EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, OCTOBER 20, 2015

Media Advisory: To contact Lakshmi Sukumaran, M.D., M.P.H., call Melissa Brower at 404-639-4718 or email mbrower@cdc.gov.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.12790

Among women who received the tetanus, diphtheria, and acellular pertussis (Tdap) vaccine during pregnancy, there was no increased risk of adverse events in the mothers or adverse birth outcomes in newborns for women who had received a tetanus-containing vaccine in the previous 5 years, according to a study in the October 20 issue of JAMA.

Pertussis (whooping cough) is a vaccine-preventable illness that has been increasing in incidence over the past decade in the United States. Neonates (a baby from birth to four weeks) and infants are at increased risk of pertussis-related hospitalization and death compared with older children and adults. The Advisory Committee on Immunization Practices recommends the Tdap vaccine for pregnant women during each pregnancy, regardless of prior immunization status. However, safety data on repeated Tdap vaccination in pregnancy has been lacking, according to background information in the article.

Lakshmi Sukumaran, M.D., M.P.H., of the Centers for Disease Control and Prevention, Atlanta, and colleagues conducted a study that included 29,155 pregnant women, ages 14 through 49 years, using data from 2007 to 2013 from 7 Vaccine Safety Datalink sites in California, Colorado, Minnesota, Oregon, Washington, and Wisconsin. The authors examined outcomes for women who received Tdap in pregnancy following a prior tetanus-containing vaccine less than 2 years before, 2 to 5 years before, and more than 5 years before.

The researchers found no significant differences in rates of acute adverse events in the mothers (fever, allergy, and local reactions) or adverse birth outcomes in neonates (small for gestational age, preterm delivery, and low birth weight) when comparing women who were vaccinated with Tdap during pregnancy regardless of the length of time since a prior tetanus-containing vaccine.

“Our findings should reassure patients and clinicians who might be hesitant to give Tdap vaccine to pregnant women who recently received a Tdap or other tetanus-containing vaccination,” the authors write.

The researchers add that future studies are needed to determine if there are differences in other important adverse pregnancy outcomes, such as stillbirth and spontaneous abortion, when Tdap is given in pregnancy in close intervals from prior tetanus-containing vaccines.

(doi:10.1001/jama.2015.12790; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This work was supported by the Centers for Disease Control and Prevention and a grant from the National Institute of Allergy and Infectious Diseases. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, OCTOBER 20, 2015

Media Advisory: To contact Ulrik Sartipy, M.D., Ph.D., email ulrik.sartipy@karolinska.se.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8690

 
Although some studies have suggested that transfusion of stored red blood cell (RBC) concentrates may be harmful, as blood undergoes several physiological changes during storage, an analysis of patients who underwent cardiac surgery in Sweden over a 16-year period found no association between duration of RBC storage and risk of death or serious complications, according to a study in the October 20 issue of JAMA.

Ulrik Sartipy, M.D., Ph.D., of Karolinska University Hospital, Stockholm, Sweden and colleagues identified all patients in Sweden who underwent coronary artery bypass graft surgery, heart valve surgery, or both between 1997 and 2012. Transfusion data were obtained from a nationwide register of blood transfusions. Linkage with national health data registers provided vital status and adverse outcomes. Blood services in Sweden are part of the public health care system and follow national guidelines, whereby the oldest available blood unit of the appropriate blood type is allocated first.

During the study period, 47,071 patients were transfused in connection with cardiac surgery in 9 Swedish hospitals. Of these patients, 37 percent exclusively received RBCs stored less than 14 days; 27 percent, RBCs stored 14-27 days; 9 percent, RBCs stored 28-42 days; and 28 percent, RBCs of mixed age. Compared with recipients of RBCs stored for less than 14 days, there was no association between transfusion of RBCs stored 14-27 days or 28-42 days and 30-day, 2-year and 10-year mortality. There was no association with risk of selected serious complications.

“These results complement recent randomized trials in providing further reassurance of the safety of current blood storage practices,” the authors write.

(doi:10.1001/jama.2015.8690; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, OCTOBER 13, 2015

Media Advisory: To contact Beth Han, M.D., Ph.D., M.P.H., call Bradford Stone at 240-276-2140 or email Bradford.Stone@SAMHSA.hhs.gov. To contact editorial co-author Lewis S. Nelson, M.D., call Rob Magyar at 212-404-3591 or email Robert.magyar@nyumc.org.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.11859 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.12397

From 2003 to 2013, the percentage of nonmedical use of prescription opioids decreased among adults in the U.S., while the prevalence of prescription opioid use disorders, frequency of use, and related deaths increased, according to a study in the October 13 issue of JAMA.

Since 1999, the United States has experienced increases in illness and death associated with nonmedical use of prescription opioids, which is being called a U.S. epidemic. During this period, emergency department visits and drug overdose deaths involving these drugs have increased rapidly. To fully understand the current status of the epidemic and who is currently most affected, an examination of nationally representative U.S. surveillance data is needed.

Beth Han, M.D., Ph.D., M.P.H., of the Substance Abuse and Mental Health Services Administration, Rockville, Md., and colleagues examined the prevalence of nonmedical use and use disorders (dependence on or abuse of alcohol, marijuana, cocaine, hallucinogens, heroin, inhalants, or nonmedical use of prescription pain relievers, sedatives, or stimulants) and related risk factors with data from 472,200 persons who participated in the 2003-2013 National Surveys on Drug Use and Health. Mortality was based on the 2003-2013 National Vital Statistics System’s Multiple Cause of Death Files.

Among adults age 18 through 64 years, the prevalence of nonmedical use of prescription opioids decreased from 5.4 percent in 2003 to 4.9 percent in 2013, but the prevalence of prescription opioid use disorders increased from 0.6 percent in 2003 to 0.9 percent in 2013. The 12-month prevalence of high-frequency use (200 days or more) also increased from 0.3 percent in 2003 to 0.4 percent in 2013.

Mortality assessed by drug overdose death rates involving prescription opioids increased from 4.5 per 100,000 in 2003 to 7.8 per 100,000 in 2013. The average number of days of nonmedical use of prescription opioids increased from 2.1 in 2003 to 2.6 in 2013. The prevalence of having prescription opioid use disorders among nonmedical users increased to 15.7 percent in 2010, 16.1 percent in 2011, 17 percent in 2012, and 16.9 percent in 2013, from 12.7 percent in 2003.

“We found a significant decrease in the percentage of nonmedical use of prescription opioids, as well as significant increases in the prevalence of prescription opioid use disorders, high-frequency use, and related mortality among adults aged 18 through 64 years in the United States over the past decade. Furthermore, the increases identified in this study occurred in the context of increasing heroin use and heroin-related overdose deaths in the United States, supporting a need to address nonmedical use of prescription opioid and heroin abuse in a coordinated and comprehensive manner,” the authors write.

“Receiving treatment for substance use disorders is particularly critical. Most adults with prescription opioid use disorders or other substance use disorders neither receive treatment nor perceive a need for treatment. In 2013, more than three-fourths of adults aged 18 through 64 years who had prescription opioid use disorders did not receive any substance use treatment. Particularly, policy and societal barriers prevent broad dissemination, access, and adoption of highly effective medication-assisted therapies for people with prescription opioid use disorders.”

(doi:10.1001/jama.2015.11859; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

Editorial: Addressing the Opioid Epidemic

“If the observed decrease in rates of new opioid users reported by Han et al is sustained, understanding the reasons behind this change is important. These are likely multifactorial and may include the use of prescribing guidelines for chronic pain, rationalizing expectations of physicians and patients for pain control and functional outcome, media attention on the consequences of addiction, and regulatory and legal efforts. It is encouraging that the culture around prescription opioids is starting to change, especially when considering the marketing of a plethora of new opioids for the treatment of chronic pain, none of which has been shown to be safe and effective over the long term,” writes Lewis S. Nelson, M.D., of the New York University School of Medicine, and colleagues.

“The chronic, relapsing nature of opioid addiction means most patients are never ‘cured,’ and the best outcome is long-term recovery. The lifelong implications of this disease far outweigh the limited benefits of opioids in the treatment of chronic pain, and in many cases the risks inherent in the treatment of acute pain with opioids. The encouraging finding of declining opioid initiation rates should be tempered by the increasing rates of nonmedical opioid use disorders and the limited utilization of treatment programs. Although multifaceted approaches are needed to successfully address the opioid epidemic, an important step is to start at the beginning and keep opioid-naive patients opioid naive.”

(doi:10.1001/jama.2015.12397; Available pre-embargo to the media at http:/media.jamanetwork.com)

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, OCTOBER 13, 2015

Media Advisory: To contact Brendan Saloner, Ph.D., call Stephanie Desmon at 410-955-7619 or email sdesmon1@jhu.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10345

During the decade from 2004 to 2013, use of treatment remained low for individuals with opioid use disorders, according to a study in the October 13 issue of JAMA.

During the last decade, nonmedical use of opioid analgesics and heroin increased substantially in the United States. In the early 2000s, less than one-sixth of individuals with opioid use disorders (OUDs) received any treatment, and use of office-based treatment was rare. It is unknown whether treatment patterns have changed in recent years. Brendan Saloner, Ph.D., and Shankar Karthikeyan, M.P.P., of the Johns Hopkins Bloomberg School of Public Health, Baltimore, used data from the 2004-2013 rounds of the National Survey of Drug Use and Health, a nationally representative annual survey of individuals age 12 years or older, to identify individuals with opioid abuse or dependence symptoms and if they received treatment for OUD in the prior 12 months. The sample was divided into two 5-year periods (2004-2008 vs 2009-2013) to provide reliable estimates.

In the combined sample, the researchers identified 6,770 respondents with OUDs. The adjusted rates for the percentage of individuals with OUDs receiving treatment were similar (18.8 percent in 2004-2008 vs 19.7 percent in 2009-2013).

The average number of treatment settings visited increased during the study period. The most common setting in both periods was self-help groups. More than half of individuals receiving treatment during both periods also visited outpatient treatment. Use of inpatient treatment increased from 37.5 percent in 2004-2008 to 52 percent in 2009-2013, and office-based treatment increased from 25 percent to 35 percent.

“Individuals in treatment received care in more settings, with the greatest increases in inpatient treatment and at physician’s offices. Although physician’s offices may provide access to buprenorphine, medication-assisted treatments are often unavailable in inpatient settings, which could hinder patient recovery,” the authors write.

(doi:10.1001/jama.2015.10345; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, OCTOBER 13, 2015

Media Advisory: To contact Julie M. Fritz, Ph.D., P.T., call Julie Kiefer at 801-587-1293 or email julie.kiefer@utah.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.11648

Early physical therapy for recent-onset low back pain resulted in statistically significant improvement in disability compared to usual care, but the improvement was modest and did not achieve a difference considered clinically important at the individual patient level, according to a study in the October 13 issue of JAMA.

Lifetime prevalence of low back pain (LBP) is about 70 percent and accounts for 2 percent to 5 percent of all physician visits. The effect of early physical therapy for LBP is unclear. Guidelines advise delaying referral to physical therapy or other specialists for a few weeks to permit spontaneous recovery. Findings from recent observational studies suggest that some patients may benefit from early physical therapy.

Julie M. Fritz, Ph.D., P.T., of the University of Utah, Salt Lake City, and colleagues randomly assigned 220 patients with recent-onset LBP to early physical therapy (n = 108; consisted of 4 physical therapy sessions [manipulation and exercise]), or usual care (n = 112; no additional interventions during the first 4 weeks). All participants received back pain related education. One-year follow-up was completed by 207 participants (94 percent).

For the primary study outcome, early physical therapy showed improvement compared to usual care on a measure of disability after 3 months. A significant difference was not found for disability between groups at 1-year follow-up. There was no improvement in pain intensity at 4-week, 3-month, or 1-year follow-up. Most differences between groups were modest. There were no differences in health care utilization at any point.

“We found that patients in both groups improved rapidly. Rapid and substantial improvement by most patients with acute LBP limits treatment effects in early intervention studies. We detected a modest difference favoring early physical therapy that was better than the natural history of acute LBP for the primary outcome at 3-month follow-up. However, the between-group difference did not achieve the threshold for minimum clinically important difference. Furthermore, differences were mostly undetectable by 1 year,” the authors write.

(doi:10.1001/jama.2015.11648; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) THURSDAY, OCTOBER 8, 2015

Media Advisory: To contact Joshua D. Schiffman, M.D., call Linda Aagard at 801-587-7639 or email linda.aagard@hci.utah.edu. To contact editorial author Mel Greaves, Ph.D., email Mel.Greaves@icr.ac.uk.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.13134 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.13153

Multiple copies of a cancer-suppression gene may play a role in why elephants have a lower-than-expected rate of cancer, findings that have the potential to provide a better understanding of the mechanisms related to cancer suppression, including in humans, according to a study published online by JAMA.

The mechanisms that prevent accumulation of genetic damage and subsequent uncontrolled proliferation of somatic cells (any cell in the body that is not involved in reproduction) remain poorly understood. Understanding the cellular mechanism of cancer suppression in animals could benefit humans at high risk of cancer. Joshua D. Schiffman, M.D., of the University of Utah School of Medicine, Salt Lake City, and colleagues investigated the cancer rate in different mammals, including elephants, identified potential molecular mechanisms of cancer resistance, and compared response to DNA damage in elephants with that in healthy human controls and patients with Li-Fraumeni syndrome (LFS; a genetic syndrome with a high lifetime risk of cancer).

A comprehensive survey of necropsy data (information on disease and cause of death) was performed across 36 mammalian species to validate cancer resistance in large and long-lived organisms, including elephants (n = 644). The African and Asian elephant genomes were analyzed for potential mechanisms of cancer resistance. Peripheral blood lymphocytes (a type of white blood cell that plays a role in immunity and defending the body against disease) from elephants, healthy human controls, and patients with LFS were tested in vitro in the laboratory for DNA damage response. The study included African and Asian elephants (n = 8), patients with LFS (n = 10), and age-matched human controls (n = 11).

The authors write that a greater number of cells and cell divisions increases the chance of accumulating mutations resulting in malignant transformation. If all mammalian cells are equally susceptible to oncogenic mutations, then cancer risk should increase with body size (number of cells) and species life span (number of cell divisions), although it has been observed that cancer incidence across animals does not appear to increase as theoretically expected for larger body size and life span.

For this study, the researchers found that across mammals, cancer mortality did not increase with body size and/or maximum life span (e.g., for rock hyrax, 1 percent; African wild dog, 8 percent; lion, 2 percent). Despite their large body size and long life span, elephants remain cancer resistant, with an estimated cancer mortality of 4.8 percent, compared with humans, who have 11 percent to 25 percent cancer mortality.

While humans have 1 copy (2 alleles [one of a pair of alternative forms of a gene]) of TP53 (a crucial tumor suppressor gene, mutated in the majority of human cancers), African elephants have at least 20 copies (40 alleles). Patients with LFS inherit only 1 functioning TP53 allele and may have a lifetime risk of cancer approaching 90 percent to 100 percent. TP53 plays a central role in response to DNA damage through apoptosis (a form of cell death) and cell cycle arrest. In response to DNA damage, elephant lymphocytes underwent p53-mediated apoptosis at higher rates than human lymphocytes proportional to TP53 status. The multiple copies of TP53 and the enhanced p53-mediated apoptosis observed in elephants may have evolved to offer such cancer protection.

“Compared with other mammalian species, elephants appeared to have a lower-than-expected rate of cancer, potentially related to multiple copies of TP53. Compared with human cells, elephant cells demonstrated increased apoptotic response following DNA damage. These findings, if replicated, could represent an evolutionary-based approach for understanding mechanisms related to cancer suppression,” the authors write.

(doi:10.1001/jama.2015.13134; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

Editorial: Evolutionary Adaptations to Cancer Risk

“It is not clear what lessons the study of elephants by Abegglen and colleagues has for informing cancer risk in humans. Perhaps the main message from this innovative investigation is to bring into focus the question of why humans appear to be so ill-adapted to cancer, given the average size and life span? The human genome is replete with footprints of positive selection in the not too distant historical past. Humans may have acquired, in one particular respect, an extra cancer suppressor gene variant early on in evolutionary history approximately 1.8 million years ago,” writes Mel Greaves, Ph.D., of the Institute of Cancer Research, London, in an accompanying editorial.

“However, in other respects, as aging occurs, modern humans appear to be exceptionally vulnerable to cancer, especially in more developed societies. The explanation for this dilemma may involve other factors that greatly increase cancer risk. For instance, most human cancers (approximately 75 percent – 90 percent) are associated with lifestyles that are not found among animals, such as smoking, reproductive, dietary, and sun­soaking habits. These behaviors are relatively recently acquired by humans, over a few hundred years, and the risks they impart far exceed prior and otherwise effective cancer suppressor mechanisms that were inherited from primate ancestors. Contrariwise, humans have inadvertently become maladapted via mismatches between current lifestyles and inherent genetics that was adaptively forged in a very different ancestral environment.”

(doi:10.1001/jama.2015.13153; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The author’s research is supported by a grant from the Wellcome Trust. The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

# # #

EMBARGOED FOR RELEASE: 8 A.M. (ET) WEDNESDAY, OCTOBER 7, 2015

Media Advisory: To contact Elie Azoulay, M.D., Ph.D., email elie.azoulay@sls.aphp.fr. To contact editorial co-author John P. Kress, M.D., email John Easton at John.Easton@uchospitals.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.12402 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.12401

Among immunocompromised patients admitted to the intensive care unit with hypoxemic (inadequate oxygenation of the blood) acute respiratory failure, early noninvasive ventilation compared with oxygen therapy alone did not reduce the risk of death at 28 days, according to a study appearing in JAMA. The study is being released to coincide with its presentation at the 28th annual congress of the European Society of Intensive Care Medicine.

The number of patients living with immune deficiencies is increasing steadily. These patients are at high risk for life-threatening complications, including acute respiratory failure warranting admission to the intensive care unit (ICU). Mortality in this situation has ranged from 40 percent to 90 percent and remains high, despite improvements in recent years. Noninvasive ventilation has been recommended to decrease mortality among immunocompromised patients with hypoxemic acute respiratory failure. However, its effectiveness has been unclear, according to background information in the article.

Elie Azoulay, M.D., Ph.D., of Saint-Louis University Hospital, Paris, and colleagues had 374 critically ill immunocompromised patients randomly assigned to early noninvasive ventilation (n = 191) or oxygen therapy alone (n = 183). Of these patients, 317 (85 percent) were receiving treatment for hematologic malignancies or solid tumors. The trial was conducted at 28 ICUs in France and Belgium.

On day 28 after randomization, 46 deaths (24 percent) had occurred in the noninvasive ventilation group vs 50 (27 percent) in the oxygen group. Oxygenation failure occurred in 155 patients overall (41 percent), 38 percent in the noninvasive ventilation group and 45 percent in the oxygen group. There were no significant differences in ICU-acquired infections, duration of mechanical ventilation, or lengths of ICU or hospital stays.

“In this multicenter randomized trial enrolling critically ill immunocompromised patients with acute respiratory failure, early noninvasive ventilation, compared with oxygen therapy alone, did not reduce the primary outcome of day-28 all-cause mortality, either overall or in any of the prespecified subgroups,” the authors write. “However, study power was limited.”

(doi:10.1001/jama.2015.12402; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The study was sponsored by 2 grants from the nonprofit organizations Legs Poix (Chancellerie des Universites de Paris) and the OUTCOMEREA study group. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: The Changing Landscape of Noninvasive Ventilation in the Intensive Care Unit

Bhakti K. Patel, M.D., and John P. Kress, M.D., of the University of Chicago, comment on this subject in an accompanying editorial.

“With additional efforts to continue to reduce the percentage of critically ill patients who require invasive mechanical ventilation, alternative strategies for noninvasive ventilation that minimize face mask leak, improve oxygenation, and decrease work of breathing with alternative interfaces such as high-flow nasal cannula will need further investigation.”

(doi:10.1001/jama.2015.12401; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 8 A.M. (ET) WEDNESDAY, OCTOBER 7, 2015

Media Advisory: To contact Paul Young, F.C.I.C.M., email paul.young@ccdhb.org.nz. To contact editorial co-author John A. Kellum, M.D., email Anita Srikameswaran at srikamav@upmc.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.12334 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.12390

There was no significant difference in the incidence of acute kidney injury or failure for intensive care unit (ICU) patients who received a buffered crystalloid or saline for fluid therapy, according to a study appearing in JAMA. The study is being released to coincide with its presentation at the 28th annual congress of the European Society of Intensive Care Medicine.

The administration of intravenous fluids to increase intravascular volume or maintain hydration is a frequent intervention in the ICU, although the choice of fluid remains controversial. Globally, 0.9 percent sodium chloride (saline) is the most commonly used resuscitation fluid. However, despite its widespread use, emerging data provide uncertainty about the safety of saline in patients who are critically ill, with a concern that the high chloride content may contribute to the development of acute kidney injury (AKI), according to background information in the article.

One alternative to saline is a buffered crystalloid solution with an electrolyte composition that more closely resembles that of plasma, such as the prototype compound sodium lactate solutions or proprietary “buffered” or “balanced” crystalloid solutions. Observational data suggest that buffered crystalloids may be associated with a decreased risk of AKI and of death compared with saline. Paul Young, F.C.I.C.M., of the Medical Research Institute of New Zealand, Wellington, and colleagues studied 2,278 patients who were receiving treatment in 4 ICUs in New Zealand and requiring crystalloid fluid therapy. Of these patients, 1,152 of 1,162 patients (99 percent) receiving buffered crystalloid and 1,110 of 1,116 patients (99.5 percent) receiving saline were analyzed.

In the buffered crystalloid group, 102 of 1,067 patients (9.6 percent) developed AKI within 90 days after enrollment compared with 94 of 1,025 patients (9.2 percent) in the saline group. In the buffered crystalloid group, renal replacement therapy (dialysis) was used in 38 of 1,152 patients (3.3 percent) compared with 38 of 1,110 patients (3.4 percent) in the saline group. Overall, 7.6 percent of patients in the buffered crystalloid group and 8.6 percent of patients in the saline group died in the hospital.

“Further large randomized clinical trials are needed to assess efficacy in higher-risk populations and to measure clinical outcomes such as mortality,” the authors write.

(doi:10.1001/jama.2015.12334; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This study was funded by the Health Research Council of New Zealand through a Research Partnership for Health Delivery grant and by Baxter Healthcare Corporation. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Assessing Toxicity of Intravenous Crystalloids in Critically Ill Patients

In an accompanying editorial, John A. Kellum, M.D., of the University of Pittsburgh, and Andrew D. Shaw, M.B., F.R.C.A., of the Vanderbilt University School of Medicine, Nashville, comment on the findings of this study.

“The results of the trial by Young et al provide reassurance that neither 0.9 percent saline nor a low-chloride electrolyte solution appears to be particularly hazardous when the total dose used in patients at low to moderate risk is about 2 L. This is an important contribution to the care of patients in the ICU. However, the large body of ‘circumstantial’ evidence that points to a harm signal for saline—with scant, if any, evidence of comparative benefit—should behoove intensivists and other clinicians to proceed with caution when ordering intravenous fluids.”

(doi:10.1001/jama.2015.12390; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) MONDAY, OCTOBER 5, 2015

Media Advisory: To contact Carlos G. Grijalva, M.D., M.P.H., call Craig Boerner at 615-322-4747 or email craig.boerner@vanderbilt.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.12160

Among children and adults hospitalized with community-acquired pneumonia, those with influenza-associated pneumonia, compared with those with pneumonia not associated with influenza, had lower odds of having received an influenza vaccination, according to a study published online by JAMA.

In the United States, seasonal influenza epidemics are responsible for an estimated average of 226,000 hospitalizations and between 3,000 and 49,000 deaths each year. Pneumonia, the leading infectious cause of hospitalization and death in the United States, is a relatively common and serious complication of influenza. Whether influenza vaccines can decrease the risk of influenza-associated hospitalizations for community acquired pneumonia remains unclear, according to background information in the article.

In an observational multicenter study of hospitalizations for community-acquired pneumonia conducted from January 2010 through June 2012 at 4 U.S. sites, Carlos G. Grijalva, M.D., M.P.H., of the Vanderbilt University School of Medicine, Nashville, Tenn., and colleagues used data from patients 6 months or older with laboratory-confirmed influenza infection and verified vaccination status during the influenza seasons. Odds ratios were calculated, comparing the odds of vaccination between influenza-positive (case) and influenza-negative (control) patients with pneumonia, controlling for various factors.

Overall, 2,767 patients hospitalized for pneumonia were eligible for the study; 162 (5.9 percent) had laboratory-confirmed influenza. Twenty-eight of 162 cases (17 percent) with influenza-associated pneumonia and 766 of 2,605 controls (29 percent) with influenza-negative pneumonia had been vaccinated. The estimated vaccine effectiveness was 57 percent, meaning that the odds of influenza vaccination among cases hospitalized with influenza-associated pneumonia was 57 percent lower than among noninfluenza pneumonia controls.

The authors note that the estimated odds ratio of vaccination between cases and controls, and derived vaccine effectiveness from this study, could be used to inform subsequent estimations of the national number of hospitalizations for pneumonia averted by influenza vaccination.

(doi:10.1001/jama.2015.12160; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This study was funded by the Influenza Division in the National Center for Immunization and Respiratory Diseases at the Centers for Disease Control and Prevention. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) MONDAY, OCTOBER 5, 2015

Media Advisory: To contact Alexander J. Kallen, M.D., M.P.H., call Melissa Brower at 404-639-4718 or email mbrower@cdc.gov. To contact editorial author Mary K. Hayden, M.D., call Charlie Jolie at 312-217-1864 or email Charles_L_Jolie@rush.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.12480 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.11629

The overall incidence in 2012-2013 was relatively low of a serious, highly drug-resistant group of bacteria (Carbapenem-resistant Enterobacteriaceae [CRE]) that are an important cause for health-care associated infections, according to a study published online by JAMA. Most CRE cases were associated with prior hospitalizations and discharge to long-term care settings.

Carbapenem-resistant Enterobacteriaceae are a worldwide clinical and public health problem. These multidrug-resistant organisms cause infections associated with high mortality and limited treatment options. Assessment of the U.S. epidemiology of CRE is needed to inform national prevention efforts, according to background information in the article.

Alexander J. Kallen, M.D., M.P.H., of the U.S. Centers for Disease Control and Prevention, Atlanta, and colleagues conducted a population- and laboratory-based active surveillance of CRE in 2012-2013 among individuals living in 1 of 7 U.S. metropolitan areas in Colorado, Georgia, Maryland, Minnesota, New Mexico, New York, and Oregon. Cases of CRE were defined as carbapenem-nonsusceptible (excluding ertapenem) and extended-spectrum cephalosporin-resistant Escherichia coli, Enterobacter aerogenes, Enterobocter cloacae complex, Klebsiella pneumoniae, or Klebsiella oxytoca that were recovered from sterile-site or urine cultures during 2012-2013.

Among 599 CRE cases in 481 individuals, 520 (87 percent) were isolated from urine and 68 (11 percent) from blood. The median age was 66 years. The overall annual CRE incidence rate per 100,000 population was 2.93. The authors note that this estimate is substantially lower than the incidence of infections due to other pathogens traditionally associated with health care exposures, including methicillin-resistant Staphylococcus aureus (25.1 per 100,000 population), invasive candidiasis (13.3-26.2 per 100,000), and Clostridium difficile (147.2 per 100,000).

Most cases occurred in individuals with prior hospitalizations (75 percent) or indwelling devices (73 percent; such as urinary catheter, central venous catheter); 56 percent of admitted cases resulted in a discharge to a long-term care setting. Death occurred in 51 cases (9 percent), including in 27.5 percent of cases with CRE isolated from normally sterile sites.

The CRE standardized incidence ratio was significantly higher than predicted for the sites in Georgia (1.65), Maryland (1.44), and New York (1.42), and significantly lower than predicted for the sites in Colorado (0.53), New Mexico (0.41), and Oregon (0.28).

“The fact that heterogeneity exists (with respect to the incidence and the types of CRE found in these different surveillance areas) further highlights the need to understand the local epidemiology to tailor prevention efforts in individual regions of the United States. The frequency with which individuals with CRE are transferred between facilities emphasizes the need for regional control efforts in all the facilities,” the authors write.

“In summary, the results of this investigation further inform local efforts to prevent CRE transmission. The low CRE incidence in the catchment areas, compared with other more established resistant organisms, highlights that CRE are emerging and suggests that control interventions implemented now could have a substantial effect.”

(doi:10.1001/jama.2015.12480; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This work was supported by the Emerging Infections Program and the National Center for Emerging and Zoonotic Infectious Diseases at the U.S. Centers for Disease Control and Prevention. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Measuring Carbapenem-Resistant Enterobacteriaceae in the United States

“The study by Guh et al represents an important step forward for CRE control in the United States,” writes Mary K. Hayden, M.D., of Rush University Medical Center, Chicago.

“Expansion of surveillance to more geographic regions, including rural settings and metropolitan areas known to have high prevalence of CRE, would provide a more complete picture of the U.S. burden. Molecular characterization of isolates would also inform prevention efforts. Whether the resources needed for this work will be made available is unclear.”

“In the meantime, physicians, infection control practitioners, and public health workers will continue to rely on the Multi-site Gram-negative Surveillance Initiative [used for this study] and other surveillance networks to measure the extent of CRE and estimate the effects of prevention efforts.”

(doi:10.1001/jama.2015.11629; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Hayden reported receiving grants from the U.S. Centers for Disease Control and Prevention.

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, OCTOBER 6, 2015

Media Advisory: To contact James Fleshman, M.D., call Craig Civale at 214-820-6251 or email Craig.Civale@baylorhealth.edu. To contact Andrew R. L. Stevenson, M.B.B.S., F.R.A.C.S., email admin@ausces.com. To contact editorial co-author Scott A. Strong, M.D., call Pat Tremmel at 847-491-4892 or email p-tremmel@northwestern.edu.

To place an electronic embedded link to these studies and editorial in your story This link to the 1^st study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10529 This link to the 2^nd study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.12009 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.11454

Compared to open resection (surgical removal) for rectal cancer, minimally invasive laparoscopic-assisted resection did not provide better cancer outcomes, according to two studies in the October 6 issue of JAMA.

Treatment of curable, locally advanced (stage II or III) rectal cancer relies on surgical resection as the core feature of a treatment process. Evidence about the efficacy of laparoscopic resection of rectal cancer is incomplete, particularly for patients with more advanced-stage disease. There are concerns that not all the cancer can be removed with minimally invasive techniques. James Fleshman, M.D., of Baylor University Medical Center, Dallas, and colleagues conducted a trial in which 486 patients with clinical stage II or Ill rectal cancer were randomly assigned to laparoscopic or open resection to examine whether laparoscopic resection is noninferior (not worse than) to open resection, as determined by several measures of the adequacy of cancer removal. A 6 percent noninferiority margin was chosen as being a clinically important difference. . The trial was conducted at 35 institutions in the United States and Canada and sponsored by the American College of Surgeons and the National Cancer Institute.

Two hundred forty patients with laparoscopic resection and 222 with open resection were evaluable for analysis. They underwent surgery by surgeons with experience and proven expertise in the operations they were performing. Pre-determined measures of overall surgical success occurred in 82 percent of laparoscopic resection cases and 87 percent of open resection cases. “Laparoscopic resection failed to meet the criterion for noninferiority for pathologic outcomes compared with open resection and was thus potentially inferior,” the authors write. In terms of cancer control, the laparoscopic procedure was not shown to be as good as the traditional, open operation.

Operative time was significantly longer for laparoscopic resection. Hospital length of stay, readmission within 30 days, and severe complications were not significantly different.

The researchers write that one explanation for their findings is that proctectomy (resection of the rectum) is challenging, and it can be even more difficult to work in the deep pelvis with in-line rigid instruments used in laparoscopic surgery. Access to this very difficult area of the body might be better with the open procedure. .

“Pending clinical oncologic outcomes [such as survival or cancer recurrence rates], the findings do not support the use of laparoscopic resection in these patients.”

(doi:10.1001/jama.2015.10529; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

In another study using the same design as the Fleshman study, Andrew R. L. Stevenson, M.B.B.S., F.R.A.C.S., of the University of Queensland, Brisbane, Australia, and colleagues conducted a phase 3 trial that included 475 patients with T1-T3 rectal cancer who were randomized to open laparotomy and rectal resection (n = 237) or laparoscopic rectal resection (n = 238) at 24 sites in Australia and New Zealand.

Proponents of the laparoscopic technique suggest that a similar tumor resection with better short-term outcomes can be achieved with minimal access surgery. Because of anatomical constraints, laparoscopic rectal resection may not be better because of limitations in performing an adequate cancer resection, according to background information in the article.

For this trial, the primary outcome of a successful resection (a composite of oncological factors, with a noninferiority margin of 8 percent) was achieved in 194 patients (82 percent) in the laparoscopic surgery group and in 208 patients (89 percent) in the open surgery group and was the same as that of the Fleshman study. Non inferiority was not shown for the laparoscopic resection, meaning that it was not shown to be as good as the open operation for rectal cancer. In fact, a post hoc test for superiority suggested that open surgery was better. Additional analysis with adjustment for baseline prognostic factors, including pathological grade, did not significantly change the overall treatment effect.

There were no differences between the two groups in hospital length of stay, intensive care unit stay or analgesic requirement.

“We were unable to establish noninferiority of laparoscopic rectal cancer surgery in this large randomized trial,” the authors write. “Even though our trial was not designed to demonstrate whether one method of rectal dissection was superior to the other, the inability to establish noninferiority suggests that surgeons should be cautious when considering the suitability of a laparoscopic approach for a patient with rectal cancer.”

(doi:10.1001/jama.2015.12009; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The study was supported by grants from the Colorectal Surgical Society of Australia and New Zealand Foundation and the National Health and Medical Research Council. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Minimally Invasive Approaches to Rectal Cancer and Diverticulitis

The large, randomized, multicenter trials reported in this issue of JAMA substantiate recent findings from similar randomized trials that a laparoscopic resection may not be oncologically justified in many patients requiring proctectomy for rectal cancer, write Scott A. Strong, M.D., and Nathaniel J. Soper, M.D., of the Northwestern University Feinberg School of Medicine, Chicago.

“The studies do not signal a moratorium on these approaches, but surgeons must proceed in a judicious manner to ensure that patients are informed about the benefits and risks associated with minimally invasive and open operations.”

“Although the surgical management of patients with rectal cancer and diverticulitis has greatly improved, many questions persist and new ones continually arise that can be answered only with well-designed, rigorously conducted clinical trials. The utility of less intrusive strategies and minimally invasive approaches will undoubtedly expand as technologies evolve, but they must be responsibly incorporated into surgical practice based on evidence rather than subjective reasons.”

(doi:10.1001/jama.2015.11454; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, OCTOBER 6, 2015

Media Advisory: To contact Anne M. Moseley, Ph.D., email amoseley@georgeinstitute.org.au.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.12180

A supervised exercise program and self-management advice, like those commonly given with physical therapy, did not improve activity limitation or quality of life compared with advice alone after removal of immobilization for patients with an uncomplicated ankle fracture, according to a study in the October 6 issue of JAMA.

Ankle fracture is a common injury and is treated with reduction (realignment), sometimes with surgical fixation, followed by a period of immobilization while the fracture heals. The benefits of rehabilitation after immobilization for ankle fracture has been unclear, according to background information in the article.

Anne M. Moseley, Ph.D., of the University of Sydney, Australia, and colleagues randomly allocated 214 patients with isolated ankle fracture presenting to fracture clinics in 7 Australian hospitals to rehabilitation (n = 106) or advice alone (n = 108), following removal of their immobilization cast. Rehabilitation consisted of a supervised exercise program (individually tailored, prescribed, monitored, and progressed by a physical therapist) and advice about self-management. Participants in the advice group were provided with a single session of self-management advice about exercise and return to activity.

There was follow-up for 170 patients (79 percent) at 6 months. Activity limitation and quality of life were assessed at study entry and at 1, 3 and 6 months. At study entry, participants had significant activity limitation and low quality of life. The researchers found that the rehabilitation program and self-management advice did not improve activity limitation or quality of life compared with advice alone. The treatment effects were not associated with fracture severity, age or sex.

“We have previously shown that recovery of activity limitation after ankle fracture is rapid in the first 6 months and that adding passive stretch or manual therapy to a supervised exercise program did not enhance the benefits of exercise alone,” the authors write. “It is possible that the lack of treatment effect we observed in this trial is attributable to the fact that rehabilitation cannot accelerate this rapid recovery. These findings and the findings of the present trial suggest that routine care for patients after isolated ankle fracture should include self-management advice at the time of removal of immobilization but not a supervised exercise program [like those typically provided in a physical therapy program].”

(doi:10.1001/jama.2015.12180 Available pre-embargo to the media at http:/media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 22, 2015

Media Advisory: To contact Jeffrey L. Cummings, M.D., Sc.D., email Janice Guhl at Guhlj@ccf.org. To contact editorial co-author Anne Corbett, Ph.D., email anne.corbett@kcl.ac.uk.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10214 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10215

In a preliminary 10-week randomized trial, patients with probable Alzheimer disease who received the combination medication dextromethorphan-quinidine demonstrated less occurrences and severity of agitation, compared to patients who received placebo, according to a study in the September 22/29 issue of JAMA.

Agitation and aggression are highly prevalent in patients with dementia and are associated with distress for patients and caregivers, greater risk of institutionalization, and accelerated progression to severe dementia and death. Nonpharmacological interventions are recommended as first-line therapy, but many patients fail to respond. Although many classes of psychotropic drugs are prescribed for agitation, safety concerns and modest or unproven efficacy limit their use, according to background information in the article.

The combination of the drugs dextromethorphan hydrobromide and quinidine sulfate is approved for the treatment of pseudobulbar affect (a neurologic disorder characterized by episodes of emotional displays such as crying), and there is evidence suggesting a potential benefit of these drugs for agitation. Jeffrey L. Cummings, M.D., Sc.D., of the Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, and colleagues randomly assigned 220 patients to receive dextromethorphan-quinidine (n = 93) or placebo (n = 127) in stage 1. In stage 2, patients receiving dextromethorphan-quinidine continued; those receiving placebo were stratified by response and re-randomized to dextromethorphan-quinidine (n = 59) or placebo (n = 60). The 10 week trial was conducted at 42 study sites.

A total of 194 patients (88 percent) completed the study. Analysis combining stages 1 (all patients) and 2 (re-randomized placebo nonresponders) showed significantly reduced measures of agitation (occurrence and severity of symptoms). Patients treated with only dextromethorphan-quinidine had an average 51 percent reduction in the measure of agitation from baseline to week 10, compared with 26 percent for those treated with only placebo.

Adverse events included falls (8.6 percent for dextromethorphan-quinidine vs 3.9 percent for placebo), diarrhea (5.9 percent vs 3.1 percent, respectively), and urinary tract infection (5.3 percent vs 3.9 percent, respectively). Serious adverse events occurred in 7.9 percent with dextromethorphan-quinidine vs 4.7 percent with placebo. Dextromethorphan-quinidine was not associated with cognitive impairment or sedation.

“These preliminary findings require confirmation in additional clinical trials with longer treatment duration,” the authors write.

(doi:10.1001/jama.2015.10214; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

Editorial: Dextromethorphan and Quinidine for Treating Agitation in Patients With Alzheimer Disease Dementia

Pending further evidence, there is a reasonably strong case to prioritize dextromethorphan-quinidine as an off-label treatment for agitation, possibly as a safer alternative to atypical antipsychotics, writes Anne Corbett, Ph.D., of King’s College London, and colleagues in an accompanying editorial.

“However, while further studies are conducted to verify the efficacy and safety of this approach, it will be important to achieve a robust international expert consensus regarding the prioritization of potential treatments for agitation in patients with dementia to improve the consistency of clinical practice. This approach also must understand and incorporate patient and caregiver views regarding the evaluation of risk and benefits in relation to these treatments.”

(doi:10.1001/jama.2015.10215; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 22, 2015

Media Advisory: To contact Clara K. Chow, M.B.B.S., Ph.D., email cchow@georgeinstitute.org.au. To contact editorial co-author Zubin J. Eapen, M.D., M.H.S., call Sarah Avery at 919-660-1306 or email sarah.avery@duke.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10945 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.11067

A simple, low-cost automated program of semi-personalized mobile phone text messages supporting lifestyle change led to improvement in low-density lipoprotein cholesterol (LDL-C) levels, blood pressure, body mass index, and smoking status in patients with coronary heart disease, according to a study in the September 22/29 issue of JAMA.

Globally, cardiovascular disease is the leading cause of death and disease burden. Cardiovascular disease prevention, including lifestyle modification, is important but underutilized. Mobile phone text messages to remind, encourage, and motivate patients regarding the adoption of healthy lifestyles might be useful, but there has been limited scientific evaluation of these interventions, according to background information in the article.

Clara K. Chow, M.B.B.S., Ph.D., of the George Institute for Global Health, University of Sydney, Australia, and colleagues randomly assigned patients with proven coronary heart disease to receive 4 text messages per week for 6 months in addition to usual care (intervention group; n = 352) or usual care (control group; n=358). Text messages provided advice, motivational reminders, and support to change lifestyle behaviors. Messages for each participant were selected from a bank of messages according to baseline characteristics (e.g., smoking) and delivered via an automated computerized message management system. The average age of the patients was 58 years; 53 percent were current smokers.

At six months, levels of LDL-C were lower in intervention participants (79 mg/dL vs 84 mg/dL), as was systolic blood pressure (128 mm Hg vs 136 mm Hg) and body mass index. After six months, there was also a lower percentage (26 percent vs 43 percent) of smokers in the intervention group, who also reported an increase in physical activity. The proportion of patients achieving 3 of 5 guideline target levels of risk factors were substantially higher in the intervention group vs the control group (63 percent vs. 34 percent).

The majority of participants reported the text messages to be useful (91 percent), easy to understand (97 percent), and appropriate in frequency (86 percent).

“The duration of these effects and hence whether they result in improved clinical outcomes remain to be determined,” the authors conclude.

(doi:10.1001/jama.2015.10945; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

Editorial: Can Mobile Health Applications Facilitate Meaningful Behavior Change?

Zubin J. Eapen, M.D., M.H.S., and Eric D. Peterson, M.D., M.P.H., of the Duke Clinical Research Institute, Durham, N.C., (Dr. Peterson is also Associate Editor, JAMA) comment in an accompanying editorial.

“Health care needs to be challenged to make its evaluation as nimble as that of technology. The U.S. health care system needs to be capable of testing novel low-risk interventions such as text messaging in the context of routine clinical care. Creating an agile and clinically integrated research framework that rigorously evaluates all interventions—drug, device, or digital—is a collective responsibility and challenge for both app developers and health care practitioners. Solving this dilemma can enable the development and use of pragmatic, scalable, and evidence-based solutions that can address a massive problem like cardiovascular disease.”

(doi:10.1001/jama.2015.11067; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 22, 2015

Media Advisory: To contact Thomas S. Valley, M.D., email Kara Gavin at kegavin@med.umich.edu. To contact Jeremy M. Kahn, M.D., M.S., call Allison Hydzik at 412-647-9975 or email hydzikam@upmc.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.11068 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.11171

Among Medicare beneficiaries hospitalized with pneumonia, intensive care unit (ICU) admission of patients which appeared to be discretionary was associated with improved survival and no significant differences in Medicare spending or hospital costs, compared with patients admitted to general wards, according to a study in the September 22/29 issue of JAMA.

Observational studies examining the relationship between ICU admission frequency and patient outcomes often suggest that greater ICU use does not achieve better outcomes. However, these results are likely influenced by factors such as indication, because sicker patients are more likely to be admitted to the ICU. Among patients whose need for intensive care is uncertain, the relationship of ICU admission with mortality and costs has been unknown, according to background information in the article.

Thomas S. Valley, M.D., of the University of Michigan, Ann Arbor, and colleagues examined the association between ICU admission and outcomes, 30-day mortality and costs, among elderly patients hospitalized for pneumonia. The study included Medicare beneficiaries (older than 64 years of age) admitted to 2,988 acute care hospitals in the United States with pneumonia from 2010 to 2012.

Among 1,112,394 Medicare beneficiaries with pneumonia, 328,404 (30 percent) were admitted to the ICU. Patients (n = 553,597) living closer than the median differential distance (less than 3.3 miles) to a hospital with high ICU admission were significantly more likely to be admitted to the ICU than patients living farther away (n = 558,797) (36 percent for patients living closer vs 23 percent for patients living farther).

For the 13 percent of patients whose ICU admission decision appeared to be discretionary (dependent only on distance), ICU admission was associated with a significantly lower adjusted 30-day mortality (14.8 percent for ICU admission vs 20.5 percent for general ward admission), yet there were no significant differences in Medicare spending or hospital costs for the hospitalization.

The authors write that contrary to the study’s prespecified hypothesis, “these findings suggest that ICU admission for borderline patients (those for whom ICU admission depends on the hospital to which they present) is associated with reduced mortality without a considerable increase in costs.”

“A randomized trial may be warranted to assess whether more liberal ICU admission policies improve mortality for patients with pneumonia.”

(doi:10.1001/jama.2015.11068 Available pre-embargo to the media at http:/media.jamanetwork.com)

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

Editorial: Assessing the Value of Intensive Care

The findings of this study “argue against active efforts to reduce ICU admissions through triage guidelines or bed supply reductions, at least for older patients with pneumonia,” write Ian J. Barbash, M.D., and Jeremy M. Kahn, M.D., M.S., of the University of Pittsburgh School of Medicine, in an accompanying editorial.

“In the current health care system, more judicious use of the ICU may well lead to higher mortality in some patient populations. Indeed, the greatest lesson from this study may be that low-value health care is difficult to find. Reducing health care spending by preventing ICU readmissions will require addressing the difficult questions about rationing ICU care and the degree to which the nation can afford to make intensive care available to anyone at any time. While this conversation is underway, the task at hand is to study why the intensive care saves lives, and then use this information to make hospital care as safe and effective for all patients, regardless of where in the hospital they receive care.”

(doi:10.1001/jama.2015.11171; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 22, 2015

Media Advisory: To contact Timothy J. Fendler, M.D., M.S., call Laurel Gifford at 816-502-8532 or email lgifford@saint-lukes.org. To contact editorial co-author Derek C. Angus, M.D., M.P.H., call Allison Hydzik at 412-647-9975 or email hydzikam@upmc.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.11069 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.11735

Although do-not-resuscitate (DNR) orders after in-hospital cardiac arrest were generally aligned with patients’ likelihood of favorable neurological survival, almost two-thirds of patients with the worst prognosis did not have DNR orders, according to a study in the September 22/29 issue of JAMA.

Do-not-resuscitate orders are often established for patients whose prognosis is poor. One such example is in-hospital cardiac arrest, which affects nearly 200,000 patients in the United States annually, with rates of favorable neurological survival (i.e., survival without severe cognitive disability) of less than 20 percent. Accordingly, this poor prognosis frequently prompts discussions about DNR status among resuscitated patients and their families. It is not known if real-world decisions for DNR orders after successful resuscitation from in-hospital cardiac arrest are aligned with patients’ likelihood of favorable neurological survival, according to background information in the article.

From a registry (Get With The Guidelines-Resuscitation), Timothy J. Fendler, M.D., M.S., of Saint Luke’s Mid America Heart Institute, Kansas City, and colleagues identified 26,327 patients with return of spontaneous circulation (ROSC) after in-hospital cardiac arrest between April 2006 and September 2012 at 406 U.S. hospitals. Using a previously validated prognostic tool, each patient’s likelihood of favorable neurological survival (i.e., without severe neurological disability) was calculated. The proportion of patients with DNR orders within each prognosis score group and the association between DNR status and actual favorable neurological survival were examined.

Overall, 5,944 (23 percent) patients had DNR orders within 12 hours of ROSC. Among patients with the best prognosis, 7 percent had DNR orders even though their predicted rate of favorable neurological survival was 65 percent. Among patients with the worst expected prognosis, 36 percent had DNR orders even though their predicted rate for favorable neurological survival was 4 percent. The actual rate of favorable neurological survival was higher for patients without DNR orders (31 percent) than it was for those with DNR orders (2 percent).

“In this national registry of in-hospital cardiac arrest, we found that DNR orders after successful resuscitation were generally aligned with patients’ likelihood for favorable neurological survival, with increasing rates of DNR orders as a patient’s likelihood to survive without neurological disability decreased. Nevertheless, almost two-thirds of patients with the worst prognosis did not have DNR orders, even though only 4.0 percent of patients within this [group] had favorable neurological survival. Moreover, patients who had DNR orders despite a good prognosis had significantly lower survival and less resource use than patients without DNR orders who had a similar prognosis after ROSC,” the authors write

“Among patients with a low likelihood of favorable neurological survival after in-hospital cardiac arrest, our findings highlight the potential to improve DNR decision making.”

(doi:10.1001/jama.2015.11069; Available pre-embargo to the media at http:/media.jamanetwork.com)

Please Note: An author audio interview will be available for this study at JAMA.com at the embargo time.

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

Editorial: Successful Resuscitation From In-Hospital Cardiac Arrest – What Happens Next?

“In summary, when a cardiac arrest occurs in hospital, health care teams are good at rushing in to provide robust resuscitative efforts,” writes Derek C. Angus, M.D., M.P.H., of the University of Pittsburgh, and Associate Editor, JAMA, in an accompanying editorial.

“However, after successful ROSC, just as after the initial response to any disaster, it is clear the work has only just begun. Hopefully in the future, standardized delivery of high-quality evidence-based resuscitation guidelines for cardiac arrest will be followed by equally high-quality standard approaches to ensure patients and families are supported optimally, regardless of prognosis.”

(doi:10.1001/jama.2015.11735; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 22, 2015

Media Advisory: To contact Anthony V. D’Amico, M.D., Ph.D., 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: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8577

Among men with unfavorable-risk prostate cancer and moderate or severe co-existing illness, long-term follow-up finds that radiation therapy alone vs radiation therapy and androgen deprivation therapy was associated with decreased overall and cardiac mortality, according to a study in the September 22/29 issue of JAMA.

Six months of androgen deprivation therapy (ADT) and radiation therapy (RT) vs RT alone prolongs survival and is the standard treatment for unfavorable-risk prostate cancer. A post-randomization analysis suggested that men with moderate or severe comorbidity (co-existing illness) had no survival benefit from combined therapy. Using updated data from this trial, Anthony V. D’Amico, M.D., Ph.D., of Brigham and Women’s Hospital, Boston, and colleagues compared overall survival and mortality from prostate cancer, cardiac, or other causes in all men and those within comorbidity subgroups by treatment group. Between December 1995 and April 2001, 206 men with unfavorable-risk prostate cancer were randomly assigned to receive RT alone or RT and 6 months of ADT at 3 academic and 3 community-based centers in Massachusetts.

The researchers found that at a median follow-up of 17 years, RT alone vs RT and ADT was associated with significantly decreased overall and cardiac mortality in men with moderate or severe comorbidity. This is in contrast to no association with overall mortality at a median follow-up of 8 years. Although RT alone vs RT and ADT was associated with increased mortality in men with none or minimal comorbidity, mortality among all men assigned to RT alone was not significantly increased.

“The association of treatment with RT alone with decreased cardiac and overall mortality in men with moderate or severe comorbidity suggests that administering ADT to treat unfavorable-risk prostate cancer in these men should be carefully considered,” the authors write.

(doi:10.1001/jama.2015.8577; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 15, 2015

Media Advisory: To contact Mingguang He, M.D., Ph.D., email mingguang_he@yahoo.com. To contact editorial author Michael X. Repka, M.D., M.B.A., call Marin Hedin at 410-502-9429 or email mhedin2@jhmi.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10803 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10723

The addition of a daily outdoor activity class at school for three years for children in Guangzhou, China, resulted in a reduction in the rate of myopia (nearsightedness, the ability to see close objects more clearly than distant objects), according to a study in the September 15 issue of JAMA.

Myopia has reached epidemic levels in young adults in some urban areas of East and Southeast Asia. In these areas, 80 percent to 90 percent of high school graduates now have myopia. Myopia also appears to be increasing, more slowly, in populations of European and Middle Eastern origin. Currently, there is no effective intervention for preventing onset. Recent studies have suggested that time spent outdoors may prevent the development of myopia, according to background information in the article.

Mingguang He, M.D., Ph.D., of Sun Yat-sen University, Guangzhou, China, and colleagues conducted a study in which children in grade 1 from 12 primary schools in Guangzhou, China (six intervention schools [n = 952 students]; six control schools [n = 951 students], were assigned to 1 additional 40-minute class of outdoor activities, added to each school day, and parents were encouraged to engage their children in outdoor activities after school hours, especially during weekends and holidays (intervention schools); or children and parents continued their usual pattern of activity (control schools). The average age of the children was 6.6 years.

The 3-year cumulative incidence rate of myopia was 30.4 percent (259 cases among 853 eligible participants) in the intervention group and 39.5 percent (287 cases among 726 eligible participants) in the control group. Cumulative change in spherical equivalent refraction (myopic shift) after 3 years was significantly less in the intervention group than in the control group.

“Our study achieved an absolute difference of 9.1 percent in the incidence rate of myopia, representing a 23 percent relative reduction in incident myopia after 3 years, which was less than the anticipated reduction. However, this is clinically important because small children who develop myopia early are most likely to progress to high myopia, which increases the risk of pathological myopia. Thus a delay in the onset of myopia in young children, who tend to have a higher rate of progression, could provide disproportionate long-term eye health benefits,” the authors write.

“Further studies are needed to assess long-term follow-up of these children and the generalizability of these findings.”

(doi:10.1001/jama.2015.10803; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

Editorial: Prevention of Myopia in Children

Michael X. Repka, M.D., M.B.A., of the Johns Hopkins University School of Medicine, Baltimore, comments on the findings of this study in an accompanying editorial.

“Future studies should include information about the content of the additional outdoor activity, if the activity could be standardized, and how it differs from other studies. This information could guide further study and implementation of outdoor activities in the school setting. Establishing the long-term effect of additional outdoor activities on the development and progression of myopia is particularly important because the intervention is essentially free and may have other health benefits.”

“Given the popular appeal of increased outdoor activities to improve the health of school-aged children in general, the potential benefit of slowing myopia development and progression by those same activities is difficult to ignore. Although prescribing this approach with the intent of helping to prevent myopia would appear to have no risk, parents should understand that the magnitude of the effect is likely to be small and the durability is uncertain.”

(doi:10.1001/jama.2015.10723; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 15, 2015

Media Advisory: To contact Anupam B. Jena, M.D., Ph.D., call David Cameron at 617-432-0441 or email David_Cameron@hms.harvard.edu. To contact Robert Sege, M.D., Ph.D., call David Ball at 617-243-9950 or email david@ballcg.com. To contact editorial co-author Carrie L. Byington, M.D., call Julie Kiefer at 801-587-1293 or email julie.kiefer@utah.edu.

To place an electronic embedded link to this study and editorial in your story This will be the link to the 1^st study at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10803 This will be the link to the 2^nd study at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8517 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10664

Women are less likely than men to be full professors at U.S. medical schools, and receive less start-up support from their institutions for biomedical research, according to two studies in the September 15 issue of JAMA.

Women now make up half of all U.S. medical school graduates. However, sex disparities in senior faculty rank persist in academic medicine. Whether differences in age, experience, specialty, and research productivity between sexes explain persistent disparities in faculty rank has not been studied. Anupam B. Jena, M.D., Ph.D., of Harvard Medical School, Boston, and colleagues analyzed sex differences in faculty rank using a comprehensive database of U.S. physicians with medical school faculty appointments in 2014 (91,073 physicians; 9.1 percent of all U.S. physicians), linked to information on physician sex, age, years since residency, specialty, publications, National Institutes of Health (NIH) funding, and clinical trial investigation.

In all, there were 30,464 women who were medical faculty vs 60,609 men. Of those, 11.9 percent of women vs 28.6 percent of men had full-professor appointments. Women faculty were younger and disproportionately represented in internal medicine and pediatrics. The average total number of publications for women was 11.6 vs 24.8 for men; the average first- or last-author publications for women was 5.9 vs 13.7 for men.

Among 9.1 percent of medical faculty with an NIH grant, 6.8 percent were women and 10.3 percent were men. In all, 6.4 percent of women vs 8.8 percent of men had a trial registered on ClinicalTrials.gov. After adjustment for age, years since residency, specialty, and measures of research productivity, men were still significantly more likely than women to have achieved full-professor status. Sex differences in full professorship were present across nearly all specialties and were consistent across medical schools with highly and less highly ranked research programs.

The researchers also found that women were less likely than men to hold the rank of associate or full professor (a combined outcome) than to hold the rank of assistant professor and that women were less likely to hold the rank of full professor than hold the rank of associate professor.

The authors write that women may face difficulties finding effective mentors and receiving recognition from senior colleagues, workplace discrimination, and inequitable allocation of institutional resources. “These challenges may adversely affect research productivity and may also explain why even after adjusting for research productivity, women are still less likely than men to be full professors.”

(doi:10.1001/jama.2015.10803; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The authors report a funding grant from the Office of the Director, National Institutes of Health. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

In another study, Robert Sege, M.D., Ph.D., of Health Resources in Action, Boston, and colleagues examined sex differences in institutional support for junior biomedical researchers.

Women are underrepresented in the biomedical research workforce. Only 30 percent of funded investigators are women. Junior faculty women have fewer peer-reviewed publications than men and are more often on clinician-educator (vs traditional research) tracks. One reason may be differences in early-career institutional support, according to background information in the article.

Application data from two New England biomedical research programs administered by the Medical Foundation Division of Health Resources in Action were analyzed. Data on start-up support provided by the employing institution (i.e., salary and other support, including research technicians, equipment, and supplies) from all applications during 2012-2014 were extracted. The researchers compared support for men and women overall, and by scientific focus and terminal degree.

The study included 219 applicants (127 men and 92 women). Most applicants (67 percent) held Ph.D. degrees. Women were in clinical research more frequently than men. There were no differences between men and women in terminal degree or years since receiving terminal degree. Overall, men reported significantly higher start-up support (median, $889,000) than women (median, $350,000); 51 men (40 percent) and 11 women (12 percent) reported support of more than $1 million.

Men had higher support regardless of degree, but the difference was statistically significant only for persons with Ph.D. degrees. In basic sciences, men reported significantly more start-up support than women. Experience (years since receiving terminal degree) did not correlate with start-up package size for men, women, or overall.

“In this preliminary study of early-career grant applicants administered by 1 organization, junior faculty women received significantly less start-up support from their institutions than men,” the authors write. “This first look suggests the need for systematic study of sex differences in institutional support and the relationship to career trajectories.”

(doi:10.1001/jama.2015.8517; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The Medical Foundation Division of Health Resources in Action provided access to the administrative data. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Addressing Disparities in Academic Medicine

“These 2 articles add to the abundance of literature focusing on the disparities of careers of women in academic medicine. Importantly, similar disparities exist for individuals from racial and ethnic minorities and for those from other marginalized communities,” write Carrie L. Byington, M.D., and Vivian Lee, M.D., Ph.D., M.B.A., of the University of Utah, Salt Lake City, in an accompanying editorial.

“As the training ground for future generations of health care providers and biomedical scientists, academic medical centers should ensure that their students, faculty, and staff represent the people they serve and that all can contribute to their fullest potential. It is time for academic medicine to move forward.”

(doi:10.1001/jama.2015.10664; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 15, 2015

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

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10842

Patients undergoing surgery for a hip fracture were older and had more medical conditions than patients who underwent an elective total hip replacement, factors that may contribute to the higher risk of in-hospital death and major postoperative complications experienced by hip fracture surgery patients, according to a study in the September 15 issue of JAMA.

Although hip surgery can improve mobility and pain, it can be associated with major postoperative medical complications and mortality. Patients undergoing surgery for a hip fracture are at substantially higher risk of mortality and medical complications compared with patients undergoing an elective total hip replacement (THR). The effect of older age and other medical conditions associated with hip fracture on this increased risk has not been known, according to background information in the article.

Yannick Le Manach, M.D., Ph.D., of McMaster University, Hamilton, Ontario, Canada and colleagues examined if there was a difference in hospital mortality among patients who underwent hip fracture surgery relative to an elective THR, after adjustment for age, sex, and preoperative medical conditions. Using the French National Hospital Discharge Database, the researchers included patients older than 45 years who underwent hip surgery at French hospitals from January 2010 to December 2013. The International Statistical Classification of Diseases and Related Health Problems, 10th Revision, codes were used to determine patients’ co-existing conditions and complications after surgery.

A total of 690,995 eligible patients were included from 864 centers in France. Patients undergoing elective THR surgery (n = 371,191) were younger, more commonly men, and had less medical comorbidity compared with patients undergoing hip fracture surgery. Following hip fracture surgery (n = 319,804), 10,931 patients (3.4 percent) died before hospital discharge and 669 patients (0.18 percent) died after elective THR.

Analysis of the matched populations (n = 234,314) demonstrated a higher risk of mortality (1.8 percent for hip fracture surgery vs 0.3 percent for elective THR) and of major postoperative complications (5.9 percent for hip fracture surgery vs 2.3 percent for elective THR) among patients undergoing hip fracture surgery.

“Patients undergoing surgery for a hip fracture were older and had more comorbidities than patients who underwent an elective THR, and these differences accounted for some of the difference in outcomes between these groups,” the authors write.

“If the absolute risk increases of 1.51 percent for in-hospital mortality and 3.54 percent for major postoperative complications were modifiable, they would be consistent with the number needed to treat of 59 patients for in-hospital mortality and 28 patients for major postoperative complications. Hip fracture may be associated with physiologic processes that are not present in circumstances leading to elective THR and increase the risk of morbidity and mortality following surgery.”

“Further studies are needed to define the causes for these differences.”

(doi:10.1001/jama.2015.10842; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 8, 2015

Media Advisory: To contact Andy Menke, Ph.D., call Mona Feldman at 301-628-3000 or email MFeldman@s-3.com. To contact editorial co-author William H. Herman, M.D., M.P.H., call Kylie O’Brien at 734-764-2220 or email kylieo@med.umich.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10029 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10030

In 2011-2012, the estimated prevalence of diabetes among U.S. adults was 12 percent to 14 percent and the prevalence of prediabetes was 37 percent to 38 percent, indicating that about half of the U.S. adult population has either diabetes or prediabetes, according to a study in the September 8 issue of JAMA. Though data from recent years suggests that the increasing prevalence of diabetes may be leveling off.

Diabetes is a major cause of illness and death in the United States, costing an estimated $245 billion in 2012 due to increased use of health resources and lost productivity. Andy Menke, Ph.D., of Social & Scientific Systems Inc., Silver Spring, Md., and colleagues estimated the U.S. prevalence and trends in diabetes and undiagnosed diabetes using National Health and Nutrition Examination Survey (NHANES) data. The researchers included data from surveys conducted between 1988-1994 and 1999-2012; 2,781 adults from 2011-2012 were used to estimate recent prevalence and an additional 23,634 adults from 1988-2010 were used to estimate trends.

The prevalence of diabetes was defined using a previous diagnosis of diabetes or, if diabetes was not previously diagnosed, by (1) a hemoglobin A_1c level of 6.5 percent or greater or a fasting plasma glucose (FPG) level of 126 mg/dL or greater (hemoglobin A_1c or FPG definition) or (2) additionally including 2-hour plasma glucose (2-hour PG) level of 200 mg/dL or greater (hemoglobin A_1c, FPG, or 2-hour PG definition). Prediabetes was defined with certain levels of these markers.

Among the findings:

In the overall 2011-2012 population, the unadjusted prevalence (using the hemoglobin A_1c, FPG, or 2-hour PG definitions for diabetes and prediabetes) was 14.3 percent for total diabetes, 9.1 percent for diagnosed diabetes, 5.2 percent for undiagnosed diabetes, and 38 percent for prediabetes; among those with diabetes, 36.4 percent were undiagnosed.

Compared with non-Hispanic white participants (11.3 percent), the prevalence of total diabetes (using the hemoglobin A_1c, FPG, or 2-hour PG definition) was higher among non-Hispanic black participants (21.8 percent), non-Hispanic Asian participants (20.6 percent), and Hispanic participants (22.6 percent).

The prevalence of prediabetes was greater than 30 percent in all sex and racial/ethnic categories, and generally highest among non-Hispanic white individuals and non-Hispanic black individuals.

The percentage of cases that were undiagnosed was higher among non-Hispanic Asian participants (50.9 percent) and Hispanic participants (49 percent) than all other racial/ethnic groups.

The prevalence of total diabetes (using the hemoglobin A_1c or FPG definition) increased from 9.8 percent) in 1988-1994 to 10.8 percent in 2001-2002 to 12.4 percent in 2011-2012 and increased significantly in every age group, in both sexes, in every racial/ethnic group and by all education levels.

The authors note that although there was an increase in diabetes prevalence between 1988- 1994 and 2011-2012, prevalence estimates changed little between 2007-2008 and 2011-2012. “This plateauing of diabetes prevalence is consistent with obesity trends in the United States showing a leveling off around the same period.”

(doi:10.1001/jama.2015.10029; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: This work was supported by a contract from the National Institute of Diabetes and Digestive and Kidney Diseases. The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Editorial: Prevalence of Diabetes in the United States

“Although obesity and type 2 diabetes remain major clinical and public health problems in the United States, the current data provide a glimmer of hope,” write William H. Herman, M.D., M.P.H., and Amy E. Rothberg, M.D., Ph.D., of the University of Michigan Health System, Ann Arbor, in an accompanying editorial.

“The shift in cultural attitudes toward obesity, the American Medical Association’s (AMA’s) recognition of obesity as a disease, and the increasing focus on societal interventions to address food policy and the built environment are beginning to address some of the broad environmental forces that have contributed to the epidemic of obesity. The effort of the AMA to promote screening, testing, and referral of high-risk patients for diabetes prevention through its Prevent Diabetes STAT program and the CDC’s efforts to increase the availability of diabetes prevention programs, ensure their quality, and promote their use appear to be helping to identify at-risk individuals and provide the infrastructure to support individual behavioral change.”

“Providing insurance coverage for intensive behavioral therapies for obesity and using behavioral economic approaches to encourage their uptake are further removing barriers to patient engagement and are providing strong incentives for individual behavioral change. Together, these multifaceted approaches addressing both environmental factors and individual behaviors appear to be slowing the increase in obesity and diabetes, and facilitating the diagnosis and management of diabetes. Progress has been made, but expanded and sustained efforts will be required.”

(doi:10.1001/jama.2015.10030; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Herman reported receiving personal fees and other from Merck Sharp & Dahme and Lexicon Pharmaceuticals; and personal fees from Profil Institute for Clinical Research. No other disclosures were reported.

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 8, 2015

Media Advisory: To contact Barbara J. Stoll, M.D., call Holly Korschun at 404-727-3990 or email hkorsch@emory.edu. To contact editorial author Roger F. Soll, M.D., call Jennifer Nachbur at 802-656-7875 or email jennifer.nachbur@uvm.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10244 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10911

 Over the last 20 years, complications have decreased and survival has improved for extremely preterm infants, according to a study in the September 8 issue of JAMA.

Advances in medicine over the past 2 decades have changed care for mothers in preterm labor and for extremely preterm infants. Evaluation of current in-hospital complications and mortality data among extremely preterm infants is important in counseling families and considering new interventions to improve outcomes. Barbara J. Stoll, M.D., of the Emory University School of Medicine, Atlanta, and colleagues reviewed trends in maternal/neonatal care, complications, and mortality among 34,636 infants, 22 to 28 weeks’ gestation, birth weight of 14.1 ounces to 3.3 lbs. born at 26 Neonatal Research Network centers between 1993 and 2012.

The researchers found that survival increased between 2009 and 2012 for infants at 23 weeks’ gestation (27 percent to 33 percent) and 24 weeks (63 percent to 65 percent), with smaller relative increases for infants at 25 and 27 weeks’ gestation, and no change for infants at 22, 26, and 28 weeks’ gestation. Survival without major complications increased approximately 2 percent per year for infants at 25 to 28 weeks’ gestation, with no change for infants at 22 to 24 weeks’ gestation.

“Perhaps the most important new finding is a significant increase in survival without major neonatal morbidity [complication] for infants born at 25 through 28 weeks. Although overall survival increased for infants aged 23 and 24 weeks, few infants younger than 25 weeks’ gestational age survived without major neonatal morbidity, underscoring the continued need for interventions to improve outcomes for the most immature infants,” the authors write.

Use of antenatal corticosteroids, an intervention recommended for improved neonatal outcomes, increased from 1993 to 2012 (24 percent to 87 percent), as did cesarean delivery (44 percent to 64 percent). Strategies to reduce lung injury, including less aggressive ventilation, are recommended. Delivery room intubation decreased from 80 percent in 1993 to 65 percent in 2012. Although most infants were ventilated, continuous positive airway pressure without ventilation increased from 7 percent in 2002 to 11 percent in 2012.

Despite no improvement from 1993 to 2004, rates of late-onset sepsis declined between 2005 and 2012 for infants of each gestational age. Rates of other complications declined, but bronchopulmonary dysplasia (a chronic lung disease developed after oxygen inhalation therapy or mechanical ventilation) increased between 2009 and 2012 for infants at 26 to 27 weeks’ gestation.

“The study provides a global overview and level of detail not presented in earlier studies. Findings demonstrate that progress is being made and outcomes of the most immature infants are improving,” the authors write. “These findings are valuable in counseling families and developing novel interventions.”

“Although survival of extremely preterm infants has increased over the past 2 decades, including survival without major morbidity, the individual and societal burden of preterm birth remains substantial, with approximately 450,000 neonates born prematurely in the United States each year. To truly affect newborn outcomes, a comprehensive and sustained effort to reduce the high rates of preterm birth is necessary.”

(doi:10.1001/jama.2015.10244; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

Editorial: Progress in the Care of Extremely Preterm Infants

Roger F. Soll, M.D., of the University of Vermont College of Medicine, Burlington, comments on this study in an accompanying editorial.

“There is no obvious breakthrough therapy emerging in the coming years. Perhaps cellular therapy, such as mesenchymal stem cells, will be an important advance in the care of these fragile infants. However, it is more likely that incremental change, such as applying quality improvement practices to outcomes other than nosocomial infection, will lead to improved outcomes.”

“Stoll and colleagues have charted the progress made over the last 2 decades. It is clear that there are still a substantial number of extremely preterm infants who either die or survive after experiencing 1 or more major neonatal morbidities known to be associated with both short- and long-term adverse consequences. Although the neonatal-perinatal medicine community can be proud of the progress made, an additional commitment must be made to further improvements in the decades to come.”

(doi:10.1001/jama.2015.10911; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reports receipt of personal fees (serving as president and member of the Board of Directors) from the Vermont Oxford Network outside the submitted work.

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 8, 2015

Media Advisory: To contact Martin N. Mwangi, Ph.D., email mart.mwangi@gmail.com. To contact editorial co-author Robert E. Black, M.D., M.P.H., call Stephanie Desmon at 410-955-7619 or email sdesmon1@jhu.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.9496 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10032

Among women in a malaria-endemic region in Kenya, daily iron supplementation during pregnancy did not result in an increased risk of malaria, according to a study in the September 8 issue of JAMA. Iron supplementation did result in increased birth weight, gestational duration, neonatal length, and a decreased risk of low birth weight and prematurity.

Anemia in pregnancy is a moderate or severe health problem in more than 80 percent of countries worldwide, but particularly in Africa, where it affects 57 percent of pregnant women. Iron deficiency is the most common cause, but iron supplementation during pregnancy has uncertain health benefits. There is some evidence to suggest that iron supplementation may increase the risk of infectious diseases, including malaria. Martin N. Mwangi, Ph.D., of Wageningen University, Wageningen, the Netherlands, and colleagues randomly assigned 470 pregnant Kenyan women living in a malaria endemic area to daily supplementation with 60 mg of iron (n = 237 women) or placebo (n = 233) until 1 month postpartum. All women received 5.7 mg iron/day through flour fortification during intervention and usual intermittent preventive treatment against malaria.

Among the 470 participating women, 40 women (22 iron, 18 placebo) were lost to follow-up or excluded at birth; 12 mothers were lost to follow-up postpartum (5 iron, 7 placebo). At study entry, 190 of 318 women (60 percent) were iron-deficient. The researchers found that in a comparison of women who received iron vs placebo, Plasmodium infection (malaria) prevalence after childbirth was 50.9 percent vs 52.1 percent. “Overall, we found no effect of daily iron supplementation during pregnancy on risk of maternal Plasmodium infection. Iron supplementation resulted in an increased birth weight [5.3 ounces], gestational duration, and neonatal length; enhanced maternal and infant iron stores at 1 month after birth; and a decreased risk of low birth weight (by 58 percent) and prematurity. The effect on birth weight was influenced by initial maternal iron status. Correction of maternal iron deficiency led to an increase in birth weight by [8.4 ounces].”

Serious adverse events were reported for 9 and 12 women who received iron and placebo, respectively.

The authors note that their results may apply to pregnant women in other low- and middle-income countries, although the effect on birth weight can vary depending on the prevalence of iron deficiency.

“In low- and middle-income countries, it is generally impractical to screen for iron status, and most countries have policies for universal iron supplementation for pregnant women. Based on our results, we believe that the benefits of universal supplementation outweigh possible risks.”

(doi:10.1001/jama.2015.9496; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

Editorial: Antenatal Iron Use in Malaria Endemic Settings

“Pregnant women living in areas with endemic malaria require quality antenatal [during pregnancy] care,” write Parul Christian, Dr.P.H., M.Sc., and Robert E. Black, M.D., M.P.H., of the Johns Hopkins Bloomberg School of Public Health, Baltimore, in an accompanying editorial.

“In a recent evaluation using Demographic and Health Survey data from 41 countries, among women with 4 or more antenatal care visits, the greatest gaps in content of care involved iron and folic acid supplementation and malaria prevention. It is important that intermittent preventive treatment and insecticide-treated net use during pregnancy be increased in malaria endemic areas to protect the mother and fetus from the effects of malaria and to decrease the possible risk of adverse effects of iron if iron­ folic acid supplements or multiple micronutrient supplements are provided.”

(doi:10.1001/jama.2015.10032; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 8, 2015

Media Advisory: To contact Raj M. Ratwani, Ph.D., call Ann Nickels at 410-409-6399 or email ann.c.nickels@medstar.net.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8372

The lack of adherence to usability testing standards among several widely used electronic health record (EHR) products that were certified as having met these requirements may be a major factor contributing to the poor usability of EHRs, according to a study in the September 8 issue of JAMA.

Many EHRs have poor usability, leading to user frustration and safety risks. The U.S. Department of Health and Human Services’ Office of the National Coordinator for Health Information Technology (ONC) has established certification requirements to promote usability practices by EHR vendors as part of a meaningful use program. To develop a certified EHR, vendors are required to attest to using user-centered design (UCD), a process that places the needs of the frontline user at the forefront of software development, and to conduct formal usability testing on 8 different EHR capabilities to ensure the product meets performance objectives.

EHR vendors are required to provide a written statement naming the UCD process they used, and the results of their usability tests. The ONC has endorsed guidelines from the National Institute of Standards and Technology stipulating that usability testing should include at least 15 representative end-user participants, according to background information in the article.

Reports must be made public once the product is certified. Raj M. Ratwani, Ph.D., of MedStar Health, Washington, D.C., and colleagues analyzed reports meeting the 2014 certification requirements for the 50 EHR vendors with the highest number of providers (hospitals and small private practices) attesting to meeting meaningful use requirements with that product between April 2013 and November 2014. From each report, the authors extracted the stated UCD process and the number and clinical background of usability test participants.

Of the 50 certified vendor reports, 41 were available for review (82 percent); the remaining 9 (18 percent) were not publicly available. Of 41 vendors, 34 percent had not met the ONC certification requirement of stating their UCD process, 46 percent used an industry standard, and 15 percent used an internally developed UCD process.

There was variability in the number of participants enrolled in the usability tests. Of the 41 vendors, 63 percent used less than the standard of 15 participants and only 22 percent used at least 15 participants with clinical backgrounds. In addition, 1 of the 41 vendors used no clinical participants, 17 percent used no physician participants, and 5 percent used their own employees. Of the 41 vendor reports available, 12 percent lacked enough detail to determine whether physicians participated and 51 percent did not provide the required demographic details.

“The lack of adherence to usability testing may be a major factor contributing to the poor usability experienced by clinicians. Enforcement of existing standards, specific usability guidelines, and greater scrutiny of vendor UCD processes may be necessary to achieve the functional and safety goals for the next generation of EHRs,” the authors conclude.

(doi:10.1001/jama.2015.8372; Available pre-embargo to the media at http:/media.jamanetwork.com)

Editor’s Note: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Fairbanks reported receiving grant support from the Agency for Healthcare Research and Quality. No other disclosures were reported.

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 1, 2015

Media Advisory: To contact George L. Bakris, M.D., call John Easton at 773-795-5225 or email John.easton@uchospitals.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10081

Among patients with diabetes and kidney disease, most receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, the addition of the medication finerenone compared with placebo resulted in improvement in albuminuria (the presence of excessive protein [chiefly albumin] in the urine), according to a study in the September 1 issue of JAMA.

Diabetes mellitus is the most common cause of end-stage re­nal disease in the developed world. Trials of pa­tients with diabetic nephropathy (kidney disease from long-standing diabetes) have shown a strong relationship between magnitude of albuminuria reduction and slowing of chronic kidney disease (CKD) progression as well as reduced cardiovascular event rates. There is an unmet need to safely manage albuminuria with­out adversely affecting potassium levels in patients with type 2 diabetes mellitus who have a clinical diagnosis of diabetic kid­ney disease, according to information in the article.

George L. Bakris, M.D., of University of Chicago Medicine, and colleagues randomly assigned 823 patients (821 received study drug) with diabetes and elevated albuminuria who were receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to varying doses of the drug finerenone or placebo. In previous research, finerenone reduced albuminuria in pa­tients with chronic kidney disease and heart failure, with a lower incidence of hyperkalemia (higher than normal levels of potassium in the blood) compared to another medication. The current study was conducted at 148 sites in 23 countries.

At study entry, 37 percent of patients treated had very high albuminuria. The researchers found that finerenone reduced albuminuria at day 90 in a dose-dependent manner, with a significant reduc­tion in albuminuria (urinary albumin-creatinine ratio) ranging from 21 percent to 38 percent in the finerenone dos­age groups of 7.5 to 20 mg/d compared with placebo.

The outcome of hyperkalemia leading to discontinuation was not observed in the placebo and finerenone 10-mg/d groups; discontinuation in the finerenone 7.5-, 15-, and 20-mg/d groups were 2.1 percent, 3.2 percent, and 1.7 percent, respectively. There were no differences in the incidence of an estimated glomerular filtration rate (a measure of kidney function) decrease of 30 percent or more or in incidences of adverse events and serious adverse events between the placebo and finerenone groups.

“Further trials are needed to compare finerenone with other active medications,” the authors write.

(doi:10.1001/jama.2015.10081; Available pre-embargo to the media at https://media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 1, 2015

Media Advisory: To contact Stephen W. Scherer, Ph.D., call Suzanne Gold at 416-813-7654, ext. 202059, or email Suzanne.gold@sickkids.ca. To contact editorial author Judith H. Miles, M.D., Ph.D., call Stephanie Baehman at 573-884-3650 or email baehmans@health.missouri.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10078 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.9577

 
The use of two newer genetic testing technologies (chromosomal microarray analysis and whole-exome sequencing) among children with autism spectrum disorder may help identify genetic mutations potentially linked to the disorder, according to a study in the September 1 issue of JAMA. The study also found that children with certain physical anomalies were more likely to have genetic mutations, findings that may help identify children who could benefit most from genetic testing.

Autism spectrum disorder (ASD) represents a diverse group of neurodevelopmental conditions. The clinical presentation and outcome vary substantially. The use of genome-wide tests to provide molecular diagnosis for individuals with ASD requires more study, according to background information in the article.

Stephen W. Scherer, Ph.D., of the Hospital for Sick Children, Toronto, and colleagues performed chromosomal microarray analysis (CMA) and whole-exome sequencing (WES) in a group of 258 unrelated children with ASD to determine the molecular diagnostic yield (the percentage of subjects with a genetic alteration [mutation] that may contribute to the features of autism spectrum disorder) of these tests. All children underwent CMA; a random subset of 95 also underwent WES. All children underwent detailed clinical assessments for the presence of any major congenital abnormalities and minor physical anomalies and were stratified into 3 groups of increasing morphological severity (physical aberrations): essential, equivocal, and complex.

Of the 258 children, 24 (9.3 percent) received a molecular diagnosis from CMA and 8 of 95 (8.4 percent) from WES. The yields were statistically different between the morphological groups. Among the children who underwent both CMA and WES testing, the estimated proportion with an identifiable genetic cause was 15.8 percent. This included 2 children who received molecular diagnoses from both tests. The clinical yield for genetic testing was much higher (37.5 percent) in children with ASD who had more complex clinical presentations based on physical examination.

“In the current study, we have demonstrated differences related to morphological stratification of ASD [children] based on clinical examination. Our data suggest that medical evaluation of ASD children may help identify populations more likely to achieve a molecular diagnosis with genetic testing,” the authors write.

“It seems likely that genetic testing of children with ASD will continue to increase. In a survey of parental interest in ASD genetic testing, 80 percent of parents indicated that they would want a sibling younger than 2 years tested to identify ASD-risk mutations even if the test could not confirm or rule out the diagnosis. For some children with positive genetic test results, treatment plans targeting ASD-associated medical conditions can be offered.”

The researchers conclude that if “replicated in additional populations, these findings may inform appropriate selection of molecular diagnostic testing for children affected by ASD.”

(doi:10.1001/jama.2015.10078; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

Editorial: Complex Autism Spectrum Disorders and Cutting-Edge Molecular Diagnostic Tests

“For ASD, as well as for other behaviorally defined disorders, the results reported by Tammimies et al provide clear guidance,” writes Judith H. Miles, M.D., Ph.D., of University of Missouri Health Care, Columbia, in an accompanying editorial.

“Foremost, the data indicate that physicians responsible for children with ASD should arrange access to a genetic evaluation using techniques that have the best chance of determining an etiologic diagnosis. It is incontrovertible that precise diagnoses pave the way to better medical care, improved surveillance, better functional outcomes, and informed genetic counseling, often with the possibility of prenatal or preimplantation diagnosis.”

(doi:10.1001/jama.2015.9577; Available pre-embargo to the media at https://media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 1, 2015

Media Advisory: To contact Jonathan Rosand, M.D., M.Sc., call Terri Ogan at 617-726-0954 or email togan@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: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10082

Survivors of an intracerebral hemorrhage (ICH; a type of hemorrhagic stroke in which bleeding occurs directly into the brain) who had inadequate blood pressure (BP) control during follow-up had a higher risk of ICH recurrence, with this association appearing stronger with worsening severity of hypertension, according to a study in the September 1 issue of JAMA.

Intracerebral hemorrhage is the most severe and least treatable form of stroke, respon­sible for almost 50 percent of stroke-related illness and death. Intracerebral hemorrhage survivors are at high risk for recurrent ICH, death, and worsening disability. Preliminary evidence from another study suggested that BP lowering reduces incidence of ICH, according to background information in the study.

Jonathan Rosand, M.D., M.Sc., of Massachusetts General Hospital, Boston, and colleagues sought to determine whether BP reduc­tion and control are associated with risk of recurrence of lobar (a particular region of the brain) or nonlobar ICH. The study included 1,145 patients with ICH who survived at least 90 days and were followed up through December 2013 (median follow-up of 37 months). Blood pressure measurements were obtained at 3, 6, 9, and 12 months, and every 6 months thereafter from medical personnel or patient self-report.

There were 102 recurrent ICH events among 505 survivors of lobar ICH and 44 recurrent ICH events among 640 survivors of nonlobar ICH. During follow-up, adequate BP control (based on American Heart Association/American Stroke Association recommendations) was achieved on at least 1 measurement by 625 patients (55 percent of total) and consistently (i.e., at all available time points) by 495 patients (43 percent of total). The researchers found that the ICH event rate for lobar and nonlobar ICH was higher among patients with inadequate BP control compared with patients with adequate BP control. Analyses indicated that inadequate BP control was associated with higher risk of recurrence of both lobar and nonlobar ICH. The association between el­evated BP and ICH recurrence appeared to become stronger with worsening severity of hypertension.

Systolic BP during follow-up was associated with increased risk of both lobar and nonlobar ICH recurrence. Diastolic BP was associated with increased risk of nonlobar ICH recurrence, but not with lobar ICH recurrence.

“These results confirm that ICH survivors are at high risk for re­currence and support the hypothesis that aggressive blood pressure control may reduce this risk substantially,” the authors write. They add that the findings suggest that randomized clinical trials are needed to address the ben­efits and risks of stricter BP control in ICH survivors.

(doi:10.1001/jama.2015.10082; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: The authors’ work on this study was supported by funding from the National Institute of Neurological Disorders and Stroke. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 1, 2015

Media Advisory: To contact Arul M. Chinnaiyan, M.D., Ph.D., call Nicole Fawcett at 734-764-2220 or email nfawcett@umich.edu. To contact editorial co-author John M. Maris, M.D., call Alison Fraser at 267-426-6054 or email frasera1@email.chop.edu.

To place an electronic embedded link to this study and editorial in your story This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10080 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.9794

In a study that included children and young adults with relapsed or refractory cancer, incorporation of integrative clini­cal genomic sequencing data into clinical management was feasible, re­vealed potentially actionable findings in nearly half of the patients, and was associated with change in treatment and family genetics counseling for a small proportion of patients, according to a study in the September 1 issue of JAMA.

Outcomes of children and young adults with cancer have improved, primarily due to enhanced understanding of tumor biology and due to the clinical application of biological discoveries through multicenter clinical trials. However, survival for many pediatric oncology pa­tients, including those with recurrent disease or metastatic dis­ease, remains poor. Advances in genomic sequencing technologies have improved the ability to detect molecular aberrations with greater sensitivity and to identify genomic alterations that can be matched to targeted therapies. However, integrating this data into clinical management in an individualized manner has proven challenging, according to background information in the article.

Arul M. Chinnaiyan, M.D., Ph.D., of the University of Michigan, Ann Arbor, and colleagues studied104 children and young adults (average age, 11 years) with relapsed, refractory, or rare cancer. Participants underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing and genetic counseling. Results were discussed by a precision medicine tumor board, which made recommendations to families and their physicians.

Of the 104 screened patients, 102 enrolled with 91 (89 percent) having adequate tumor tissue to complete sequencing. Only the 91 patients were included in all calculations, including 28 (31 percent) with hematological malignancies and 63 (69 percent) with solid tumors. Forty-two patients (46 percent) had actionable findings that changed cancer management: 15 of 28 (54 percent) with hematological malignancies and 27 of 63 (43 percent) with solid tumors. Individualized actions were taken in 23 of the 91 (25 percent) based on clinical sequencing findings, including change in treatment for 14 patients (15 percent) and genetic counseling for 9 patients (10 percent).

Nine of 91 (10 percent) of the personalized clinical interventions resulted in ongoing partial clinical remission of 8 to 16 months or helped sustain complete clinical remission of 6 to 21 months. All 9 patients and families with actionable incidental genetic findings agreed to genetic counseling and screening.

“Many of these families had no significant family history and would likely have not been referred to genetic counseling under routine clinical care,” the authors write.

The researchers note that the lack of a control group limited assessing whether better clinical outcomes resulted from integrative clini­cal sequencing than outcomes that would have occurred with standard care.

(doi:10.1001/jama.2015.10080; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Improving Patient Outcomes With Cancer Genomics

John M. Maris, M.D., of Children’s Hospital of Philadelphia, and colleagues comment on this study in an accompanying editorial.

“The study by Mody and colleagues represents an impor­tant contribution to the care of children with cancer. It makes clear that approaches that are rapidly evolving in adults are ap­plicable to the care of children with cancer. These data strongly suggest that precision medicine enhanced by genetic evalua­tion may improve the outcomes of children with cancer.”

(doi:10.1001/jama.2015.9794; Available pre-embargo to the media at https://media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, SEPTEMBER 1, 2015

Media Advisory: To contact Benjamin N. Breyer, M.D., M.A.S., call Elizabeth Fernandez at 415-514-1592 or email Elizabeth.Fernandez@UCSF.edu.

To place an electronic embedded link to this study in your story This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8295

Between 1998 and 2013, there was a large increase in bicycle-related injuries and hospital admissions of adults in the United States, with the increase in injuries driven by more injuries among adults older than 45 years of age, according to a study in the September 1 issue of JAMA.

Cycling is associated with many health benefits, but also with the risk of injury. Trends in bicycle-related injuries are difficult to assess because the majority of nonfatal injuries sustained while cycling are not reported to police and thus are not included in traffic statistics. Benjamin N. Breyer, M.D., M.A.S., of the University of California, San Francisco, and colleagues analyzed data from the National Electronic Injury Surveillance System (NEISS), a national probability sample of approximately 100 emergency departments that gathers product-related injury data. The researchers queried the NEISS for injuries associated with bicycles from 1998 to 2013. The number of bicycle-related injuries in adults age 18 years or older was recorded in 2-year intervals.

During the study period, the 2-year age-adjusted incidence of injuries increased by 28 percent; the incidence of hospital admissions increased by 120 percent. The percentage of injured cyclists with head injuries increased from 10 percent to 16 percent. Overall, 35 percent of injuries occurred in women, with no significant change in sex ratio of injuries over time.

The proportion of injuries occurring in individuals older than 45 years increased 81 percent, from 23 percent to 42 percent, and the proportion of hospital admissions in individuals older than 45 years increased 66 percent, from 39 percent to 65 percent. “These injury trends likely reflect the trends in overall bicycle ridership in the United States in which multiple sources show an increase in ridership in adults older than 45 years,” the authors write.

“Other possible factors contributing to the increase in overall injuries and hospital admissions include an increase in street accidents and an increase in sport cycling associated with faster speeds. As the population of cyclists in the United States shifts to an older demographic, further investments in infrastructure and promotion of safe riding practices are needed to protect bicyclists from injury.”

(doi:10.1001/jama.2015.8295; Available pre-embargo to the media at http:/media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 7:45 A.M. (ET) SUNDAY, AUGUST 30, 2015

Media Advisory: To contact Gregory Y. H Lip, M.D., email g.y.h.lip@bham.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: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.10725

Among patients with heart failure with or without atrial fibrillation, use of a common clinical risk score was associated with risk of ischemic stroke, thromboembolism (blood clot), and death; however, predictive accuracy was modest, and the clinical usefulness of this score in patients with heart failure remains to be determined, according to a study appearing in JAMA. The study is being released to coincide with its presentation at the European Society of Cardiology Congress 2015.

Heart failure (HF) is associated with an increased risk of ischemic stroke and death. Risk stratification using readily available clinical variables may help identify sub­groups at low and high risk of ischemic stroke and thromboembolic events (TE) in an HF population. The CHA₂DS₂-VASc score (congestive heart failure, hypertension, age 75 years or older [doubled], diabetes, stroke/transient ischemic attack/thromboembolism [doubled], vascular disease [prior heart attack, peripheral artery disease, or aortic plaque], age 65-75 years, sex category [female]) is already used clinically for stroke risk stratification in patients with atrial fibrillation (AF). Its usefulness in a population of patients with HF has been unclear, according to background information in the article.

Gregory Y. H Lip, M.D., of Aalborg University, Aalborg, Denmark, and colleagues investigated whether CHA₂DS₂-VASc predicts ischemic stroke, thromboembolism, and death within one year in patients with a new diagnosis of HF with and without AF. Using Danish registries, the study included 42,987 patients (22 percent with concomitant [accompanying] AF) not receiving anticoagulation who were diagnosed as having new onset HF during 2000-2012. End of follow-up was December 31, 2012. Levels of the CHA₂DS₂-VASc score (based on 10 possible points, with higher scores indicating higher risk) were stratified by presence of AF at study entry.

The researchers found that pa­tients with HF had a high risk of ischemic stroke, TE, and death whether or not AF was present. However, the CHA₂DS₂-VASc score was only modestly able to predict these outcomes. At high CHA₂DS₂-VASc scores, patients with HF without AF had high absolute risk of ischemic stroke, TE, and death, and the absolute risk increased in a comparable manner in patients with HF, with and without AF. The absolute risk of thromboembolic com­plications was higher among patients without AF compared with patients with concomitant AF with high CHA₂DS₂-VASc scores.

“The poor progno­sis of AF for ischemic stroke and death in patients with HF was evident in our study, but the observation that additional risk factors in patients with HF are particularly significant among those without AF is an important result. Indeed, preventa­tive strategies to reduce ischemic stroke and TE risk in this large patient population require further investigation,” the authors write.

(doi:10.1001/jama.2015.10725; Available pre-embargo to the media at https://media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 25, 2015

Media Advisory: To contact Kaycee M. Sink, M.D., M.A.S., call Marguerite Beck at 336-716-2415 or email marbeck@wakehealth.edu. To contact Emily Y. Chew, M.D., call Joe Balintfy at 301-496-5248 or email neinews@nei.nih.gov. To contact editorial co-author Sudeep S. Gill, M.D., M.Sc., email Anne Craig at anne.craig@queensu.ca.

To place an electronic embedded link to these studies and editorial in your story  This link to the 1^st study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.9617. This link to the 2nd study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.9677. This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.9526.

Two studies in the August 25 issue of JAMA examine the effect of physical activity and nutrient supplementation on cognitive function.

In one study, Kaycee M. Sink, M.D., M.A.S., of the Wake Forest School of Medicine, Winston-Salem, N.C., and colleagues evaluated whether a 24-month physical activity program would result in better cognitive function, lower risk of mild cognitive impairment (MCI) or dementia, or both, compared with a health education program.

Epidemiological evidence suggests that physical activity is associated with lower rates of cognitive decline. Exercise is associated with improved cerebral blood flow and neuronal connectivity and maintenance or improvement in brain volume. However, evidence from randomized trials has been limited and mixed, according to background information in the article.

Participants in the Lifestyle Interventions and Independence for Elders (LIFE) study (n = 1,635; 70 to 89 years of age) were randomly assigned to a structured, moderate-intensity physical activity program (n = 818) that included walking, resistance training, and flexibility exercises or a health education program (n = 817) of educational workshops and upper-extremity stretching. Participants were sedentary adults who were at risk for mobility disability but able to walk about a quarter mile.  Measures of cognitive function and incident MCI or dementia were determined at 24 months.

The researchers found that the moderate-intensity physical activity intervention did not result in better global or domain-specific cognition compared with the health education program. There was also no significant difference between groups in the incidence of MCI or dementia (13.2 percent in the physical activity group vs 12.1 percent in the health education group), although this outcome had limited statistical power.

“Cognitive function remained stable over 2 years for all participants. We cannot rule out that both interventions were successful at maintaining cognitive function,” the authors write.

Participants in the physical activity group who were 80 years or older and those with poorer baseline physical performance had better changes in executive function composite scores compared with the health education group. “This finding is important because executive function is the most sensitive cognitive domain to exercise interventions, and preserving it is required for independence in instrumental activities of daily living. Future physical activity interventions, particularly in vulnerable older adult groups (e.g., ≥80 years of age and those with especially diminished physical functioning levels), may be warranted.”

(doi:10.1001/jama.2015.9617; Available pre-embargo to the media at https://media.jamanetwork.com)

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

In another study, Emily Y. Chew, M.D., of the National Eye Institute/National Institutes of Health, Bethesda, Md., and colleagues tested the effects of oral supplementation with nutrients on cognitive function.

The prevalence of Alzheimer disease, estimated to have affected 5.2 million people in the United States in 2013, may triple in the next 4 decades. Epidemiologic studies have suggested that diets high in omega-3 long-chain polyunsaturated fatty acids (LCPUFAs) have a protective role in maintaining cognitive function. However, numerous randomized clinical trials (RCTs) failed to show omega-3 LCPUFAs to be effective in treating dementia, according to background in the article.

Participants in the Age-Related Eye Disease Study 2 [AREDS2]), who were at risk for developing late age-related macular degeneration (AMD), were randomly assigned to LCPUFAs (1 g) and/or the dietary supplements lutein (10 mg)/zeaxanthin (2 mg) vs placebo. All participants were also given varying combinations of vitamins C. E. beta carotene, and zinc. In addition to annual eye examinations, several validated cognitive function tests were administered via telephone by trained personnel at baseline and every 2 years during the 5-year study. A total of 89 percent (3,741/4,203) of AREDS2 participants consented to the ancillary cognitive function study and 94 percent (3,501/3,741) underwent cognitive function testing. The average age of the participants was 73 years, and 57.5 percent were women.

There were no statistically significant differences in change of measures of cognitive function for participants randomized to receive supplements vs those who were not. The yearly change in the composite cognitive function score was -0.19 for participants randomized to receive LCPUFAs vs -0.18 for those randomized to no LCPUFAs. Similarly, the yearly change in the composite cognitive function score was -0.18 for participants randomized to receive lutein/zeaxanthin vs -0.19 for those randomized to not receive lutein/zeaxanthin.

Regarding the lack of effect of the supplements, the authors speculate that the supplements were started too late in the aging process and that supplementation duration of 5 years may be insufficient. “The process of cognitive decline may occur over decades, thus a short-term supplementation given too late in the disease may not be effective.”

They add that the observational data regarding dietary intake of specific nutrients such as omega-3 LCPUFAs and antioxidants suggest strong inverse associations with dementia, yet the RCTs have failed to show beneficial effects. “It is possible that eating foods rather than taking any specific single supplement may have an effect.”

(doi:10.1001/jama.2015.9677; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Lifestyles and Cognitive Health

“Although the well-designed RCTs presented by Sink and colleagues and Chew and colleagues failed to demonstrate significant cognitive benefits, these results should not lead to nihilism involving lifestyle factors in older adults. It is still likely that lifestyle factors such as diet and physical activity have important roles in the prevention of cognitive decline, dementia, and performance of the activities of daily living,” write Sudeep S. Gill, M.D., M.Sc., and Dallas P. Seitz, M.D., Ph.D., of Queen’s University, Kingston, Ontario, Canada, in an accompanying editorial.

“Physicians should encourage patients of all ages to optimize physical activity levels throughout their life, which may help to reduce the risk of developing dementia and many other adverse health outcomes. An active lifestyle throughout the lifespan may be more effective in preventing cognitive decline than starting physical activity after the onset of cognitive symptoms. Similarly, adherence to Mediterranean or heart healthy diets throughout life are likely to be most beneficial in preventing cognitive decline or the onset of dementia in contrast to isolated nutritional supplements initiated late in life.”

(doi:10.1001/jama.2015.9526; Available pre-embargo to the media at https://media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 25, 2015

Media Advisory: To contact Michael W. Donnino, M.D., call Kelly Lawman at 617-667-7305 or email klawman@bidmc.harvard.edu. To contact editorial co-author Adrienne G. Randolph, M.D., M.Sc., call Kristen Dattoli at 617-919-3110 or email kristen.dattoli@childrens.harvard.edu.

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8950

This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.9527

Among children with in-hospital cardiac arrest with an initial nonshockable heart rhythm who received epinephrine (adrenaline), delay in administration of epinephrine was associated with a decreased chance of 24-hour survival and survival to hospital discharge, according to a study in the August 25 issue of JAMA.

Approximately 16,000 children in the United States have a cardiac arrest each year, predominantly in a hospital setting. Epinephrine is recommended by both the American Heart Association and the European Resuscitation Council in pediatric cardiac arrest. Delay in administration of the first epinephrine dose is associated with decreased survival among adults after in-hospital, nonshockable (pulseless electrical activity or asystole) cardiac arrest. Whether this association is the same for children has not been known, according to background information in the article.

Michael W. Donnino, M.D., of Beth Israel Deaconess Medical Center, Boston, and colleagues examined whether time to first epinephrine dose is associated with improved clinical outcomes in pediatric in-hospital cardiac arrest. The researchers performed an analysis of data from the Get With the Guidelines–Resuscitation registry and included U.S. pediatric patients (age <18 years) with an in-hospital cardiac arrest and an initial nonshockable rhythm who received at least 1 dose of epinephrine.

A total of 1,558 patients (median age, 9 months) were included in the final analysis. Among these patients, 487 (31 percent) survived to hospital discharge. The median time to first epinephrine dose was 1 minute. Delay in administration of epinephrine was associated with a decreased chance of return of spontaneous circulation (ROSC), 24-hour survival, survival to hospital discharge, and survival to hospital discharge with a favorable neurological outcome. These associations remained when accounting for multiple patient, event, and hospital characteristics.

Patients with time to epinephrine administration of longer than 5 minutes (233/1,558) compared with those with time to epinephrine of 5 minutes or less (1,325/1,558) had lower likelihood of in-hospital survival to discharge (21 percent vs 33.1 percent).

“Although the observational design precludes ascertainment of causality, the strong association with outcomes suggests that early epinephrine may be beneficial in pediatric cardiac arrest,” the authors write.

(doi:10.1001/jama.2015.8950; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Pediatric Pulseless Arrest With “Nonshockable” Rhythm

“The study by Andersen et al reinforces that pediatric patients with in-hospital cardiac arrest and nonshockable rhythms have poor overall prognosis: less than one-third survive to hospital discharge, and survival with favorable neurocognitive outcome was even lower, at best 17 percent, even when epinephrine was given within first 5 minutes of resuscitation,” write Robert C. Tasker, M.B.B.S., M.D., and Adrienne G. Randolph, M.D., M.Sc., of Boston Children’s Hospital, in an accompanying editorial.

“Given there will never be a randomized clinical trial and that epinephrine is listed in the pediatric advanced life support guidelines as the next step after CPR for nonshockable rhythms, these new data provide fairly strong evidence that following the guidelines with regards to epinephrine dosing and timing is best practice, with this study likely providing an AHA Class I strength of recommendation. The data support what is currently recommended and show some benefit in the first 5 minutes. It is not known if epinephrine should be given within 2 minutes, as a good number of patients did not receive the drug at all and had ROSC in that time.”

(doi:10.1001/jama.2015.9527; Available pre-embargo to the media at https://media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 25, 2015

Media Advisory: To contact Adi V. Gundlapalli, M.D., Ph.D., M.S., call Jill Atwood at 801-584-1252 or email Jill.atwood@va.gov.

To place an electronic embedded link to this study in your story  This link for the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.8207

Among U.S. veterans who returned from Afghanistan and Iraq, being separated from the military for misconduct was associated with an increased risk of homelessness, according to a study in the August 25 issue of JAMA.

Adi V. Gundlapalli, M.D., Ph.D., M.S., of the VA Salt Lake City Health Care System, Salt Lake City, and colleagues analyzed Veterans Health Administration (VHA) data from U.S. active-duty military service members who were separated (end date of last deployment) from the military between October 2001 and December 2011, deployed in Afghanistan or Iraq, and eligible for and subsequently used VHA services. Homelessness was determined by a coding assignment of “lack of housing” during a VHA encounter, by participation in a VHA homelessness program, or both. The U.S. Department of Defense assigns a code upon separation from military service. These codes were categorized into misconduct (drugs, alcoholism, offenses, infractions, other), disability, early release, disqualified, normal, and other or unknown.

The analysis included 448,290 active-duty service members separated during this time period. Homelessness was determined by code (43 percent), participation in a homelessness program (35 percent), or both (27 percent). Although only 6 percent (n = 24,992) separated for misconduct, they represented 26 percent of homeless veterans at first VHA encounter (n = 322), 28 percent within 1 year (n = 1,141), and 21 percent within 5 years (n = 709). Incidence of homelessness was significantly greater for misconduct vs normal separations at first VHA encounter (1.3 percent vs 0.2 percent) and increased with time since first VHA encounter: within 1 year (5.4 percent vs 0.6 percent);  at 5 years (9.8 percent vs 1.4 percent).

The authors write that these findings support reports of recently returned veterans with records of misconduct having difficulties reentering civilian life. “This association takes on added significance because the incidence of misconduct-related separations is increasing at a time when ending homelessness among veterans is a federal government priority.”

“Identification of those with misconduct-related separations and provision of case management and rehabilitative services at separation by the Department of Defense and the VHA should be investigated as methods to prevent homelessness.”

(doi:10.1001/jama.2015.8207; Available pre-embargo to the media at https://media.jamanetwork.com)

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

# # #

EMBARGOED FOR RELEASE: 11 A.M. (ET) TUESDAY, AUGUST 25, 2015

Media Advisory: To contact Timothy J. Ley, M.D., call Diane Duke Williams at 314-286-0111 or email williamsdia@wustl.edu. To contact editorial co-author Ross L. Levine, M.D., call Nicole McNamara at 646-227-3633 or email mcnamarn@mskcc.org. An author interview podcast also will be available when the embargo lifts on the JAMA website: https://bit.ly/1NKdoAj

To place an electronic embedded link to this study and editorial in your story  This link to the study will be live at the embargo time: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.9643 This will be the link to the editorial: https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.9452

In preliminary research, the detection of persistent leukemia-associated genetic mutations in at least 5 percent of bone marrow cells in day 30 remission samples among adult patients with acute myeloid leukemia was associated with an increased risk of relapse and reduced overall survival, according to a study in the August 25 issue of JAMA.

Approximately 20 percent of adult patients with acute myeloid leukemia (AML) fail to achieve remission with initial induction chemotherapy, and approximately 50 percent ultimately experience relapse after achieving complete remission. Even though potentially curative therapy (e.g., allogeneic hematopoietic stem cell transplantation) is now available for many patients, this therapy is expensive and is associated with significant side effects. Identifying patients at high risk for relapse would be helpful clinically, according to background information in the article.

Timothy J. Ley, M.D., of the Washington University School of Medicine, St. Louis, and colleagues sought to determine whether genomic approaches can provide prognostic information for adult patients with AML. Whole-genome or exome sequencing was performed on samples obtained at disease presentation from 71 patients with AML (average age, 51 years) treated with standard induction chemotherapy at a single center starting in March 2002, with follow-up through January 2015. In addition, deep digital sequencing (next generation sequencing that permits sequencing of hundreds to thousands of individual molecules of DNA) was performed on paired diagnosis and remission samples from 50 patients (including 32 with intermediate-risk AML), approximately 30 days after successful induction therapy. Twenty-five of the 50 were from the cohort of 71 patients, and 25 were new, additional cases.

Analysis of comprehensive genomic data from the 71 patients did not improve outcome assessment over current standard-of-care metrics. In an analysis of 50 patients with both presentation and documented remission samples, 24 (48 percent) had persistent leukemia-associated mutations (mutations that are known to exist in a leukemia sample when the patient presents with the disease, but are not cleared after the initial chemotherapy is given, and the bone marrow recovers) in at least 5 percent of bone marrow cells at remission. The 24 with persistent mutations had significantly reduced event-free (6 vs. 17.9 months) and overall survival (10.5 vs. 42.2 months) vs the 26 who cleared all mutations (leukemia specific mutations that are found in the presentation sample that are completely eliminated after initial chemotherapy). These associations also were found among the 32 AML cases with intermediate risk cytogenetics (a risk classification category for AML based on looking at the tumor cell’s chromosomes).

“The data presented in this report begin to define a genomic method for the risk stratification of patients with AML that places greater emphasis on the clearance of somatic mutations [mutations that are not inherited] after chemotherapy than the identification of specific mutations at the time of presentation,” the authors write. “Although this study was not designed to determine the optimal clearance threshold for the association with outcomes, it represents a foundation for prospective trials focused on the role of digital sequencing to improve risk stratification for AML patients, and perhaps other cancer types as well.”

(doi:10.1001/jama.2015.9643; Available pre-embargo to the media at https://media.jamanetwork.com)

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

Editorial: Next-Generation Sequencing and Detection of Minimal Residual Disease in Acute Myeloid Leukemia

Friederike Pastore, M.D., and Ross L. Levine, M.D., of the Memorial Sloan Kettering Cancer Center, New York City, comment on the findings of this study in an accompanying editorial.

“Although many important questions remain, the findings reported by Klco and colleagues provide critical insights into the role of molecular monitoring in AML and into the dynamics of genetic mutations during AML treatment. The next steps should involve development of assays that can be used to enumerate minimal residual disease (MRD) in the clinic, performance studies to enumerate how best to use MRD monitoring in clinical care, and formulation of therapeutic regimens to target MRD and eradicate mutant clones to improve outcomes for patients with AML.”

(doi:10.1001/jama.2015.9452; Available pre-embargo to the media at https://media.jamanetwork.com)

Editor’s Note: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Pastore reports receiving a grant from the German Research Foundation. No other disclosures were reported.

# # #