the For the Media website)

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, AUGUST 9, 2016

Media Advisory: To contact Ian H. de Boer, M.D., M.S., call Bobbi Nodell at 206-543-7129 or email bnodell@uw.edu.

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Among U.S. adults with diabetes from 1988 to 2014, the overall prevalence of diabetic kidney disease did not change significantly, while the prevalence of albuminuria declined and the prevalence of reduced estimated glomerular filtration rate increased, according to a study appearing in the August 9 issue of JAMA.

Diabetes mellitus is the most common cause of chronic kidney disease in the world, leading to multiple complications including end-stage renal disease, cardiovascular disease, infection, and death. Chronic kidney disease in the setting of diabetes or diabetic kidney disease (DKD), manifests clinically as albuminuria (the presence of excessive protein in the urine), reduced glomerular filtration rate (GFR; a measure of kidney function), or both. Changes in demographics and treatments may affect the prevalence and clinical manifestations of diabetic kidney disease.

Ian H. de Boer, M.D., M.S., of the University of Washington, Seattle, and colleagues analyzed data of 6,251 adults with diabetes mellitus participating in National Health and Nutrition Examination Surveys from 1988 through 2014.

The researchers found that the prevalence of any diabetic kidney disease, defined as persistent albuminuria, persistent reduced estimated (e) GFR, or both, did not significantly change over time from 28 percent in 1988-1994 to 26 percent in 2009-2014. However, the prevalence of albuminuria decreased progressively over time from 21 percent in 1988-1994 to 16 percent in 2009-2014. In contrast, the prevalence of reduced eGFR increased from 9 percent in 1988-1994 to 14 percent in 2009-2014, with a similar pattern for severely reduced eGFR.

Significant heterogeneity in the trend for albuminuria was noted by age and race/ethnicity, with a decreasing prevalence of albuminuria observed only among adults younger than 65 years and non-Hispanic whites, whereas the prevalence of reduced GFR increased without significant differences by age or race/ethnicity. In 2009-2014, approximately 8.2 million adults with diabetes had albuminuria, reduced eGFR, or both.

The authors write that the lower prevalence of albuminuria observed over time may be attributable to a higher rate of prescribed diabetes therapies (glucose-lowering medications, renin-angiotensin-aldosterone system [RAAS] inhibitors, and statins). And that while reasons for the increasing prevalence of reduced eGFR cannot be conclusively discerned from these data, it is possible that hemodynamic effects of RAAS inhibitors and improved blood pressure control could contribute to lower eGFR. Alternatively, an increasing duration of diabetes may be contributing to kidney damage.

(doi:10.1001/jama.2016.10924; the study is available pre-embargo to the media at the For the Media website)

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, AUGUST 9, 2016

Media Advisory: To contact Eric D. Peterson, M.D., M.P.H., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.9356

In a study appearing in the August 9 issue of JAMA, Sean D. Pokorney, M.D., M.B.A., Eric D. Peterson, M.D., M.P.H., of Duke University Medical Center, Durham, N.C., and colleagues examined whether patients receiving warfarin who have stable international normalized ratio (INR) values remain stable over time.

Warfarin substantially decreases stroke risk among patients with atrial fibrillation yet has a narrow therapeutic window (INR values of 2.0-3.0) and is associated with multiple drug and food interactions. Non-vitamin K oral anticoagulants do not require drug monitoring and have similar or improved safety and efficacy relative to warfarin but are more costly. Whether patients previously stable on warfarin should be switched to non-vitamin K oral anticoagulants remains controversial.

Data for this study were obtained from a prospective registry of patients with atrial fibrillation from 176 clinics who were enrolled June 2010 through August 2011 and followed up for 3 years through November 2014. Patients receiving warfarin at study entry with 3 or more INR values in the first 6 months and 6 or more in the subsequent year were included. Stability was defined as 80 percent or more INRs in therapeutic range (2.0-3.0).

Of 10,132 registry patients, 6,383 were not taking warfarin or had insufficient INR values and were excluded. Among 3,749 patients taking warfarin (average age, 75 years), 968 (26 percent) had 80 percent or more of INR values in 2.0-3.0 range during the first 6 months. Of patients with stable INRs during the first 6 months, 34 percent remained stable over the subsequent year. Stability during the baseline period had limited predictive ability of stability over the subsequent year. Among patients with 80 percent or more INRs in range at baseline, 36 percent had 1 or more well-out-of-range INR in the following year, demonstrating limited predictive ability of stability on well-out-of-range INRs.

“A common belief has been that patients with stable INRs while taking warfarin would continue to be stable and derive less benefit from switching to non-vitamin K oral anticoagulants. This analysis suggests warfarin stability is difficult to predict and challenges the notion that patients who have done well taking warfarin should maintain taking warfarin,” the authors write.

(doi:10.1001/jama.2016.9356; the study is available pre-embargo to the media at the For the Media website)

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, AUGUST 2, 2016

Media Advisory: To contact Daniel J. Cantillon, M.D., call Andrea Pacetti at 216-444-8168 or email Pacetta@ccf.org.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.10258

Among non-critically ill patients, use of standardized cardiac telemetry with an off-site central monitoring unit was associated with detection and notification of cardiac rhythm and rate changes within 1 hour prior to the majority of emergency response team activations, and also with a reduction in the number of monitored patients, without an increase in cardiopulmonary arrest events, according to a study appearing in the August 2 issue of JAMA.

In studies involving traditional on-site monitoring for non-intensive care unit patients, more than 90 percent of alarms were without immediate clinical relevance and contributed to clinical desensitization referred to as alarm fatigue. It is unknown if dedicated monitoring personnel at an off-site, central monitoring unit (CMU) can provide effective detection and notification to clinical nursing personnel and also integrate with the dedicated emergency response teams in a large multihospital system. Off-site monitoring can minimize noise distraction from hospital activity, centralize staffing, and allow standardized practices.

Daniel J. Cantillon, M.D., of the Cleveland Clinic, and colleagues evaluated the clinical outcomes associated with an off-site CMU applying standardized cardiac telemetry. A dedicated off-site facility provided continuous cardiac rhythm monitoring for non-intensive care unit (ICU) patients at the Cleveland Clinic and 3 regional hospitals over 13 months. In this model, 1 monitoring technician provides continuous cardiac monitoring for up to 48 patients and also provides blood pressure, pulse oximetry, and respiratory rate notifications on request. Lead technicians provide on-site oversight and supervision for real-time rhythm interpretation and management requiring clinical attention to charge nursing personnel.

The CMU received electronic telemetry orders for 99,048 patients and provided 410,534 notifications (48 percent arrhythmia/hemodynamic [blood pressure]) among 61 nursing units. Emergency response team (ERT) activation occurred among 3,243 patients, including 979 patients (30 percent) with rhythm/rate changes occurring 1 hour or less prior to the ERT activation. The CMU detected and provided accurate notification for 772 (79 percent) of those events. In addition, the CMU provided discretionary direct ERT notification of the impending worsening of the condition of 105 patients to elicit urgent clinical intervention, including advance warning of 27 cardiopulmonary arrest events (26 percent) for which return of circulation was achieved in 25 patients (93 percent). Telemetry standardization was associated with an average 15.5 percent weekly census reduction in the number of non-ICU monitored patients per week when compared with the prior 13-month period. The number of cardiopulmonary arrests was 126 in the 13 months preintervention and 122 postintervention.

“Normal hospital activities occurring at the nursing station might potentially distract on-site personnel from continuous vigilant patient monitoring, in addition to the possibility of vigilance being divided by other on-site duties. Off-site monitoring allows dedicated personnel to provide patient monitoring removed from the hospital wards with centralized staffing and standardized practices. A CMU also allows oversight and supervision by lead technicians (i.e., somebody to watch those who are watching) to try to ensure continuous monitoring and mitigate lapses,” the authors write.

“These data demonstrate that integrating a CMU and an ERT team is feasible, which is particularly important for hospital systems with dedicated emergency response teams in which operational and capital costs permit scalability. Once the required resources are in place, the CMU can extend its operability to hospitals that are widely geographically separated while interfacing directly with site-specific ERTs. Future work and technological innovation are needed to further improve efficiency and reduce costs.”

(doi:10.1001/jama.2016.10258; the study is available pre-embargo at the For the Media website)

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

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 2, 2016

Media Advisory: To contact Kenneth B. Margulies, M.D., call Abbey Anderson at 215-349-8369 or email abbey.anderson@uphs.upenn.edu.

To place an electronic embedded link to this study in your story  This link will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.10260

Among patients recently hospitalized with heart failure and reduced left ventricular ejection fraction (LVEF; a measure of heart function), the use of the drug liraglutide did not lead to greater post-hospitalization clinical stability, according to a study appearing in the August 2 issue of JAMA.

Heart failure is the leading cause of hospitalization in the United States with more than 4 million admissions per year from 2003-2009. Abnormal cardiac metabolism contributes to the pathophysiology of advanced heart failure with reduced LVEF. A class of drugs, glucagon-like peptide 1 (GLP-1) agonists have shown cardioprotective effects in early clinical studies of patients with advanced heart failure.

Kenneth B. Margulies, M.D., of the University of Pennsylvania, Philadelphia, and colleagues randomly assigned patients with established heart failure and reduced LVEF who were recently hospitalized to the GLP-1 agonist liraglutide (n = 154) or placebo (n = 146) via a daily subcutaneous injection; study drug was advanced to a dosage of 1.8 mg/d during the first 30 days as tolerated and continued for 180 days. The primary outcome for the study was a score in which all patients, regardless of treatment assignment, were ranked across 3 hierarchical tiers: time to death, time to rehospitalization for heart failure, and time-averaged proportional change in N-terminal pro-B-type natriuretic peptide level from study entry to 180 days. Higher values indicate better health (stability).

Among the 300 patients who were randomized, 271 completed the study. Compared with placebo, liraglutide had no significant effect on the primary end point. There were no significant between-group differences in the number of deaths (12 percent in the liraglutide group vs 11 percent in the placebo group) or rehospitalizations for heart failure (41 percent vs 34 percent) or for the exploratory secondary  end points (primary end point components, cardiac structure and function, 6-minute walk distance, quality of life, and combined events). Prespecified subgroup analyses in patients with diabetes did not reveal any significant between-group differences.

“The GLP-1 agonist liraglutide did not improve posthospitalization clinical stability in patients with advanced heart failure and reduced LVEF despite prior studies indicating that GLP-1 therapy might ameliorate mechanisms of myocardial insulin resistance reported in patients with severe cardiomyopathies,” the authors write.

“These findings do not support the use of liraglutide in this clinical situation.”

(doi:10.1001/jama.2016.10260; the study is available pre-embargo at the For the Media website)

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, AUGUST 2, 2016

Media Advisory: To contact co-author Stephen J. Brett, M.D., email stephen.brett@imperial.ac.uk.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.10485

Early use of vasopressin to treat septic shock did not improve the number of kidney failure-free days compared with norepinephrine, according to a study appearing in the August 2 issue of JAMA.

In 2015, it was estimated that there were more than 230,000 cases of septic shock, with more than 40,000 deaths in the United States each year. Norepinephrine is currently recommended as the first-line vasopressor (an agent that produces vasoconstriction and a rise in blood pressure) in septic shock; however, early vasopressin use has been proposed as an alternative.

Anthony C. Gordon, M.D., of Imperial College London, and colleagues randomly assigned patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock to vasopressin and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103). The primary outcome was kidney failure-free days during the 28-day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both. The trial was conducted at 18 intensive care units in the U.K.

A total of 409 patients (median age, 66 years) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57 percent) in the vasopressin group and 93 of 157 patients (59 percent) in the norepinephrine group. The median number of kidney failure-free days for patients who did not survive, who experienced kidney failure, or both was 9 days in the vasopressin group and 13 days in the norepinephrine group.

There was less use of renal replacement therapy in the vasopressin group than in the norepinephrine group. There was no significant difference in mortality rates between groups. In total, 11 percent of patients had a serious adverse event in the vasopressin group vs 8 percent in the norepinephrine group.

“Among adults with septic shock, the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure-free days. Although these findings do not support the use of vasopressin to replace norepinephrine as initial treatment in this situation, the confidence interval included a potential clinically important benefit for vasopressin, and larger trials may be warranted to assess this further,” the authors write.

(doi:10.1001/jama.2016.10485; the study is available pre-embargo at the For the Media website)

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, AUGUST 2, 2016

Media Advisory: To contact David M. Levine, M.D., M.A., call Lori Schroth at 617-525-6374 or email Ljschroth@partners.org.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.9124

In a study appearing in the August 2 issue of JAMA, David M. Levine, M.D., M.A., of Brigham and Women’s Hospital, Boston, and colleagues examined trends in seniors’ use of digital health technology in the U.S. from 2011-2014.

The sickest, most expensive, and fastest growing segment of the U.S. population are seniors 65 years and older. Digital health technology has been advocated as a solution to improve health care quality, cost, and safety. However, little is known about digital health use among seniors. For this study, the researchers analyzed results from the National Health and Aging Trends Study (NHATS), a nationally representative survey of community-dwelling Medicare beneficiaries 65 years and older. Each year, NHATS asks the same respondents about every day (nonhealth) technology use and 4 digital health modalities: use of the internet to fill prescriptions, contact a clinician, address insurance matters, and research health conditions. This study included participants in 2011 who were followed yearly until 2014.

In 2011, the average age of the 7,609 participants was 75 years; 57 percent were women. Although 76 percent of seniors used cell phones and 64 percent computers, fewer used internet (43 percent) and email and texting (40 percent). Less than 20 percent used internet banking, internet shopping, social network sites (2013 data), and tablets (2013 data). Fewer seniors used digital health technology: 16 percent obtained health information, 8 percent filled prescriptions, 7 percent contacted clinicians, and 5 percent handled insurance online. In 2011, variables associated with less use of any digital health were older age; black, Latino, and other race/ethnicity; divorce; and poor health. By 2014, although cell phone and computer use were stable, small statistically significant increases were noted in other every day technologies. Use of 3 of 4 digital health technologies increased. The proportion of seniors who used any digital health increased from 21 percent in 2011 to 25 percent in 2014.

“Digital health is not reaching most seniors and is associated with socioeconomic disparities, raising concern about its ability to improve quality, cost, and safety of their health care. Future innovations should focus on usability, adherence, and scalability to improve the reach and effectiveness of digital health for seniors,” the authors write.

(doi:10.1001/jama.2016.9124; the study is available pre-embargo at the For the Media website)

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, JULY 26, 2016

Media Advisory: To contact the U.S. Preventive Services Task Force, email the Media Coordinator at Newsroom@USPSTF.net or call 202-572-2044.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.8465

The U.S. Preventive Services Task Force (USPSTF) has concluded that the current evidence is insufficient to assess the balance of benefits and harms of visual skin examination by a clinician to screen for skin cancer in asymptomatic adults. The report appears in the July 26 issue of JAMA.

This is an I statement, indicating that that the current evidence is insufficient to assess the balance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined.

Basal and squamous cell carcinoma are the most common types of cancer in the United States and represent the vast majority of all cases of skin cancer; however, they rarely result in death or substantial morbidity, whereas melanoma skin cancer has notably higher mortality rates. In 2016, an estimated 76,400 U.S. men and women will develop melanoma and 10,100 will die from the disease. To update its 2009 recommendation, the USPSTF reviewed the evidence on the effectiveness of screening for skin cancer with a clinical visual skin examination in reducing skin cancer morbidity and mortality and death from any cause; its potential harms, including any harms resulting from associated diagnostic follow-up; its test characteristics when performed by a primary care clinician vs a dermatologist; and whether its use leads to earlier detection of skin cancer compared with usual care.

The USPSTF is an independent, volunteer panel of experts that makes recommendations about the effectiveness of specific preventive care services such as screenings, counseling services, and preventive medications.

Detection

Evidence is adequate that visual skin examination by a clinician has modest sensitivity and specificity for detecting melanoma. Evidence is more limited and inconsistent regarding the accuracy of the clinical visual skin examination for detecting nonmelanoma skin cancer.

Benefits of Early Detection and Treatment

Evidence is inadequate to reliably conclude that early detection of skin cancer through visual skin examination by a clinician reduces morbidity or mortality.

Harms of Early Detection and Treatment

Evidence is adequate that visual skin examination by a clinician to screen for skin cancer leads to harms that are at least small, but current data are insufficient to precisely bound the upper magnitude of these harms. Potential harms of skin cancer screening include misdiagnosis, overdiagnosis, and the resulting cosmetic and—more rarely— functional adverse effects resulting from biopsy and overtreatment.

Summary

Evidence to assess the net benefit of screening for skin cancer with a clinical visual skin examination is limited. Direct evidence on the effectiveness of screening in reducing melanoma morbidity and mortality is limited to a single fair-quality ecologic study with important methodological limitations. Information on harms is similarly sparse. The potential for harm clearly exists, including a high rate of unnecessary biopsies, possibly resulting in cosmetic or, more rarely, functional adverse effects, and the risk of overdiagnosis and overtreatment.

(doi:10.1001/jama.2016.8465; the full report is available pre-embargo to the media at the For the Media website)

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

Note: More information about the U.S. Preventive Services Task Force, its process, and its recommendations can be found on the newsroom page of its website.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JULY 26, 2016

Media Advisory: To contact Paul D. Brown, M.D., email Joe Dangor at dangor.yusuf@mayo.edu. To contact editorial co-author Carey K. Anders, M.D., email Laura Oleniacz at laura_oleniacz@med.unc.edu.

To place an electronic embedded link to this study and editorial in your story  These links will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.9839  http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.8692

Among patients with 1 to 3 brain metastases, the use of stereotactic radiosurgery (SRS) alone, compared with SRS combined with whole brain radiotherapy, resulted in less cognitive deterioration at 3 months, according to a study appearing in the July 26 issue of JAMA.

Approximately 30 percent of patients with cancer develop brain metastases, and the incidence of these lesions is rising. Most patients present with limited intracranial metastases, usually defined as 1 to 3 lesions. Stereotactic radiosurgery is an effective and commonly used treatment for brain metastases, but intracranial tumor progression is frequent after SRS alone, primarily because of the development of new metastatic lesions. Whole brain radiotherapy (WBRT) significantly improves tumor control in the brain after SRS, yet because of its association with cognitive decline, its role in the treatment of patients with brain metastases remains controversial.

Paul D. Brown, M.D., of Mayo Clinic, Rochester, Minn., and colleagues conducted a study in which 213 patients with 1 to 3 brain metastases were randomly assigned to receive SRS alone (n = 111) or SRS plus WBRT (n = 102). The study was conducted at 34 institutions in North America; average patient age was 61 years. The primary outcome measured for the study was cognitive deterioration among patients who completed assessments at study entry and 3 months. Other measured outcomes included quality of life, functional independence, long-term cognitive status, and overall survival.

The researchers found that there was less cognitive deterioration at 3 months after SRS alone (40/63 patients [64 percent]) than when combined with WBRT (44/48 patients [92 percent]. Quality of life was higher at 3 months with SRS alone, including overall quality of life. There was no significant difference in functional independence at 3 months between the treatment groups. Median overall survival was 10.4 months for SRS alone and 7.4 months for SRS plus WBRT. For long-term survivors, the incidence of cognitive deterioration was less after SRS alone at 3 months and at 12 months.

“In the absence of a difference in overall survival, these findings suggest that for patients with 1 to 3 brain metastases amenable to radiosurgery, SRS alone may be a preferred strategy,” the authors write.

(doi:10.1001/jama.2016.9839; the study is available pre-embargo at the For the Media website)

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

Editorial: Whole Brain Radiotherapy for Brain Metastases

“The debate between WBRT and SRS has been resolved for the specific type of patient (with 1-3 metastases) who enrolled in the current study, and there is little role for WBRT for these patients,” write Carey K. Anders, M.D., of the University of North Carolina at Chapel Hill, and colleagues in an accompanying editorial.

“However, both treatment modes have a valid position in clinical practice because many patients do not precisely fit the characteristics for study entry. Thus, based on the robust findings from the current study and until proven otherwise, WBRT may still have an important role for treatment of patients who are not in this specific disease category (i.e., 1-3 brain metastases). However, the study results cannot be extrapolated to infer that SRS is the standard for patients with 4 or more metastases or that WBRT no longer has a role in the treatment of brain metastases.”

(doi:10.1001/jama.2016.8692; the study is available pre-embargo at the For the Media website)

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, JULY 26, 2016

Media Advisory: To contact Jennifer L. Richards, M.P.H., email Melva Robertson at melva.robertson@emory.edu. To contact editorial author Catherine Y. Spong, M.D., email Robert Bock at nichdpress@mail.nih.gov.

To place an electronic embedded link to this study and editorial in your story  These links will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.9635  http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.9851

Between 2006 and 2014, late preterm and early term birth rates decreased in the United States and an association was observed between early term birth rates and decreasing clinician-initiated obstetric interventions, according to a study appearing in the July 26 issue of JAMA.

Late preterm and early term births are of emerging clinical and public health importance and concern due to the associated risks of adverse neonatal and childhood outcomes. Preterm and early term births may occur spontaneously or be initiated by clinicians through the use of obstetric interventions such as labor induction or cesarean delivery. Clinicians have been urged to delay the use of obstetric interventions until 39 weeks or later in the absence of maternal or fetal indications for intervention.

Jennifer L. Richards, M.P.H., of Emory University, Atlanta, and colleagues examined trends in late preterm and early term birth rates across 6 high-income countries in North America and Europe, and assessed the association between these trends and changes in the use of clinician-initiated obstetric interventions. The researchers analyzed live births from 2006 to the latest available year (ranging from 2010 to 2015) in Canada, Denmark, Finland, Norway, Sweden, and the United States and determined annual country-specific late preterm (34-36 weeks) and early term (37-38 weeks) birth rates.

The study population included approximately 30 million births. The researchers found that late preterm birth rates decreased in Norway and the United States. Early term birth rates decreased in Norway, Sweden and the United States. In the United States, early term birth rates decreased from 33 percent in 2006 to 21 percent in 2014 among births with clinician-initiated obstetric intervention, and from 30 percent in 2006 to 27 percent in 2014 among births without clinician-initiated obstetric intervention. Rates of clinician-initiated obstetric intervention increased among late preterm births in Canada, Denmark and Finland and among early term births in Denmark and Finland.

The authors note that the U.S. findings were consistent with several recent hospital- and regional-based studies reporting reductions in elective obstetric intervention at early term gestations and may reflect the success of perinatal quality collaboratives aimed at reducing elective deliveries prior to 39 weeks. “Concerns have been expressed that delaying interventions until 39 weeks might increase stillbirth rates, and this is an area requiring further study.”

(doi:10.1001/jama.2016.9635; the study is available pre-embargo at the For the Media website)

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

Note: Previous related content from JAMA: Relationship Between Cesarean Delivery Rate and Maternal and Neonatal Mortality

Editorial: Improving Birth Outcomes Key to Improving Global Health

“Richards and colleagues have provided a thoughtful multinational picture of late preterm and early term deliveries and their association with obstetric interventions,” writes Catherine Y. Spong, M.D., of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Md., in an accompanying editorial.

“More data are needed to better understand the differences between countries and changes over time. Better tools and technologies to date pregnancies are now available, and, as studies continue to demonstrate, it is critical to wait until full term for delivery in uncomplicated pregnancies. However, physicians cannot become too devoted to decreasing late preterm and early term birth rates. For pregnancies in which there is a complication and when delivery will optimize the pregnancy outcome, delivery should occur and will require an obstetrical intervention.”

(doi:10.1001/jama.2016.9851; the editorial is available pre-embargo at the For the Media website)

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, JULY 26, 2016

Media Advisory: To contact Katherine E. Nelson, M.D., email Suzanne Gold at suzanne.gold@sickkids.ca.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.9819

Among children born with the chromosome disorders trisomy 13 or 18 in Ontario, Canada, early death was the most common outcome, but 10 percent to 13 percent survived for 10 years, according to a study appearing in the July 26 issue of JAMA. Among children who underwent surgical interventions, 1-year survival was high.

Trisomy 13 and 18 are genetic diagnoses associated with characteristic physical features and organ anomalies, often including cardiac malformations and neurologic impairments that occur in approximately 8 to 15 per 100,000 live births. Most children with these disorders die shortly after birth, although limited data suggest some children survive longer. Surgeries are controversial, and little evidence is available about outcomes. Lack of information about longer-term survival complicates clinical decision making.

Katherine E. Nelson, M.D., of the Hospital for Sick Children, Toronto, and colleagues examined survival and utilization of any type of surgery among children born in Ontario between April 1991 and March 2012 with a diagnosis code for trisomy 13 or 18 on a hospital record in the first year of life. All procedures classified as occurring in an operating room were categorized as major, intermediate, or minor surgeries.

The study included 174 children with trisomy 13 and 254 children with trisomy 18. Median survival times were 12.5 days for trisomy 13 and 9 days for trisomy 18. Average 1-year survival for trisomy 13 was 20 percent and 13 percent for trisomy 18. Ten-year survival for trisomy 13 was 13 percent and 10 percent for trisomy 18. Survival did not change over the study period. Forty-one children (24 percent) with trisomy 13 and 35 children (14 percent) with trisomy 18 underwent surgeries. Median age at first surgery for trisomy 13 was 92 days and for trisomy 18 it was 206 days. Analysis indicated 1-year survival after first surgery of 71 percent for trisomy 13 and 69 percent for trisomy 18.

The authors note that longer-term survival and use of surgical interventions were more common in this study than previously reported in population-based studies. They add that one factor likely contributing to this was the use of health administrative data from Ontario’s single-payer health care system, which captures all surgical procedures and deaths.

(doi:10.1001/jama.2016.9819; the study is available pre-embargo at the For the Media website)

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

Note: Available pre-embargo at the For The Media website is an accompanying editorial, “Trisomy 13 and 18—Treatment Decisions in a Stable Gray Zone ” by John D. Lantos, M.D., of Children’s Mercy Hospital, University of Missouri-Kansas City.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JULY 19, 2016

Media Advisory: To contact Richard N. Rosenthal, M.D., email Sasha Walek at sasha.walek@mountsinai.org. To contact editorial co-author Wilson M. Compton, M.D., M.P.E., email media@nida.nih.gov.

To place an electronic embedded link to this study and editorial in your story  These links will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.9382

http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.8897

In a study appearing in the July 19 issue of JAMA, Richard N. Rosenthal, M.D., of the Icahn School of Medicine at Mount Sinai, New York, and colleagues examined if 6-month subdermal buprenorphine implants maintained low to no illicit opioid use relative to daily sublingual (beneath the tongue) buprenorphine among currently stable opioid-dependent patients receiving buprenorphine maintenance treatment.

Opioid dependence is a growing public health concern in the United States, associated with spread of human immunodeficiency virus and hepatitis C and fatal over dose when left untreated. The effectiveness of treatment with the medication buprenorphine is limited by suboptimal adherence. In this study, 177 opioid-dependent patients with stable abstinence were randomly assigned to sublingual buprenorphine with placebo implants (n = 90) or buprenorphine implants with sublingual placebo (n = 87); 165 of 177 patients (93 percent) completed the trial.

Eighty-one of 84 (96 percent) receiving buprenorphine implants and 78 of 89 (88 percent) receiving sublingual buprenorphine were responders (≥ 4 of 6 months without opioid-positive urine test result [monthly and 4 times randomly] and self-report). Over 6 months, 72 of 84 (86 percent) receiving buprenorphine implants and 64 of 89 (72 percent) receiving sublingual buprenorphine maintained opioid abstinence. Non-implant-related and implant-related adverse events occurred in 48 percent and 23 percent of the buprenorphine implant group and in 53 percent and 13.5 percent of participants in the sublingual buprenorphine group, respectively.

“Buprenorphine is an effective treatment for opioid dependence; however, adherence to daily dosing for management of chronic disorders is challenging. An implantable buprenorphine delivery system reduces adherence issues and may improve efficacy,” the authors write.

“Among adults with opioid dependence maintaining abstinence with a stable dose of sublingual buprenorphine, the use of buprenorphine implants compared with continued sublingual buprenorphine did not result in an inferior likelihood of remaining a responder. However, the study population had an exceptionally high response rate in the control group, and further studies are needed in broader populations to assess the efficacy in other settings.”

(doi:10.1001/jama.2016.9382; the study is available pre-embargo at the For the Media website)

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

Editorial: Improving Outcomes for Persons With Opioid Use Disorders

“This novel implant system may help buttress patients’ decision-making deficits that are a core component of the addiction by making these lifesaving medication adherence decisions far more infrequent,” write Wilson M. Compton, M.D., M.P.E., and Nora D. Volkow, M.D., of the National Institute on Drug Abuse, Bethesda, Md., in an accompanying editorial.

“However, buprenorphine implants are currently approved by the U.S. Food and Drug Administration for only up to 1 year of treatment for a subgroup of patients who have already achieved and sustained prolonged clinical stability while receiving low to moderate doses of oral transmucosal buprenorphine, a caveat clearly stated in the product label. Even so, this novel approach to delivering care may open up treatment for new, previously difficult-to-reach populations or for those in the criminal justice system. Although further research is needed to determine which populations would benefit the most from these new formulations, the potential of these agents to have a positive role in the current opioid crisis is undeniable.”

(doi:10.1001/jama.2016.8897; the editorial is available pre-embargo at the For the Media website)

Editor’s Note: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Compton reports stock ownership in Pfizer, General Electric, and 3M. No other disclosures were reported.

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EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JULY 19, 2016

Media Advisory: To contact Alexandra W. van den Belt-Dusebout, Ph.D., email Nadine Böke at n.boke@nki.nl.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.9389

Among women undergoing fertility treatment in the Netherlands between 1980 and 1995, the use of in vitro fertilization (IVF) compared with non-IVF treatment was not associated with increased risk of breast cancer after a median follow-up of 21 years, according to a study appearing in the July 19 issue of JAMA.

For decades, breast cancer has been the most common malignancy among women worldwide. Both exogenous and endogenous estrogens and progestogens have been shown to affect breast cancer risk. Since IVF procedures temporarily cause decreased estradiol and progesterone levels, as well as strongly elevated hormone levels, IVF might influence breast cancer risk. Because of the high incidence of breast cancer and the large numbers of women undergoing ovarian stimulation for IVF, even a small risk increase would have important public health implications. Previous studies of breast cancer risk after IVF treatment were inconclusive due to limited follow-up.

Alexandra W. van den Belt-Dusebout, Ph.D., of the Netherlands Cancer Institute, Amsterdam, and colleagues assessed long-term risk of breast cancer after ovarian stimulation for IVF among 19,158 women who started IVF treatment between 1983 and 1995 (IVF group) and 5,950 women starting other fertility treatments between 1980 and 1995 (non-IVF group). The median age at end of follow-up was 54 years for the IVF group and 55 years for the non-IVF group. The incidence of invasive and in situ breast cancers in women who underwent fertility treatments was obtained through linkage with the Netherlands Cancer Registry (1989-2013).

Among 25,108 women (average age at study entry, 33 years; average number of IVF cycles, 3.6), 839 cases of invasive breast cancer and 109 cases of in situ breast cancer occurred after a median follow-up of 21 years. Analysis indicated that breast cancer risk in IVF-treated women was not significantly different from that in the general population and from the risk in the non-IVF group. The cumulative incidences of breast cancer at age 55 were 3 percent for the IVF group and 2.9 percent for the non-IVF group.

The risk did not differ by type of fertility drugs or subfertility diagnosis and was not increased at 20 or more years after IVF treatment. Women with 7 or more IVF cycles had a significantly decreased risk compared with women treated with 1 to 2 IVF cycles. Poor response to the first IVF cycle was also associated with decreased breast cancer risk.

“These findings are consistent with the absence of a significant increase in the long-term risk of breast cancer among women treated with these IVF regimens,” the authors write.

(doi:10.1001/jama.2016.9389; the study is available pre-embargo at the For the Media website)

Editor’s Note: This work was supported by the Dutch Cancer Society; the Health Research and Development Counsel; and the Dutch Ministry of Health.  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, JULY 19, 2016

Media Advisory: To contact Andy Menke, Ph.D., email Mona Feldman at MFeldman@s-3.com.

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In a study appearing in the July 19 issue of JAMA, Andy Menke, Ph.D., of Social & Scientific Systems, Silver Spring, Md., and colleagues estimated the prevalence of diabetes among U.S. adolescents, the percentage of those who were unaware of their diabetes, and the prevalence of prediabetes using nationally representative data.

The researchers used 2005-2014 National Health and Nutrition Examination Survey (NHANES) data (in which all relevant glucose data were available) from adolescents age 12 to 19 years who were randomly selected for a morning examination session after fasting.

Of 2,606 adolescents included, 62 had diabetes, 20 were undiagnosed, and 512 had prediabetes. The weighted prevalence of diabetes was 0.8 percent, of which 29 percent was undiagnosed, and the prevalence of prediabetes was 18 percent. Prediabetes was more common in males (22 percent) than females (13 percent). Compared with non-Hispanic white participants, the percentage of adolescents with diabetes who were undiagnosed (4.6 percent) and the prediabetes prevalence (15 percent) were higher in non-Hispanic black participants  (50 percent and 21 percent, respectively) and Hispanic participants  (40 percent and 23 percent, respectively). Diabetes and prediabetes prevalences did not change over time.

“To our knowledge, these are the first estimates of diabetes in a nationally representative sample of U.S. adolescents using all 3 American Diabetes Association recommended biomarkers. The estimates are higher than previously reported; 1 study found diagnosed diabetes in 0.34 percent of participants aged 10 to 19 years. A relatively large proportion was unaware of the condition, particularly among non-Hispanic black participants and Hispanic participants, indicating a need for improved diabetes screening among adolescents. These findings may have important public health implications because diabetes in youth is associated with early onset of risk factors and complications,” the authors write.

(doi:10.1001/jama.2016.8544; the study is available pre-embargo at the For the Media website)

Editor’s Note: This work was supported by a contract from the National Institute of Diabetes and Digestive and Kidney Diseases. 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, JULY 19, 2016

Media Advisory: To contact Giovanni F.M. Strippoli, Ph.D., email gfmstrippoli@gmail.com.

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Among nearly 120,000 adults with type 2 diabetes, there were no significant differences in the associations between any of 9 available classes of glucose-lowering drugs (alone or in combination) and the risk of cardiovascular or all-cause mortality, according to a study appearing in the July 19 issue of JAMA.

Diabetes was estimated to account for approximately 1.5 million deaths in 2012, and disability (blindness, limb amputation, kidney failure, cardiovascular events) among 47 million people in 2010. Lifestyle modification and glucose-lowering drug treatment are the mainstay of therapy to prevent and delay diabetes-related complications. A large number of glucose-lowering drug classes are approved for type 2 diabetes. Randomized clinical trials of diabetes medications have been generally insufficiently powered to establish the role of drug treatment for preventing cardiovascular death.

Giovanni F.M. Strippoli, Ph.D., of the University of Bari, Italy, and Diaverum, Lund, Sweden, and colleagues conducted a systematic review with network meta-analysis to estimate the relative efficacy and safety associated with glucose-lowering drugs including insulin. The researchers identified 301 clinical trials that met criteria for inclusion in the study.

Of the trials included in the study, 177 (56,598 patients) were of drugs given as monotherapy; 109 trials (53,030 patients) of drugs added to metformin (dual therapy); and 29 trials (10,598 patients) of drugs added to metformin and sulfonylurea (triple therapy). The researchers found no significant differences in associations between any drug class as monotherapy, dual therapy, or triple therapy with odds of cardiovascular, all-cause mortality, serious adverse events, heart attack or stroke. Considerable uncertainty about the association of drug treatment with cardiovascular mortality existed within trial evidence, largely because of few events in most available studies.

The authors note that a central finding in this meta-analysis was that despite more than 300 available clinical trials involving nearly 120,000 adults, there was limited evidence that any glucose-lowering drug stratified by coexisting treatment prolonged life expectancy or prevented cardiovascular disease.

“Metformin was associated with lower or no significant difference in HbA_lC levels compared with any other drug classes. All drugs were estimated to be effective when added to metformin. These findings are consistent with American Diabetes Association recommendations for using metformin monotherapy as initial treatment for patients with type 2 diabetes and selection of additional therapies based on patient-specific considerations,” the researchers write.

(doi:10.1001/jama.2016.9400; the study is available pre-embargo at the For the Media website)

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: 5 P.M. (ET) MONDAY, JULY 11, 2016

For media inquiries: email press@who.eop.gov.

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United States Health Care Reform

Progress to Date and Next Steps

The Affordable Care Act has made significant progress toward solving long-standing challenges facing the U.S. health care system related to access, affordability, and quality of care, although major opportunities to improve the health care system remain, according to an article published online by JAMA from President Barack Obama, Executive Office of the President, Washington, D.C.

The Affordable Care Act (ACA) is the most important health care legislation enacted in the United States since the creation of Medicare and Medicaid in 1965. This article examines the factors influencing the decision to pursue health reform and the evidence on the effects of the law to date, provides recommendations on actions that could improve the health care system, and identifies general lessons for public policy from the ACA. The article involved an analysis of publicly available data (from 1963 to early 2016), data obtained from government agencies and published research findings.

Progress Under the ACA

The ACA has succeeded in sharply increasing insurance coverage. Since the ACA became law, the uninsured rate has declined by 43 percent, from 16 percent in 2010 to 9.1 percent in 2015, with most of that decline occurring after the law’s main coverage provisions took effect in 2014. The number of uninsured individuals in the United States has declined from 49 million in 2010 to 29 million in 2015.

Early evidence indicates that expanded coverage is improving access to treatment, financial security, and health for the newly insured. Following the expansion through early 2015, nonelderly adults experienced substantial improvements in the share of individuals who have a personal physician (increase of 3.5 percentage points) and easy access to medicine (increase of 2.4 percentage points) and substantial decreases in the share who are unable to afford care (decrease of 5.5 percentage points) and reporting fair or poor health (decrease of 3.4 percentage points) relative to the pre-ACA trend. Research has also found that Medicaid expansion has improved the financial security of the newly insured (for example, by reducing the amount of debt sent to a collection agency by an estimated $600 – $1,000 per person gaining Medicaid coverage).

The law has also begun the process of transforming health care payment systems, with an estimated 30 percent of traditional Medicare payments now flowing through alternative payment models like bundled payments or accountable care organizations. These and related reforms have contributed to a sustained period of slow growth in per-enrollee health care spending and improvements in health care quality. From 2010 through 2014, average annual growth in real per-enrollee Medicare spending has actually been negative. Similarly, average real per-enrollee growth in private insurance spending has been 1.1 percent per year since 2010, compared with an average of 6.5 percent from 2000 through 2005 and 3.4 percent from 2005 to 2010. The rate of hospital-acquired conditions (such as adverse drug events, infections, and pressure ulcers) has declined, as has the rate at which Medicare patients are readmitted to the hospital within 30 days after discharge

According to the article, despite the progress that has been made toward a more affordable, high-quality, and accessible health care system, too many Americans still strain to pay for their physician visits and prescriptions, cover their deductibles, or pay their monthly insurance bills; struggle to navigate a complex, sometimes bewildering system; and remain uninsured. More work to reform the health care system is necessary, and suggestions are offered in the article.

Conclusion

“Policy makers should build on progress made by the Affordable Care Act by continuing to implement the Health Insurance Marketplaces and delivery system reform, increasing federal financial assistance for Marketplace enrollees, introducing a public plan option in areas lacking individual market competition, and taking actions to reduce prescription drug costs. Although partisanship and special interest opposition remain, experience with the Affordable Care Act demonstrates that positive change is achievable on some of the nation’s most complex challenges.”

(doi:10.1001/jama.2016.9797)

Editor’s Note: Please see the article for financial disclosure information.

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Accompanying editorials published by JAMA available pre-embargo at the For the Media website.

To place an electronic embedded link to an editorial in your story The following links to the editorials will be live at the embargo time.

The Affordable Care Act and the Future of U.S. Health Care

Howard Bauchner, M.D., Editor in Chief, JAMA

http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.9872

U.S. Health Care Reform – Cost Containment and Improvement in Quality

Peter R. Orszag, Ph.D., Lazard, New York

http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.9876

The Future of the Affordable Care Act – Reassessment and Revision

Stuart M. Butler, Ph.D., M.A., Brookings, Washington, D.C.

http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.9881

The Past and Future of the Affordable Care Act

Jonathan Skinner, Ph.D., Dartmouth College, Hanover, N.H., and Amitabh Chandra, Ph.D., Harvard University, Cambridge, Mass.

http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.10158

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, JULY 12, 2016

Media Advisory: To contact Alison J. Rodger, M.D., email alison.rodger@ucl.ac.uk. To contact editorial co-author Eric S. Daar, M.D., email edaar@labiomed.org.

To place an electronic embedded link to this study and editorial in your story  These links will be live at the embargo time: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.5148  http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.5636

Among nearly 900 serodifferent (one partner is HIV-positive, one is HIV-negative) heterosexual and men who have sex with men couples in which the HIV-positive partner was using suppressive antiretroviral therapy and who reported condomless sex, during a median follow-up of 1.3 years per couple, there were no documented cases of within-couple HIV transmission, according to a study appearing in the July 12 issue of JAMA, an HIV/AIDS theme issue.

A key factor in assessing the effectiveness and cost-effectiveness of antiretroviral therapy (ART) as a prevention strategy is the absolute risk of HIV transmission through condomless sex with suppressed HIV-1 RNA viral load for both anal and vaginal sex. Alison J. Rodger, M.D., of University College London, and colleagues evaluated the rate of within-couple HIV transmission (heterosexual and men who have sex with men [MSM]) during periods of sex without condoms and when the HIV-positive partner had HIV-1 RNA load less than 200 copies/ml. The study was conducted at 75 clinical sites in 14 European countries and enrolled 1,166 HIV serodifferent couples (HIV-positive partner taking suppressive ART) (September 2010 to May 2014).

Among the 1,166 enrolled couples, 888 (62 percent heterosexual, 38 percent MSM) provided 1,238 eligible couple-years of follow-up (median follow-up, 1.3 years). At study entry, couples reported condomless sex for a median of 2 years. Condomless sex with other partners was reported by 108 HIV-negative MSM (33 percent) and 21 heterosexuals (4 percent). During follow-up, couples reported condomless sex a median of 37 times per year, with MSM couples reporting approximately 22,000 condomless sex acts and heterosexuals approximately 36,000. Although 11 HIV-negative partners became HIV-positive (10 MSM; 1 heterosexual; 8 reported condomless sex with other partners), no phylogenetically (molecular characteristics that indicate whether a virus is similar or different from another) linked transmissions occurred over eligible couple-years of follow-up, giving a rate of within-couple HIV transmission of zero.

The authors note that the confidence limits used in the study suggest that with eligible couple-years accrued so far, appreciable levels of risk cannot be excluded, particularly for anal sex and when considered from the perspective of a cumulative risk over several years.

“Although these results cannot directly provide an answer to the question of whether it is safe for serodifferent couples to practice condomless sex, this study provides informative data (especially for heterosexuals) for couples to base their personal acceptability of risk on.”

The researchers note that additional longer-term follow-up is necessary to provide a similar level of confidence for the risk from anal sex compared to vaginal sex.

(doi:10.1001/jama.2016.5148; the study is available pre-embargo to the media at the For the Media website)

Editor’s Note: This work was funded by the National Institute for Health Research under its Programme Grants for Applied Research Programme. The study coordinating centre was also supported by the Danish National Research Foundation. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Condomless Sex With Virologically Suppressed HIV-Infected Individuals – How Safe Is It?

“For individuals who want to routinely or intermittently not use condoms with an HIV-infected partner, clinicians can indicate that the risk of HIV transmission appears small in the setting of continued viral suppression, emphasizing that the duration the HIV-infected partner needs to be virologically suppressed before achieving optimal protection is unknown, although appears to be for at least 6 months, based on the best available data,” write Eric S. Daar, M.D., and Katya Corado, M.D., of the Harbor-UCLA Medical Center, Torrance, Calif., in an accompanying editorial.

“Moreover, clinicians need to be clear that even though the overall risk for HIV transmission may be small, the risk is not zero and the actual number is not known, especially for higher-risk groups such as MSM. Although more research is needed with larger numbers of couples and longer follow-up, it is not known if or when such data will emerge. Consequently, for now, clinicians and public health officials must share the data that exist in an honest and understandable way so that serodiscordant couples can be fully informed when individualizing their decision making about sexual practices.”

(doi:10.1001/jama.2016.5636; the study is available pre-embargo to the media at the For the Media website)

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, JULY 12, 2016

Media Advisory: To contact Lisa R. Metsch, Ph.D., call Stephanie Berger at 212-305-4372 or email sb2247@columbia.edu.

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In a study appearing in the July 12 issue of JAMA, an HIV/AIDS theme issue, Lisa R. Metsch, Ph.D., of Columbia University, New York, and colleagues assessed the effect of structured patient navigation (care coordination with case management) interventions with or without financial incentives to improve HIV-l viral suppression rates among hospitalized patients with elevated HIV-1 viral loads and substance use.

The U.S. National HIV/AIDS Strategy calls for improved engagement in care and increased viral suppression for people living with HIV. Yet it has been estimated that only 30 percent of the 1.2 million persons with HIV infection in the United States in 2011 were virally suppressed, and according to data collected during 1999-2007, many were hospitalized with conditions preventable through HIV treatment. Substance use is likely a major factor in poor HIV clinical outcomes. To improve their health, persons with HIV infection and substance use may require treatment for substance use disorders in concert with HIV treatment. Patient navigation and the use of financial incentives for achieving predetermined outcomes are interventions increasingly promoted to engage patients in substance use disorders treatment and HIV care, but there is little evidence for their efficacy in improving HIV-1 viral suppression rates.

In this study, 801 patients with HIV infection and substance use from 11 hospitals across the United States were randomly assigned to receive patient navigation alone (n = 266), patient navigation plus financial incentives (n = 271), or treatment as usual (n = 264). Patient navigation included up to 11 sessions of care coordination with case management and motivational interviewing techniques over 6 months. Financial incentives (up to $1,160) were provided for achieving targeted behaviors aimed at reducing substance use, increasing engagement in HIV care, and improving HIV outcomes. Treatment as usual was the standard practice at each hospital for linking hospitalized patients to outpatient HIV care and substance use disorders treatment. HIV-1 plasma viral load was measured at study entry and at 6 and 12 months.

The researchers found that there were no differences in rates of HIV viral suppression (≤ 200 copies/ml) versus nonsuppression or death among the 3 groups at 12 months. Eighty-five of 249 patients (34 percent) in the usual-treatment group experienced treatment success (HIV viral suppression) compared with 89 of 249 patients (36 percent) in the navigation-only group for a treatment difference of 1.6 percent and compared with 98 of 254 patients (39 percent) in the navigation-plus-incentives group for a treatment difference of 4.5 percent. The treatment difference between the navigation-only and the navigation-plus­ incentives group was -2.8 percent.

“Among hospitalized patients with HIV infection and substance use, patient navigation with or without financial incentives did not have a beneficial effect on HIV viral suppression relative to nonsuppression or death at 12 months compared with treatment as usual. These findings do not support these interventions in this setting and indicate that other approaches are needed to improve HIV outcomes in this vulnerable population,” the authors write.

(doi:10.1001/jama.2016.8914; the study is available pre-embargo to the media at the For the Media website)

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, JULY 12, 2016

Media Advisory: To contact Xiangrong Kong, Ph.D., email Stephanie Desmon (sdesmon1@jhu.edu) or Barbara Benham (bbenham1@jhu.edu).

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In a study appearing in the July 12 issue of JAMA, an HIV/AIDS theme issue, Xiangrong Kong, Ph.D., of the Johns Hopkins Bloomberg School of Public Health, Baltimore, and colleagues examined whether increasing community medical male circumcision and antiretroviral therapy (ART) coverage was associated with reduced community HIV incidence in Uganda.

Randomized trials have shown that medical male circumcision (MMC) reduces male HIV acquisition by 50 percent to 60 percent, and that early initiation of ART reduces HIV transmission by more than 90 percent in HIV-discordant couples. There are limited data on the population-level effect of scale-up of these interventions in sub-Saharan Africa. Such evaluation is important for planning and resource allocation.

Using data from population-based surveys conducted from 1999 through 2013 in 45 rural Rakai, Uganda communities, community-level ART and MMC coverage, sociodemographics, sexual behaviors, and HIV prevalence and incidence were estimated in 3 periods: prior to the availability of ART and MMC (1999-2004), during early availability of ART and MMC (2004-2007), and during mature program scale-up (2007-2013).

From 1999 through 2013, 44,688 persons participated in 1 or more surveys. Median community MMC coverage increased from 19 percent to 39 percent, and median community ART coverage rose from 0 percent to 21 percent in males and from 0 percent to 26 percent in females. Median community HIV incidence declined from 1.25 to 0.84 per 100 person-years in males, and from 1.25 to 0.99 per 100 person-years in females. Analysis indicated that increasing community-level coverage of MMC was associated with significant reductions in male community HIV incidence. For example, in communities with MMC more than 40 percent, male HIV incidence was 0.66 per 100 person-years lower than in communities with MMC coverage 10 percent or less.

“This difference is substantial to these communities and suggests that increasing MMC coverage more than 40 percent could reduce male incidence by approximately 39 percent at a population-level. This is comparable with the estimated reduction in individual HIV acquisition risk associated with comparable ART coverage in South Africa,” the authors write.

“Because MMC provides direct protection against male HIV acquisition, this association is plausible and consistent with the estimated associations of increasing MMC coverage with male HIV prevalence from cross-sectional analyses in South Africa. Female community HIV incidence was not significantly associated with male MMC coverage during the study period, consistent with mathematical models suggesting that the HIV prevention benefits of MMC to women accrue over longer periods.”

The researchers write that if similar associations are found elsewhere regarding increasing community MMC and female ART coverage, this would support further scale-up of MMC and ART for HIV prevention in sub-Saharan Africa.

(doi:10.1001/jama.2016.7292; the study is available pre-embargo to the media at the For the Media website)

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, JULY 12, 2016

Media Advisory: To contact co-author Paul A. Volberding, M.D., email Jeff Sheehy at jeff.sheehy@ucsf.edu; to contact co-author Michael S. Saag, M.D., email Alicia Rohan at ARohan@uab.edu. To contact editorial co-author Kenneth H. Mayer, M.D., email Christopher Viveiros at cviveiros@fenwayhealth.org.

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In a report appearing in the July 12 issue of JAMA, an HIV/AIDS theme issue, Huldrych F. Gunthard, M.D., of University Hospital Zurich, Switzerland, and colleagues with the International Antiviral Society-USA panel, updated recommendations for the use of antiretroviral therapy in adults with established HIV infection, including when to start treatment, initial regimens, and changing regimens, along with recommendations for using antiretroviral drugs for preventing HIV among those at risk, including preexposure and postexposure prevention.

There have been substantial advances in the use of antiretroviral drugs (ARVs) for the treatment and prevention of HIV infection since the last version of these recommendations in 2014, warranting an update to the recommendations. A panel of experts in HIV research and patient care convened by the International Antiviral Society-USA reviewed data published in peer-reviewed journals, presented by regulatory agencies, or presented as conference abstracts at peer-reviewed scientific conferences since the 2014 report, for new data or evidence that would change previous recommendations or their ratings. Comprehensive literature searches were conducted. Recommendations were by consensus, and each recommendation was rated by strength and quality of the evidence.

Recommendations

Newer data support the widely accepted recommendation that antiretroviral therapy should be started in all individuals with HIV infection with detectable viremia regardless of CD4 cell count. Recommended optimal initial regimens for most patients are 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus an integrase strand transfer inhibitor (InSTI). Other effective regimens include nonnucleoside reverse transcriptase inhibitors or boosted protease inhibitors with 2 NRTIs. Recommendations for special populations and in the settings of opportunistic infections and concomitant conditions are provided.

Reasons for switching therapy include convenience, tolerability, simplification, anticipation of potential new drug interactions, pregnancy or plans for pregnancy, elimination of food restrictions, virologic failure, or drug toxicities. Laboratory assessments are recommended before treatment, and monitoring during treatment is recommended to assess response, adverse effects, and adherence. Approaches are recommended to improve linkage to and retention in care are provided. Daily tenofovir disoproxil fumarate/emtricitabine is recommended for use as preexposure prophylaxis to prevent HIV infection in persons at high risk. When indicated, postexposure prophylaxis should be started as soon as possible after exposure.

“Antiretroviral agents remain the cornerstone of HIV treatment and prevention. All HIV-infected individuals with detectable plasma virus should receive treatment, with recommended initial regimens consisting of an InSTI plus 2 NRTIs. Preexposure prophylaxis should be considered as part of an HIV prevention strategy for at-risk individuals. When used effectively, currently available ARVs can sustain HIV suppression and can prevent new HIV infection. With these treatment regimens, survival rates among HIV-infected adults who are retained in care can approach those of uninfected adults,” the authors conclude.

(doi:10.1001/jama.2016. 8900; the study is available pre-embargo to the media at the For the Media website)

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

Editorial: Antiretrovirals for HIV Treatment and Prevention – The Challenges of Success

“The current IAS-USA guidelines reflect the hard-won success of 35 years of clinical research,” write Kenneth H. Mayer, M.D., and Douglas S. Krakower, M.D., of Fenway Health, Boston, in an accompanying editorial.

“Although challenges remain to optimize the cascade of care and to prevent new infections, and an aging epidemic will present new challenges, these concerns reflect the successes of highly effective antiretroviral therapy. Historians may wonder whether the pace of discovery in the early days of the epidemic could have been accelerated, but no one can doubt the signal accomplishments of biobehavioral research and community engagement in forging a common strategy to deal with this global pandemic, one that continues to pose new challenges.”

(doi:10.1001/jama.2016.8902; the editorial is available pre-embargo to the media at the For the Media website)

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, JULY 12, 2016

Media Advisory: To contact Claire K. Ankuda, M.D., M.P.H., email Kara Gavin at kegavin@med.umich.edu.

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In a study appearing in the July 12 issue of JAMA, Claire K. Ankuda, M.D., M.P.H., and Deborah A. Levine, M.D., M.P.H., of the University of Michigan, Ann Arbor, examined trends in caregiving for home-dwelling older adults with functional disability.

As more people in the United States age with chronic disease, needs for caregiving increase. Whether the source of caregiving for disabled older adults is changing is unknown. This study used data from the nationally representative U.S. Health and Retirement Study, and included home-dwelling adults 55 years and older with 1 or more impairments in activities of daily living or instrumental activities of daily living (ADL/IADLs) who were surveyed between 1998 and 2012.

There were 5,198 individuals and 39,060 observations of home-dwelling older adults with 1 or more impairments. The researchers found that individuals increasingly reported caregiver help, from 42 percent in 1998 to 50 percent in 2012. Assistance was increasingly provided by spouses, children, other family, and paid caregivers over each 2-year period.

The greatest increase in caregiving was among those with fewer ADL and IADL impairments. “Although this is likely in part because those with more impairments have already sought caregivers, it may also be that more adults with 1 or 2 impairments are aging in their communities as opposed to nursing homes,” the authors write.

“Further work is needed to assess the balance between functional needs in the population and capacity for caregiver support, as well as the burden on unpaid caregivers.”

(doi:10.1001/jama.2016.6824; the study is available pre-embargo to the media at the For the Media website)

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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