Showing papers in "JAMA in 2015"

Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993-2012.

Abstract: Importance Extremely preterm infants contribute disproportionately to neonatal morbidity and mortality. Objective To review 20-year trends in maternal/neonatal care, complications, and mortality among extremely preterm infants born at Neonatal Research Network centers. Design, Setting, Participants Prospective registry of 34 636 infants, 22 to 28 weeks’ gestation, birth weight of 401 to 1500 g, and born at 26 network centers between 1993 and 2012. Exposures Extremely preterm birth. Main Outcomes and Measures Maternal/neonatal care, morbidities, and survival. Major morbidities, reported for infants who survived more than 12 hours, were severe necrotizing enterocolitis, infection, bronchopulmonary dysplasia, severe intracranial hemorrhage, cystic periventricular leukomalacia, and/or severe retinopathy of prematurity. Regression models assessed yearly changes and were adjusted for study center, race/ethnicity, gestational age, birth weight for gestational age, and sex. Results Use of antenatal corticosteroids increased from 1993 to 2012 (24% [348 of 1431 infants]) to 87% (1674 of 1919 infants];P Conclusions and Relevance Among extremely preterm infants born at US academic centers over the last 20 years, changes in maternal and infant care practices and modest reductions in several morbidities were observed, although bronchopulmonary dysplasia increased. Survival increased most markedly for infants born at 23 and 24 weeks’ gestation and survival without major morbidity increased for infants aged 25 to 28 weeks. These findings may be valuable in counseling families and developing novel interventions. Trial Registration clinicaltrials.gov Identifier:NCT00063063.

Nonalcoholic Fatty Liver Disease: A Systematic Review

Abstract: Importance Nonalcoholic fatty liver disease and its subtype nonalcoholic steatohepatitis affect approximately 30% and 5%, respectively, of the US population. In patients with nonalcoholic steatohepatitis, half of deaths are due to cardiovascular disease and malignancy, yet awareness of this remains low. Cirrhosis, the third leading cause of death in patients with nonalcoholic fatty liver disease, is predicted to become the most common indication for liver transplantation. Objectives To illustrate how to identify patients with nonalcoholic fatty liver disease at greatest risk of nonalcoholic steatohepatitis and cirrhosis; to discuss the role and limitations of current diagnostics and liver biopsy to diagnose nonalcoholic steatohepatitis; and to provide an outline for the management of patients across the spectrum of nonalcoholic fatty liver disease. Evidence Review PubMed was queried for published articles through February 28, 2015, using the search termsNAFLD and cirrhosis, mortality, biomarkers,andtreatment. A total of 88 references were selected, including 14 randomized clinical trials, 19 cohort or case-control studies, 1 population-based study, 2 practice guidelines, 7 meta-analyses, 43 classified as other, and 2 webpages. Findings Sixty-six percent of patients older than 50 years with diabetes or obesity are thought to have nonalcoholic steatohepatitis with advanced fibrosis. Even though the ability to identify the nonalcoholic steatohepatitis subtype within those with nonalcoholic fatty liver disease still requires liver biopsy, biomarkers to detect advanced fibrosis are increasingly reliable. Lifestyle modification is the foundation of treatment for patients with nonalcoholic steatosis. Available treatments with proven benefit include vitamin E, pioglitazone, and obeticholic acid; however, the effect size is modest ( Conclusions and Relevance Between 75 million and 100 million individuals in the United States are estimated to have nonalcoholic fatty liver disease and its potential morbidity extends beyond the liver. It is important that primary care physicians, endocrinologists, and other specialists be aware of the scope and long-term effects of the disease. Early identification of patients with nonalcoholic steatohepatitis may help improve patient outcomes through treatment intervention, including transplantation for those with decompensated cirrhosis.

Transfusion of plasma, platelets, and red blood cells in a 1: 1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: The PROPPR randomized clinical trial

Abstract: Importance Severely injured patients experiencing hemorrhagic shock often require massive transfusion. Earlier transfusion with higher blood product ratios (plasma, platelets, and red blood cells), defined as damage control resuscitation, has been associated with improved outcomes; however, there have been no large multicenter clinical trials. Objective To determine the effectiveness and safety of transfusing patients with severe trauma and major bleeding using plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. Design, Setting, and Participants Pragmatic, phase 3, multisite, randomized clinical trial of 680 severely injured patients who arrived at 1 of 12 level I trauma centers in North America directly from the scene and were predicted to require massive transfusion between August 2012 and December 2013. Interventions Blood product ratios of 1:1:1 (338 patients) vs 1:1:2 (342 patients) during active resuscitation in addition to all local standard-of-care interventions (uncontrolled). Main Outcomes and Measures Primary outcomes were 24-hour and 30-day all-cause mortality. Prespecified ancillary outcomes included time to hemostasis, blood product volumes transfused, complications, incidence of surgical procedures, and functional status. Results No significant differences were detected in mortality at 24 hours (12.7% in 1:1:1 group vs 17.0% in 1:1:2 group; difference, −4.2% [95% CI, −9.6% to 1.1%]; P = .12) or at 30 days (22.4% vs 26.1%, respectively; difference, −3.7% [95% CI, −10.2% to 2.7%]; P = .26). Exsanguination, which was the predominant cause of death within the first 24 hours, was significantly decreased in the 1:1:1 group (9.2% vs 14.6% in 1:1:2 group; difference, −5.4% [95% CI, −10.4% to −0.5%]; P = .03). More patients in the 1:1:1 group achieved hemostasis than in the 1:1:2 group (86% vs 78%, respectively; P = .006). Despite the 1:1:1 group receiving more plasma (median of 7 U vs 5 U, P P Conclusions and Relevance Among patients with severe trauma and major bleeding, early administration of plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio did not result in significant differences in mortality at 24 hours or at 30 days. However, more patients in the 1:1:1 group achieved hemostasis and fewer experienced death due to exsanguination by 24 hours. Even though there was an increased use of plasma and platelets transfused in the 1:1:1 group, no other safety differences were identified between the 2 groups. Trial Registration clinicaltrials.gov Identifier:NCT01545232

Cannabinoids for Medical Use: A Systematic Review and Meta-analysis.

Abstract: Importance Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms, but their efficacy for specific indications is not clear. Objective To conduct a systematic review of the benefits and adverse events (AEs) of cannabinoids. Data Sources Twenty-eight databases from inception to April 2015. Study Selection Randomized clinical trials of cannabinoids for the following indications: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette syndrome. Data Extraction and Synthesis Study quality was assessed using the Cochrane risk of bias tool. All review stages were conducted independently by 2 reviewers. Where possible, data were pooled using random-effects meta-analysis. Main Outcomes and Measures Patient-relevant/disease-specific outcomes, activities of daily living, quality of life, global impression of change, and AEs. Results A total of 79 trials (6462 participants) were included; 4 were judged at low risk of bias. Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs 20%; odds ratio [OR], 3.82 [95% CI, 1.55-9.42]; 3 trials), reduction in pain (37% vs 31%; OR, 1.41 [95% CI, 0.99-2.00]; 8 trials), a greater average reduction in numerical rating scale pain assessment (on a 0-10-point scale; weighted mean difference [WMD], −0.46 [95% CI, −0.80 to −0.11]; 6 trials), and average reduction in the Ashworth spasticity scale (WMD, −0.12 [95% CI, −0.24 to 0.01]; 5 trials). There was an increased risk of short-term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination. Conclusions and Relevance There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short-term AEs.

Prevalence of and Trends in Diabetes Among Adults in the United States, 1988-2012

Abstract: Importance Previous studies have shown increasing prevalence of diabetes in the United States. New US data are available to estimate prevalence of and trends in diabetes. Objective To estimate the recent prevalence and update US trends in total diabetes, diagnosed diabetes, and undiagnosed diabetes using National Health and Nutrition Examination Survey (NHANES) data. Design, setting, and participants Cross-sectional surveys conducted between 1988-1994 and 1999-2012 of nationally representative samples of the civilian, noninstitutionalized US population; 2781 adults from 2011-2012 were used to estimate recent prevalence and an additional 23,634 adults from 1988-2010 were used to estimate trends. Main outcomes and measures The prevalence of diabetes was defined using a previous diagnosis of diabetes or, if diabetes was not previously diagnosed, by (1) a hemoglobin A1c level of 6.5% or greater or a fasting plasma glucose (FPG) level of 126 mg/dL or greater (hemoglobin A1c or FPG definition) or (2) additionally including 2-hour plasma glucose (2-hour PG) level of 200 mg/dL or greater (hemoglobin A1c, FPG, or 2-hour PG definition). Prediabetes was defined as a hemoglobin A1c level of 5.7% to 6.4%, an FPG level of 100 mg/dL to 125 mg/dL, or a 2-hour PG level of 140 mg/dL to 199 mg/dL. Results In the overall 2011-2012 population, the unadjusted prevalence (using the hemoglobin A1c, FPG, or 2-hour PG definitions for diabetes and prediabetes) was 14.3% (95% CI, 12.2%-16.8%) for total diabetes, 9.1% (95% CI, 7.8%-10.6%) for diagnosed diabetes, 5.2% (95% CI, 4.0%-6.9%) for undiagnosed diabetes, and 38.0% (95% CI, 34.7%-41.3%) for prediabetes; among those with diabetes, 36.4% (95% CI, 30.5%-42.7%) were undiagnosed. The unadjusted prevalence of total diabetes (using the hemoglobin A1c or FPG definition) was 12.3% (95% CI, 10.8%-14.1%); among those with diabetes, 25.2% (95% CI, 21.1%-29.8%) were undiagnosed. Compared with non-Hispanic white participants (11.3% [95% CI, 9.0%-14.1%]), the age-standardized prevalence of total diabetes (using the hemoglobin A1c, FPG, or 2-hour PG definition) was higher among non-Hispanic black participants (21.8% [95% CI, 17.7%-26.7%]; P Conclusions and relevance In 2011-2012, the estimated prevalence of diabetes was 12% to 14% among US adults, depending on the criteria used, with a higher prevalence among participants who were non-Hispanic black, non-Hispanic Asian, and Hispanic. Between 1988-1994 and 2011-2012, the prevalence of diabetes increased in the overall population and in all subgroups evaluated.

Preferred Reporting Items for a Systematic Review and Meta-analysis of Individual Participant Data: The PRISMA-IPD Statement

Abstract: Importance Systematic reviews and meta-analyses of individual participant data (IPD) aim to collect, check, and reanalyze individual-level data from all studies addressing a particular research question and are therefore considered a gold standard approach to evidence synthesis. They are likely to be used with increasing frequency as current initiatives to share clinical trial data gain momentum and may be particularly important in reviewing controversial therapeutic areas. Objective To develop PRISMA-IPD as a stand-alone extension to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) Statement, tailored to the specific requirements of reporting systematic reviews and meta-analyses of IPD. Although developed primarily for reviews of randomized trials, many items will apply in other contexts, including reviews of diagnosis and prognosis. Design Development of PRISMA-IPD followed the EQUATOR Network framework guidance and used the existing standard PRISMA Statement as a starting point to draft additional relevant material. A web-based survey informed discussion at an international workshop that included researchers, clinicians, methodologists experienced in conducting systematic reviews and meta-analyses of IPD, and journal editors. The statement was drafted and iterative refinements were made by the project, advisory, and development groups. The PRISMA-IPD Development Group reached agreement on the PRISMA-IPD checklist and flow diagram by consensus. Findings Compared with standard PRISMA, the PRISMA-IPD checklist includes 3 new items that address (1) methods of checking the integrity of the IPD (such as pattern of randomization, data consistency, baseline imbalance, and missing data), (2) reporting any important issues that emerge, and (3) exploring variation (such as whether certain types of individual benefit more from the intervention than others). A further additional item was created by reorganization of standard PRISMA items relating to interpreting results. Wording was modified in 23 items to reflect the IPD approach. Conclusions and Relevance PRISMA-IPD provides guidelines for reporting systematic reviews and meta-analyses of IPD.

Comparison of MR/Ultrasound Fusion–Guided Biopsy With Ultrasound-Guided Biopsy for the Diagnosis of Prostate Cancer

Abstract: Importance Targeted magnetic resonance (MR)/ultrasound fusion prostate biopsy has been shown to detect prostate cancer. The implications of targeted biopsy alone vs standard extended-sextant biopsy or the 2 modalities combined are not well understood. Objective To assess targeted vs standard biopsy and the 2 approaches combined for the diagnosis of intermediate- to high-risk prostate cancer. Design, setting, and participants Prospective cohort study of 1003 men undergoing both targeted and standard biopsy concurrently from 2007 through 2014 at the National Cancer Institute in the United States. Patients were referred for elevated level of prostate-specific antigen (PSA) or abnormal digital rectal examination results, often with prior negative biopsy results. Risk categorization was compared among targeted and standard biopsy and, when available, whole-gland pathology after prostatectomy as the "gold standard." Interventions Patients underwent multiparametric prostate magnetic resonance imaging to identify regions of prostate cancer suspicion followed by targeted MR/ultrasound fusion biopsy and concurrent standard biopsy. Main outcomes and measures The primary objective was to compare targeted and standard biopsy approaches for detection of high-risk prostate cancer (Gleason score ≥ 4 + 3); secondary end points focused on detection of low-risk prostate cancer (Gleason score 3 + 3 or low-volume 3 + 4) and the biopsy ability to predict whole-gland pathology at prostatectomy. Results Targeted MR/ultrasound fusion biopsy diagnosed 461 prostate cancer cases, and standard biopsy diagnosed 469 cases. There was exact agreement between targeted and standard biopsy in 690 men (69%) undergoing biopsy. Targeted biopsy diagnosed 30% more high-risk cancers vs standard biopsy (173 vs 122 cases, P Conclusions and relevance Among men undergoing biopsy for suspected prostate cancer, targeted MR/ultrasound fusion biopsy, compared with standard extended-sextant ultrasound-guided biopsy, was associated with increased detection of high-risk prostate cancer and decreased detection of low-risk prostate cancer. Future studies will be needed to assess the ultimate clinical implications of targeted biopsy. Trial registration clinicaltrials.gov Identifier: NCT00102544.

Breast Cancer Screening for Women at Average Risk: 2015 Guideline Update From the American Cancer Society

Abstract: Importance Breast cancer is a leading cause of premature mortality among US women. Early detection has been shown to be associated with reduced breast cancer morbidity and mortality. Objective To update the American Cancer Society (ACS) 2003 breast cancer screening guideline for women at average risk for breast cancer. Process The ACS commissioned a systematic evidence review of the breast cancer screening literature to inform the update and a supplemental analysis of mammography registry data to address questions related to the screening interval. Formulation of recommendations was based on the quality of the evidence and judgment (incorporating values and preferences) about the balance of benefits and harms. Evidence Synthesis Screening mammography in women aged 40 to 69 years is associated with a reduction in breast cancer deaths across a range of study designs, and inferential evidence supports breast cancer screening for women 70 years and older who are in good health. Estimates of the cumulative lifetime risk of false-positive examination results are greater if screening begins at younger ages because of the greater number of mammograms, as well as the higher recall rate in younger women. The quality of the evidence for overdiagnosis is not sufficient to estimate a lifetime risk with confidence. Analysis examining the screening interval demonstrates more favorable tumor characteristics when premenopausal women are screened annually vs biennially. Evidence does not support routine clinical breast examination as a screening method for women at average risk. Recommendations The ACS recommends that women with an average risk of breast cancer should undergo regular screening mammography starting at age 45 years (strong recommendation). Women aged 45 to 54 years should be screened annually (qualified recommendation). Women 55 years and older should transition to biennial screening or have the opportunity to continue screening annually (qualified recommendation). Women should have the opportunity to begin annual screening between the ages of 40 and 44 years (qualified recommendation). Women should continue screening mammography as long as their overall health is good and they have a life expectancy of 10 years or longer (qualified recommendation). The ACS does not recommend clinical breast examination for breast cancer screening among average-risk women at any age (qualified recommendation). Conclusions and Relevance These updated ACS guidelines provide evidence-based recommendations for breast cancer screening for women at average risk of breast cancer. These recommendations should be considered by physicians and women in discussions about breast cancer screening.

Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.

Abstract: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies.

Prevalence of the metabolic syndrome in the United States, 2003-2012.

Abstract: Prevalence of the Metabolic Syndrome in the United States, 2003-2012 The metabolic syndrome contributes to cardiovascular morbidity and mortality.1-4 Data from the National Health and Nutrition Examination Survey (NHANES) 1999-2006 reported a metabolic syndrome prevalence of 34%.5 Understanding updated prevalence trends may be important given the potential effect of the metabolic syndrome and its associated health complications on the aging US population. We investigated trends in the prevalence of the metabolic syndrome through 2012.

Maintenance therapy with tumor-Treating fields plus temozolomide vs temozolomide alone for glioblastoma a randomized clinical trial

Abstract: Importance Glioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly. Objective To evaluate the efficacy and safety of TTFields used in combination with temozolomide maintenance treatment after chemoradiation therapy for patients with glioblastoma. Design, Setting, and Participants After completion of chemoradiotherapy, patients with glioblastoma were randomized (2:1) to receive maintenance treatment with either TTFields plus temozolomide (n = 466) or temozolomide alone (n = 229) (median time from diagnosis to randomization, 3.8 months in both groups). The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea. The trial was terminated based on the results of this planned interim analysis. Interventions Treatment with TTFields was delivered continuously (>18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide (150-200 mg/m 2 /d) was given for 5 days of each 28-day cycle. Main Outcomes and Measures The primary end point was progression-free survival in the intent-to-treat population (significance threshold of .01) with overall survival in the per-protocol population (n = 280) as a powered secondary end point (significance threshold of .006). This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up. Results The interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2 months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43-0.89]; P = .001). Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7-25.0 months) in the TTFields plus temozolomide group (n = 196) and 15.6 months (95% CI, 13.3-19.1 months) in the temozolomide alone group (n = 84) (HR, 0.64 [99.4% CI, 0.42-0.98]; P = .004). Conclusions and Relevance In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival. Trial Registration clinicaltrials.gov Identifier:NCT00916409

Trends in Prescription Drug Use Among Adults in the United States From 1999-2012.

Abstract: Importance It is important to document patterns of prescription drug use to inform both clinical practice and research. Objective To evaluate trends in prescription drug use among adults living in the United States. Design, Setting, and Participants Temporal trends in prescription drug use were evaluated using nationally representative data from the National Health and Nutrition Examination Survey (NHANES). Participants included 37 959 noninstitutionalized US adults, aged 20 years and older. Seven NHANES cycles were included (1999-2000 to 2011-2012), and the sample size per cycle ranged from 4861 to 6212. Exposures Calendar year, as represented by continuous NHANES cycle. Main Outcomes and Measures Within each NHANES cycle, use of prescription drugs in the prior 30 days was assessed overall and by drug class. Temporal trends across cycles were evaluated. Analyses were weighted to represent the US adult population. Results Results indicate an increase in overall use of prescription drugs among US adults between 1999-2000 and 2011-2012 with an estimated 51% of US adults reporting use of any prescription drugs in 1999-2000 and an estimated 59% reporting use of any prescription drugs in 2011-2012 (difference, 8% [95% CI, 3.8%-12%]; P for trend P for trend Conclusions and Relevance In this nationally representative survey, significant increases in overall prescription drug use and polypharmacy were observed. These increases persisted after accounting for changes in the age distribution of the population. The prevalence of prescription drug use increased in the majority of, but not all, drug classes.

Prevalence of Depression and Depressive Symptoms Among Resident Physicians: A Systematic Review and Meta-analysis.

Abstract: Importance Physicians in training are at high risk for depression. However, the estimated prevalence of this disorder varies substantially between studies. Objective To provide a summary estimate of depression or depressive symptom prevalence among resident physicians. Data Sources and Study Selection Systematic search of EMBASE, ERIC, MEDLINE, and PsycINFO for studies with information on the prevalence of depression or depressive symptoms among resident physicians published between January 1963 and September 2015. Studies were eligible for inclusion if they were published in the peer-reviewed literature and used a validated method to assess for depression or depressive symptoms. Data Extraction and Synthesis Information on study characteristics and depression or depressive symptom prevalence was extracted independently by 2 trained investigators. Estimates were pooled using random-effects meta-analysis. Differences by study-level characteristics were estimated using meta-regression. Main Outcomes and Measures Point or period prevalence of depression or depressive symptoms as assessed by structured interview or validated questionnaire. Results Data were extracted from 31 cross-sectional studies (9447 individuals) and 23 longitudinal studies (8113 individuals). Three studies used clinical interviews and 51 used self-report instruments. The overall pooled prevalence of depression or depressive symptoms was 28.8% (4969/17 560 individuals, 95% CI, 25.3%-32.5%), with high between-study heterogeneity ( Q = 1247, τ 2 = 0.39, I2 = 95.8%, P Q = 14.4, τ 2 = 0.04, I2 = 79.2%) to 43.2% for the 2-item PRIME-MD (1349/2891 individuals, 95% CI, 37.6%-49.0%, Q = 45.6, τ 2 = 0.09, I2 = 84.6%). There was an increased prevalence with increasing calendar year (slope = 0.5% increase per year, adjusted for assessment modality; 95% CI, 0.03%-0.9%, P = .04). In a secondary analysis of 7 longitudinal studies, the median absolute increase in depressive symptoms with the onset of residency training was 15.8% (range, 0.3%-26.3%; relative risk, 4.5). No statistically significant differences were observed between cross-sectional vs longitudinal studies, studies of only interns vs only upper-level residents, or studies of nonsurgical vs both nonsurgical and surgical residents. Conclusions and Relevance In this systematic review, the summary estimate of the prevalence of depression or depressive symptoms among resident physicians was 28.8%, ranging from 20.9% to 43.2% depending on the instrument used, and increased with calendar year. Further research is needed to identify effective strategies for preventing and treating depression among physicians in training.

Effect of Laparoscopic-Assisted Resection vs Open Resection of Stage II or III Rectal Cancer on Pathologic Outcomes: The ACOSOG Z6051 Randomized Clinical Trial

Abstract: Importance Evidence about the efficacy of laparoscopic resection of rectal cancer is incomplete, particularly for patients with more advanced-stage disease. Objective To determine whether laparoscopic resection is noninferior to open resection, as determined by gross pathologic and histologic evaluation of the resected proctectomy specimen. Design, setting, and participants A multicenter, balanced, noninferiority, randomized trial enrolled patients between October 2008 and September 2013. The trial was conducted by credentialed surgeons from 35 institutions in the United States and Canada. A total of 486 patients with clinical stage II or III rectal cancer within 12 cm of the anal verge were randomized after completion of neoadjuvant therapy to laparoscopic or open resection. Interventions Standard laparoscopic and open approaches were performed by the credentialed surgeons. Main outcomes and measures The primary outcome assessing efficacy was a composite of circumferential radial margin greater than 1 mm, distal margin without tumor, and completeness of total mesorectal excision. A 6% noninferiority margin was chosen according to clinical relevance estimation. Results Two hundred forty patients with laparoscopic resection and 222 with open resection were evaluable for analysis of the 486 enrolled. Successful resection occurred in 81.7% of laparoscopic resection cases (95% CI, 76.8%-86.6%) and 86.9% of open resection cases (95% CI, 82.5%-91.4%) and did not support noninferiority (difference, -5.3%; 1-sided 95% CI, -10.8% to ∞; P for noninferiority = .41). Patients underwent low anterior resection (76.7%) or abdominoperineal resection (23.3%). Conversion to open resection occurred in 11.3% of patients. Operative time was significantly longer for laparoscopic resection (mean, 266.2 vs 220.6 minutes; mean difference, 45.5 minutes; 95% CI, 27.7-63.4; P Conclusions and relevance Among patients with stage II or III rectal cancer, the use of laparoscopic resection compared with open resection failed to meet the criterion for noninferiority for pathologic outcomes. Pending clinical oncologic outcomes, the findings do not support the use of laparoscopic resection in these patients. Trial registration clinicaltrials.gov Identifier: NCT00726622.

Effect of Laparoscopic-Assisted Resection vs Open Resection on Pathological Outcomes in Rectal Cancer: The ALaCaRT Randomized Clinical Trial

Abstract: Importance Laparoscopic procedures are generally thought to have better outcomes than open procedures. Because of anatomical constraints, laparoscopic rectal resection may not be better because of limitations in performing an adequate cancer resection. Objective To determine whether laparoscopic resection is noninferior to open rectal cancer resection for adequacy of cancer clearance. Design, Setting, and Participants Randomized, noninferiority, phase 3 trial (Australasian Laparoscopic Cancer of the Rectum; ALaCaRT) conducted between March 2010 and November 2014. Twenty-six accredited surgeons from 24 sites in Australia and New Zealand randomized 475 patients with T1-T3 rectal adenocarcinoma less than 15 cm from the anal verge. Interventions Open laparotomy and rectal resection (n = 237) or laparoscopic rectal resection (n = 238). Main Outcomes and Measures The primary end point was a composite of oncological factors indicating an adequate surgical resection, with a noninferiority boundary of Δ = −8%. Successful resection was defined as meeting all the following criteria: (1) complete total mesorectal excision, (2) a clear circumferential margin (≥1 mm), and (3) a clear distal resection margin (≥1 mm). Pathologists used standardized reporting and were blinded to the method of surgery. Results A successful resection was achieved in 194 patients (82%) in the laparoscopic surgery group and 208 patients (89%) in the open surgery group (risk difference of −7.0% [95% CI, −12.4% to ∞]; P = .38 for noninferiority). The circumferential resection margin was clear in 222 patients (93%) in the laparoscopic surgery group and in 228 patients (97%) in the open surgery group (risk difference of −3.7% [95% CI, −7.6% to 0.1%]; P = .06), the distal margin was clear in 236 patients (99%) in the laparoscopic surgery group and in 234 patients (99%) in the open surgery group (risk difference of −0.4% [95% CI, −1.8% to 1.0%]; P = .67), and total mesorectal excision was complete in 206 patients (87%) in the laparoscopic surgery group and 216 patients (92%) in the open surgery group (risk difference of −5.4% [95% CI, −10.9% to 0.2%]; P = .06). The conversion rate from laparoscopic to open surgery was 9%. Conclusions and Relevance Among patients with T1-T3 rectal tumors, noninferiority of laparoscopic surgery compared with open surgery for successful resection was not established. Although the overall quality of surgery was high, these findings do not provide sufficient evidence for the routine use of laparoscopic surgery. Longer follow-up of recurrence and survival is currently being acquired. Trial Registration anzctr.org Identifier:ACTRN12609000663257

Association of Electronic Cigarette Use With Initiation of Combustible Tobacco Product Smoking in Early Adolescence

Abstract: Importance Exposure to nicotine in electronic cigarettes (e-cigarettes) is becoming increasingly common among adolescents who report never having smoked combustible tobacco. Objective To evaluate whether e-cigarette use among 14-year-old adolescents who have never tried combustible tobacco is associated with risk of initiating use of 3 combustible tobacco products (ie, cigarettes, cigars, and hookah). Design, Setting, and Participants Longitudinal repeated assessment of a school-based cohort at baseline (fall 2013, 9th grade, mean age = 14.1 years) and at a 6-month follow-up (spring 2014, 9th grade) and a 12-month follow-up (fall 2014, 10th grade). Ten public high schools in Los Angeles, California, were recruited through convenience sampling. Participants were students who reported never using combustible tobacco at baseline and completed follow-up assessments at 6 or 12 months (N = 2530). At each time point, students completed self-report surveys during in-classroom data collections. Exposure Student self-report of whether he or she ever used e-cigarettes (yes or no) at baseline. Main Outcomes and Measures Six- and 12-month follow-up reports on use of any of the following tobacco products within the prior 6 months: (1) any combustible tobacco product (yes or no); (2) combustible cigarettes (yes or no), (3) cigars (yes or no); (4) hookah (yes or no); and (5) number of combustible tobacco products (range: 0-3). Results Past 6-month use of any combustible tobacco product was more frequent in baseline e-cigarette ever users (n = 222) than never users (n = 2308) at the 6-month follow-up (30.7% vs 8.1%, respectively; difference between groups in prevalence rates, 22.7% [95% CI, 16.4%-28.9%]) and at the 12-month follow-up (25.2% vs 9.3%, respectively; difference between groups, 15.9% [95% CI, 10.0%-21.8%]). Baseline e-cigarette use was associated with greater likelihood of use of any combustible tobacco product averaged across the 2 follow-up periods in the unadjusted analyses (odds ratio [OR], 4.27 [95% CI, 3.19-5.71]) and in the analyses adjusted for sociodemographic, environmental, and intrapersonal risk factors for smoking (OR, 2.73 [95% CI, 2.00-3.73]). Product-specific analyses showed that baseline e-cigarette use was positively associated with combustible cigarette (OR, 2.65 [95% CI, 1.73-4.05]), cigar (OR, 4.85 [95% CI, 3.38-6.96]), and hookah (OR, 3.25 [95% CI, 2.29-4.62]) use and with the number of different combustible products used (OR, 4.26 [95% CI, 3.16-5.74]) averaged across the 2 follow-up periods. Conclusions and Relevance Among high school students in Los Angeles, those who had ever used e-cigarettes at baseline compared with nonusers were more likely to report initiation of combustible tobacco use over the next year. Further research is needed to understand whether this association may be causal.

Irritable Bowel Syndrome: A Clinical Review

Abstract: Importance Irritable bowel syndrome (IBS) affects 7% to 21% of the general population. It is a chronic condition that can substantially reduce quality of life and work productivity. Objectives To summarize the existing evidence on epidemiology, pathophysiology, and diagnosis of IBS and to provide practical treatment recommendations for generalists and specialists according to the best available evidence. Evidence Review A search of Ovid (MEDLINE) and Cochrane Database of Systematic Reviews was performed for literature from 2000 to December 2014 for the terms pathophysiology , etiology , pathogenesis , diagnosis , irritable bowel syndrome , and IBS . The range was expanded from 1946 to December 2014 for IBS , irritable bowel syndrome , diet , treatment , and therapy . Findings The database search yielded 1303 articles, of which 139 were selected for inclusion. IBS is not a single disease but rather a symptom cluster resulting from diverse pathologies. Factors important to the development of IBS include alterations in the gut microbiome, intestinal permeability, gut immune function, motility, visceral sensation, brain-gut interactions, and psychosocial status. The diagnosis of IBS relies on symptom-based criteria, exclusion of concerning features (symptom onset after age 50 years, unexplained weight loss, family history of selected organic gastrointestinal diseases, evidence of gastrointestinal blood loss, and unexplained iron-deficiency anemia), and the performance of selected tests (complete blood cell count, C-reactive protein or fecal calprotectin, serologic testing for celiac disease, and age-appropriate colorectal cancer screening) to exclude organic diseases that can mimic IBS. Determining the predominant symptom (IBS with diarrhea, IBS with constipation, or mixed IBS) plays an important role in selection of diagnostic tests and treatments. Various dietary, lifestyle, medical, and behavioral interventions have proven effective in randomized clinical trials. Conclusions and Relevance The diagnosis of IBS relies on the identification of characteristic symptoms and the exclusion of other organic diseases. Management of patients with IBS is optimized by an individualized, holistic approach that embraces dietary, lifestyle, medical, and behavioral interventions.

Psychotherapy for Military-Related PTSD: A Review of Randomized Clinical Trials.

Abstract: Importance Posttraumatic stress disorder (PTSD) is a disabling psychiatric disorder common among military personnel and veterans. First-line psychotherapies most often recommended for PTSD consist mainly of “trauma-focused” psychotherapies that involve focusing on details of the trauma or associated cognitive and emotional effects. Objective To examine the effectiveness of psychotherapies for PTSD in military and veteran populations. Evidence Review PubMed, PsycINFO, and PILOTS were searched for randomized clinical trials (RCTs) of individual and group psychotherapies for PTSD in military personnel and veterans, published from January 1980 to March 1, 2015. We also searched reference lists of articles, selected reviews, and meta-analyses. Of 891 publications initially identified, 36 were included. Findings Two trauma-focused therapies, cognitive processing therapy (CPT) and prolonged exposure, have been the most frequently studied psychotherapies for military-related PTSD. Five RCTs of CPT (that included 481 patients) and 4 RCTs of prolonged exposure (that included 402 patients) met inclusion criteria. Focusing on intent-to-treat outcomes, within-group posttreatment effect sizes for CPT and prolonged exposure were large (Cohen d range, 0.78-1.10). CPT and prolonged exposure also outperformed waitlist and treatment-as-usual control conditions. Forty-nine percent to 70% of participants receiving CPT and prolonged exposure attained clinically meaningful symptom improvement (defined as a 10- to 12-point decrease in interviewer-assessed or self-reported symptoms). However, mean posttreatment scores for CPT and prolonged exposure remained at or above clinical criteria for PTSD, and approximately two-thirds of patients receiving CPT or prolonged exposure retained their PTSD diagnosis after treatment (range, 60%-72%). CPT and prolonged exposure were marginally superior compared with non–trauma-focused psychotherapy comparison conditions. Conclusions and Relevance In military and veteran populations, trials of the first-line trauma-focused interventions CPT and prolonged exposure have shown clinically meaningful improvements for many patients with PTSD. However, nonresponse rates have been high, many patients continue to have symptoms, and trauma-focused interventions show marginally superior results compared with active control conditions. There is a need for improvement in existing PTSD treatments and for development and testing of novel evidence-based treatments, both trauma-focused and non–trauma-focused.

Efficacy of Liraglutide for Weight Loss Among Patients With Type 2 Diabetes The SCALE Diabetes Randomized Clinical Trial

Abstract: Importance Weight loss of 5% to 10% can improve type 2 diabetes and related comorbidities. Few safe, effective weight-management drugs are currently available. Objective To investigate efficacy and safety of liraglutide vs placebo for weight management in adults with overweight or obesity and type 2 diabetes. Design, Setting, and Participants Fifty-six–week randomized (2:1:1), double-blind, placebo-controlled, parallel-group trial with 12-week observational off-drug follow-up period. The study was conducted at 126 sites in 9 countries between June 2011 and January 2013. Of 1361 participants assessed for eligibility, 846 were randomized. Inclusion criteria were body mass index of 27.0 or greater, age 18 years or older, taking 0 to 3 oral hypoglycemic agents (metformin, thiazolidinedione, sulfonylurea) with stable body weight, and glycated hemoglobin level 7.0% to 10.0%. Interventions Once-daily, subcutaneous liraglutide (3.0 mg) (n = 423), liraglutide (1.8 mg) (n = 211), or placebo (n = 212), all as adjunct to 500 kcal/d dietary deficit and increased physical activity (≥150 min/wk). Main Outcomes and Measures Three coprimary end points: relative change in weight, proportion of participants losing 5% or more, or more than 10%, of baseline weight at week 56. Results Baseline weight was 105.7 kg with liraglutide (3.0-mg dose), 105.8 kg with liraglutide (1.8-mg dose), and 106.5 kg with placebo. Weight loss was 6.0% (6.4 kg) with liraglutide (3.0-mg dose), 4.7% (5.0 kg) with liraglutide (1.8-mg dose), and 2.0% (2.2 kg) with placebo (estimated difference for liraglutide [3.0 mg] vs placebo, −4.00% [95% CI, −5.10% to −2.90%]; liraglutide [1.8 mg] vs placebo, −2.71% [95% CI, −4.00% to −1.42%]; P P P P = .006). More gastrointestinal disorders were reported with liraglutide (3.0 mg) vs liraglutide (1.8 mg) and placebo. No pancreatitis was reported. Conclusions and Relevance Among overweight and obese participants with type 2 diabetes, use of subcutaneous liraglutide (3.0 mg) daily, compared with placebo, resulted in weight loss over 56 weeks. Further studies are needed to evaluate longer-term efficacy and safety. Trial Registration clinicaltrials.gov Identifier:NCT01272232

Wearable Devices as Facilitators, Not Drivers, of Health Behavior Change

Abstract: Several large technology companies including Apple, Google, and Samsung are entering the expanding market of population health with the introduction of wearable devices. This technology, worn in clothing or accessories, is part of a larger movement often referred to as the “quantified self.” The notion is that by recording and reporting information about behaviors such as physical activity or sleep patterns, these devices can educate and motivate individuals toward better habits and better health. The gap between recording information and changing behavior is substantial, however, and while these devices are increasing in popularity, little evidence suggests that they are bridging that gap. Only 1% to 2% of individuals in the United States have used a wearable device, but annual sales are projected to increase to more than $50 billion by 2018. 1 Some of these devices aim at individuals already motivated to change their health behaviors. Others are being considered by health care organizations, employers, insurers, and clinicians who see promise in using these devices to better engage less motivated individuals. Some of these devices may justify that promise, but less because of their technology and more because of the behavioral change strat

Blood Pressure Lowering in Type 2 Diabetes: A Systematic Review and Meta-analysis

Abstract: RESULTS Forty trials judged to be of low risk of bias (100 354 participants) were included. Each 10–mm Hg lower systolic BP was associated with a significantly lower risk of mortality (relative risk [RR], 0.87; 95% CI, 0.78-0.96); absolute risk reduction (ARR) in events per 1000 patient-years (3.16; 95% CI, 0.90-5.22), cardiovascular events (RR, 0.89 [95% CI, 0.83-0.95]; ARR, 3.90 [95% CI, 1.57-6.06]), coronary heart disease (RR, 0.88 [95% CI, 0.80-0.98]; ARR, 1.81 [95% CI, 0.35-3.11]), stroke (RR, 0.73 [95% CI, 0.64-0.83]; ARR, 4.06 [95% CI, 2.53-5.40]), albuminuria (RR, 0.83 [95% CI, 0.79-0.87]; ARR, 9.33 [95% CI, 7.13-11.37]), and retinopathy (RR, 0.87 [95% CI, 0.76-0.99]; ARR, 2.23 [95% CI, 0.15-4.04]). When trials were stratified by mean baseline systolic BP at greater than or less than 140 mm Hg, RRs for outcomes other than stroke, retinopathy, and renal failure were lower in studies with greater baseline systolic BP (P interaction <0.1). The associations between BP-lowering treatments and outcomes were not significantly different, irrespective of drug class, except for stroke and heart failure. Estimates were similar when all trials, regardless of risk of bias, were included. CONCLUSIONS AND RELEVANCE Among patients with type 2 diabetes, BP lowering was associated with improved mortality and other clinical outcomes with lower RRs observed among those with baseline BP of 140 mm Hg and greater. These findings support the use of medications for BP lowering in these patients.

Effect of time spent outdoors at school on the development of myopia among children in China a randomized clinical trial

Abstract: Importance Myopia has reached epidemic levels in parts of East and Southeast Asia. However, there is no effective intervention to prevent the development of myopia. Objective To assess the efficacy of increasing time spent outdoors at school in preventing incident myopia. Design, Setting, and Participants Cluster randomized trial of children in grade 1 from 12 primary schools in Guangzhou, China, conducted between October 2010 and October 2013. Interventions For 6 intervention schools (n = 952 students), 1 additional 40-minute class of outdoor activities was added to each school day, and parents were encouraged to engage their children in outdoor activities after school hours, especially during weekends and holidays. Children and parents in the 6 control schools (n = 951 students) continued their usual pattern of activity. Main Outcomes and Measures The primary outcome measure was the 3-year cumulative incidence rate of myopia (defined using the Refractive Error Study in Children spherical equivalent refractive error standard of ≤−0.5 diopters [D]) among the students without established myopia at baseline. Secondary outcome measures were changes in spherical equivalent refraction and axial length among all students, analyzed using mixed linear models and intention-to-treat principles. Data from the right eyes were used for the analysis. Results There were 952 children in the intervention group and 951 in the control group with a mean (SD) age of 6.6 (0.34) years. The cumulative incidence rate of myopia was 30.4% in the intervention group (259 incident cases among 853 eligible participants) and 39.5% (287 incident cases among 726 eligible participants) in the control group (difference of −9.1% [95% CI, −14.1% to −4.1%]; P P = .04). Elongation of axial length was not significantly different between the intervention group (0.95 mm) and the control group (0.98 mm) (difference of −0.03 mm [95% CI, −0.07 to 0.003 mm]; P = .07). Conclusions and Relevance Among 6-year-old children in Guangzhou, China, the addition of 40 minutes of outdoor activity at school compared with usual activity resulted in a reduced incidence rate of myopia over the next 3 years. Further studies are needed to assess long-term follow-up of these children and the generalizability of these findings. Trial Registration clinicaltrials.gov Identifier:NCT00848900

Emergency Department–Initiated Buprenorphine/Naloxone Treatment for Opioid Dependence: A Randomized Clinical Trial

Abstract: RESULTS Seventy-eight percent of patients in the buprenorphine group (89 of 114 [95% CI, 70%-85%]) vs 37% in the referral group (38 of 102 [95% CI, 28%-47%]) and 45% in the brief intervention group (50 of 111 [95% CI, 36%-54%]) were engaged in addiction treatment on the 30th day after randomization (P < .001). The buprenorphine group reduced the number of days of illicit opioid use per week from 5.4 days (95% CI, 5.1-5.7) to 0.9 days (95% CI, 0.5-1.3) vs a reduction from 5.4 days (95% CI, 5.1-5.7) to 2.3 days (95% CI, 1.7-3.0) in the referral group and from 5.6 days (95% CI, 5.3-5.9) to 2.4 days (95% CI, 1.8-3.0) in the brief intervention group (P < .001 for both time and intervention effects; P = .02 for the interaction effect). The rates of urine samples that tested negative for opioids did not differ statistically across groups, with 53.8% (95% CI, 42%-65%) in the referral group, 42.9% (95% CI, 31%-55%) in the brief intervention group, and 57.6% (95% CI, 47%-68%) in the buprenorphine group (P = .17). There were no statistically significant differences in HIV risk across groups (P = .66). Eleven percent of patients in the buprenorphine group (95% CI, 6%-19%) used inpatient addiction treatment services, whereas 37% in the referral group (95% CI, 27%-48%) and 35% in the brief intervention group (95% CI, 25%-37%) used inpatient addiction treatment services (P < .001).

The Propensity Score

Abstract: Two recent studies published in JAMA involved the analysis of observational data to estimate the effect of a treatment on patient outcomes. In the study by Roze et al,1 a large observational data set was analyzed to estimate the relationship between early echocardiography screening for patent ductus arteriosus and mortality among preterm infants. The authors compared mortality rates of 847 infants who were screened for patent ductus arteriosus and 666 who were not. The 2 infant groups were dissimilar; infants who were screened were younger, more likely female, and less likely to have received corticosteroids. The authors used propensity score matching to create 605 matched infant pairs from the original cohort to adjust for these differences. In the study by Huybrechts et al,2 the Medicaid Analytic eXtract data set was analyzed to estimate the association between antidepressant use during pregnancy and persistent pulmonary hypertension of the newborn. The authors included 3 789 330 women, of which 128 950 had used antidepressants. Women who used antidepressants were different from those who had not, with differences in age, race/ethnicity, chronic illnesses, obesity, tobacco use, and health care use. The authors adjusted for these differences using, in part, the technique of propensity score stratification.

Underlying Reasons Associated With Hospital Readmission Following Surgery in the United States

Abstract: Importance Financial penalties for readmission have been expanded beyond medical conditions to include surgical procedures. Hospitals are working to reduce readmissions; however, little is known about the reasons for surgical readmission. Objective To characterize the reasons, timing, and factors associated with unplanned postoperative readmissions. Design, Setting, and Participants Patients undergoing surgery at one of 346 continuously enrolled US hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) between January 1, 2012, and December 31, 2012, had clinically abstracted information examined. Readmission rates and reasons (ascertained by clinical data abstractors at each hospital) were assessed for all surgical procedures and for 6 representative operations: bariatric procedures, colectomy or proctectomy, hysterectomy, total hip or knee arthroplasty, ventral hernia repair, and lower extremity vascular bypass. Main Outcomes and Measures Unplanned 30-day readmission and reason for readmission. Results The unplanned readmission rate for the 498 875 operations was 5.7%. For the individual procedures, the readmission rate ranged from 3.8% for hysterectomy to 14.9% for lower extremity vascular bypass. The most common reason for unplanned readmission was surgical site infection (SSI) overall (19.5%) and also after colectomy or proctectomy (25.8%), ventral hernia repair (26.5%), hysterectomy (28.8%), arthroplasty (18.8%), and lower extremity vascular bypass (36.4%). Obstruction or ileus was the most common reason for readmission after bariatric surgery (24.5%) and the second most common reason overall (10.3%), after colectomy or proctectomy (18.1%), ventral hernia repair (16.7%), and hysterectomy (13.4%). Only 2.3% of patients were readmitted for the same complication they had experienced during their index hospitalization. Only 3.3% of patients readmitted for SSIs had experienced an SSI during their index hospitalization. There was no time pattern for readmission, and early (≤7 days postdischarge) and late (>7 days postdischarge) readmissions were associated with the same 3 most common reasons: SSI, ileus or obstruction, and bleeding. Patient comorbidities, index surgical admission complications, non-home discharge (hazard ratio [HR], 1.40 [95% CI, 1.35-1.46]), teaching hospital status (HR, 1.14 [95% CI 1.07-1.21]), and higher surgical volume (HR, 1.15 [95% CI, 1.07-1.25]) were associated with a higher risk of hospital readmission. Conclusions and Relevance Readmissions after surgery were associated with new postdischarge complications related to the procedure and not exacerbation of prior index hospitalization complications, suggesting that readmissions after surgery are a measure of postdischarge complications. These data should be considered when developing quality indicators and any policies penalizing hospitals for surgical readmission.

Accuracy of smartphone applications and wearable devices for tracking physical activity data.

Abstract: Accuracy of Smartphone Applications and Wearable Devices for Tracking Physical Activity Data Despite the potential of pedometers to increase physical activity and improve health,1 there is little evidence of broad adoption by the general population. In contrast, nearly twothirds of adults in the United States own a smartphone2 and technology advancements have enabled these devices to track health behaviors such as physical activity and provide convenient feedback.3 New wearable devices that may have more consumer appeal have also been developed. Even though these devices and applications might better engage individuals in their health, for example through workplace wellness programs,3 there has been little evaluation of their use.3-5 The objective of this study was to evaluate the accuracy of smartphone applications and wearable devices compared with direct observation of step counts, a metric successfully used in interventions to improve clinical outcomes.1

Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial.

Abstract: Importance Panretinal photocoagulation (PRP) is the standard treatment for reducing severe visual loss from proliferative diabetic retinopathy. However, PRP can damage the retina, resulting in peripheral vision loss or worsening diabetic macular edema (DME). Objective To evaluate the noninferiority of intravitreous ranibizumab compared with PRP for visual acuity outcomes in patients with proliferative diabetic retinopathy. Design, Setting, and Participants Randomized clinical trial conducted at 55 US sites among 305 adults with proliferative diabetic retinopathy enrolled between February and December 2012 (mean age, 52 years; 44% female; 52% white). Both eyes were enrolled for 89 participants (1 eye to each study group), with a total of 394 study eyes. The final 2-year visit was completed in January 2015. Interventions Individual eyes were randomly assigned to receive PRP treatment, completed in 1 to 3 visits (n = 203 eyes), or ranibizumab, 0.5 mg, by intravitreous injection at baseline and as frequently as every 4 weeks based on a structured re-treatment protocol (n = 191 eyes). Eyes in both treatment groups could receive ranibizumab for DME. Main Outcomes and Measures The primary outcome was mean visual acuity change at 2 years (5-letter noninferiority margin; intention-to-treat analysis). Secondary outcomes included visual acuity area under the curve, peripheral visual field loss, vitrectomy, DME development, and retinal neovascularization. Results Mean visual acuity letter improvement at 2 years was +2.8 in the ranibizumab group vs +0.2 in the PRP group (difference, +2.2; 95% CI, −0.5 to +5.0; P P P P P P = .58). One eye in the ranibizumab group developed endophthalmitis. No significant differences between groups in rates of major cardiovascular events were identified. Conclusions and Relevance Among eyes with proliferative diabetic retinopathy, treatment with ranibizumab resulted in visual acuity that was noninferior to (not worse than) PRP treatment at 2 years. Although longer-term follow-up is needed, ranibizumab may be a reasonable treatment alternative, at least through 2 years, for patients with proliferative diabetic retinopathy. Trial Registration clinicaltrials.gov Identifier:NCT01489189

Association of Cardiometabolic Multimorbidity With Mortality

Abstract: IMPORTANCE: The prevalence of cardiometabolic multimorbidity is increasing. OBJECTIVE: To estimate reductions in life expectancy associated with cardiometabolic multimorbidity. DESIGN, SETTING, AND PARTICIPANTS: Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. EXPOSURES: A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI). MAIN OUTCOMES AND MEASURES: All-cause mortality and estimated reductions in life expectancy. RESULTS: In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy. CONCLUSIONS AND RELEVANCE: Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT Randomized Clinical Trial

Abstract: Importance Saline (0.9% sodium chloride) is the most commonly administered intravenous fluid; however, its use may be associated with acute kidney injury (AKI) and increased mortality. Objective To determine the effect of a buffered crystalloid compared with saline on renal complications in patients admitted to the intensive care unit (ICU). Design and Setting Double-blind, cluster randomized, double-crossover trial conducted in 4 ICUs in New Zealand from April 2014 through October 2014. Three ICUs were general medical and surgical ICUs; 1 ICU had a predominance of cardiothoracic and vascular surgical patients. Participants All patients admitted to the ICU requiring crystalloid fluid therapy were eligible for inclusion. Patients with established AKI requiring renal replacement therapy (RRT) were excluded. All 2278 eligible patients were enrolled; 1152 of 1162 patients (99.1%) receiving buffered crystalloid and 1110 of 1116 patients (99.5%) receiving saline were analyzed. Interventions Participating ICUs were assigned a masked study fluid, either saline or a buffered crystalloid, for alternating 7-week treatment blocks. Two ICUs commenced using 1 fluid and the other 2 commenced using the alternative fluid. Two crossovers occurred so that each ICU used each fluid twice over the 28 weeks of the study. The treating clinician determined the rate and frequency of fluid administration. Main Outcomes and Measures The primary outcome was proportion of patients with AKI (defined as a rise in serum creatinine level of at least 2-fold or a serum creatinine level of ≥3.96 mg/dL with an increase of ≥0.5 mg/dL); main secondary outcomes were incidence of RRT use and in-hospital mortality. Results In the buffered crystalloid group, 102 of 1067 patients (9.6%) developed AKI within 90 days after enrollment compared with 94 of 1025 patients (9.2%) in the saline group (absolute difference, 0.4% [95% CI, −2.1% to 2.9%]; relative risk [RR], 1.04 [95% CI, 0.80 to 1.36]; P = .77). In the buffered crystalloid group, RRT was used in 38 of 1152 patients (3.3%) compared with 38 of 1110 patients (3.4%) in the saline group (absolute difference, −0.1% [95% CI, −1.6% to 1.4%]; RR, 0.96 [95% CI, 0.62 to 1.50]; P = .91). Overall, 87 of 1152 patients (7.6%) in the buffered crystalloid group and 95 of 1110 patients (8.6%) in the saline group died in the hospital (absolute difference, −1.0% [95% CI, −3.3% to 1.2%]; RR, 0.88 [95% CI, 0.67 to 1.17]; P = .40). Conclusions and Relevance Among patients receiving crystalloid fluid therapy in the ICU, use of a buffered crystalloid compared with saline did not reduce the risk of AKI. Further large randomized clinical trials are needed to assess efficacy in higher-risk populations and to measure clinical outcomes such as mortality. Trial Registration clinicaltrials.gov Identifier:ACTRN12613001370796

Changes in Self-reported Insurance Coverage, Access to Care, and Health Under the Affordable Care Act

Abstract: Importance The Affordable Care Act (ACA) completed its second open enrollment period in February 2015. Assessing the law’s effects has major policy implications. Objectives To estimate national changes in self-reported coverage, access to care, and health during the ACA’s first 2 open enrollment periods and to assess differences between low-income adults in states that expanded Medicaid and in states that did not expand Medicaid. Design, Setting, and Participants Analysis of the 2012-2015 Gallup-Healthways Well-Being Index, a daily national telephone survey. Using multivariable regression to adjust for pre-ACA trends and sociodemographics, we examined changes in outcomes for the nonelderly US adult population aged 18 through 64 years (n = 507 055) since the first open enrollment period began in October 2013. Linear regressions were used to model each outcome as a function of a linear monthly time trend and quarterly indicators. Then, pre-ACA (January 2012-September 2013) and post-ACA (January 2014-March 2015) changes for adults with incomes below 138% of the poverty level in Medicaid expansion states (n = 48 905 among 28 states and Washington, DC) vs nonexpansion states (n = 37 283 among 22 states) were compared using a differences-in-differences approach. Exposures Beginning of the ACA’s first open enrollment period (October 2013). Main Outcomes and Measures Self-reported rates of being uninsured, lacking a personal physician, lacking easy access to medicine, inability to afford needed care, overall health status, and health-related activity limitations. Results Among the 507 055 adults in this survey, pre-ACA trends were significantly worsening for all outcomes. Compared with the pre-ACA trends, by the first quarter of 2015, the adjusted proportions who were uninsured decreased by 7.9 percentage points (95% CI, −9.1 to −6.7); who lacked a personal physician, −3.5 percentage points (95% CI, −4.8 to −2.2); who lacked easy access to medicine, −2.4 percentage points (95% CI, −3.3 to −1.5); who were unable to afford care, −5.5 percentage points (95% CI, −6.7 to −4.2); who reported fair/poor health, −3.4 percentage points (95% CI, −4.6 to −2.2); and the percentage of days with activities limited by health, −1.7 percentage points (95% CI, −2.4 to −0.9). Coverage changes were largest among minorities; for example, the decrease in the uninsured rate was larger among Latino adults (−11.9 percentage points [95% CI, −15.3 to −8.5]) than white adults (−6.1 percentage points [95% CI, −7.3 to −4.8]). Medicaid expansion was associated with significant reductions among low-income adults in the uninsured rate (differences-in-differences estimate, −5.2 percentage points [95% CI, −7.9 to −2.6]), lacking a personal physician (−1.8 percentage points [95% CI, −3.4 to −0.3]), and difficulty accessing medicine (−2.2 percentage points [95% CI, −3.8 to −0.7]). Conclusions and Relevance The ACA’s first 2 open enrollment periods were associated with significantly improved trends in self-reported coverage, access to primary care and medications, affordability, and health. Low-income adults in states that expanded Medicaid reported significant gains in insurance coverage and access compared with adults in states that did not expand Medicaid.