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1.  Association Between Hospitalization for Pneumonia and Subsequent Risk of Cardiovascular Disease 
JAMA  2015;313(3):264-274.
IMPORTANCE
The risk of cardiovascular disease (CVD) after infection is poorly understood.
OBJECTIVE
To determine whether hospitalization for pneumonia is associated with an increased short-term and long-term risk of CVD.
DESIGN, SETTINGS, AND PARTICIPANTS
We examined 2 community-based cohorts: the Cardiovascular Health Study (CHS, n = 5888; enrollment age, ≥65 years; enrollment period, 1989–1994) and the Atherosclerosis Risk in Communities study (ARIC, n = 15 792; enrollment age, 45-64 years; enrollment period, 1987–1989). Participants were followed up through December 31, 2010. We matched each participant hospitalized with pneumonia to 2 controls. Pneumonia cases and controls were followed for occurrence of CVD over 10 years after matching. We estimated hazard ratios (HRs) for CVD at different time intervals, adjusting for demographics, CVD risk factors, subclinical CVD, comorbidities, and functional status.
EXPOSURES
Hospitalization for pneumonia.
MAIN OUTCOMES AND MEASURES
Incident CVD (myocardial infarction, stroke, and fatal coronary heart disease).
RESULTS
Of 591 pneumonia cases in CHS, 206 had CVD events over 10 years after pneumonia hospitalization. Compared with controls, CVD risk among pneumonia cases was highest during the first year after hospitalization and remained significantly higher than among controls through 10 years. In ARIC, of 680 pneumonia cases, 112 had CVD events over 10 years after hospitalization. After the second year, CVD risk among pneumonia cases was not significantly higher than among controls.
PneumoniaCasesControlsHR (95% CI)CHSNo. of participants5911182CVD events 0-30 d5464.07 (2.86-5.27) 31-90 d1192.94 (2.18-3.70) 91 d-1 y22552.10 (1.59-2.60) 9-10 y4121.86 (1.18-2.55)ARICNo. of participants6801360CVD events 0-30 d432.38 (1.12-3.63) 31-90 d402.40 (1.23-3.47) 91 d-1 y1182.19 (1.20-3.19) 1-2 y871.88 (1.10-2.66)
CONCLUSIONS AND RELEVANCE
Hospitalization for pneumonia was associated with increased short-term and long-term risk of CVD, suggesting that pneumonia may be a risk factor for CVD.
doi:10.1001/jama.2014.18229
PMCID: PMC4687729  PMID: 25602997
2.  Association between Asthma and Risk of Developing Obstructive Sleep Apnea 
JAMA  2015;313(2):156-164.
Importance
Obstructive sleep apnea (OSA) is more common among patients with asthma; whether asthma is associated with the development of OSA is unknown.
Objective
To examine the prospective relationship of asthma with incident OSA.
Design
Population-based prospective epidemiology study (the Wisconsin Sleep Cohort).
Setting
Beginning in 1988, adult participants were recruited from a random sample of Wisconsin state employees to attend overnight polysomnography studies at 4-year intervals. Asthma and covariate information were assessed during polysomnography studies through March 2013.
Participants
Participants identified as free of OSA (apnea-hypopnea index<5 events/hr and not treated) by two baseline polysomnography studies and that had at least one additional polysomnography study were included. 547 participants (52% women; mean [SD] baseline age = 50 [8] years) provided 1105 4-year follow-up intervals.
Exposure
Questionnaire-assessed presence and duration of self-reported physician-diagnosed asthma.
Main Outcome
The associations of presence and duration of asthma with 4-year incidences of both OSA (apnea-hypopnea index ≥ 5 or positive airway pressure treatment) and OSA concomitant with habitual daytime sleepiness were estimated using repeated-measures Poisson regression, adjusting for confounders.
Results
Twenty-two out of 81 (27% [95% CI=17%–37%]) participants with asthma experienced incident OSA over their first observed 4-year follow-up interval compared to 75 incident cases of OSA among 466 participants without asthma (16% [95% CI, 13%–19%]). Using all 4-year intervals, participants with asthma experienced 45 incident OSA cases during 167 4-year intervals (27% [95% CI, 20%–34%]) and participants without asthma experienced 160 incident OSA cases during 938 4-year intervals (17% [95% CI, 15%–19%]); the corresponding adjusted relative risk was 1.39 (95% CI, 1.06–1.82), controlling for sex, age, baseline and change in body mass index, and other factors. Asthma was also associated with new-onset OSA with habitual sleepiness (relative risk: 2.72 [95% CI, 1.26–5.89], p=0.04). Asthma duration was related to both incident OSA (relative risk: 1.07 per 5-year increment in asthma duration [95% CI, 1.02–1.13], p=0.01) and incident OSA with habitual sleepiness (relative risk: 1.18 [95% CI, 1.07–1.31], p=0.02).
Conclusions and Relevance
Asthma was associated with increased risk of new-onset OSA. Studies investigating the value of periodic OSA evaluation in patients with asthma are warranted.
doi:10.1001/jama.2014.17822
PMCID: PMC4334115  PMID: 25585327
asthma; lung; sleep apnea; obstructive
3.  Declining psychiatrist participation in health insurance networks: Where do we go from here? 
JAMA  2015;313(2):190-191.
doi:10.1001/jama.2014.12472
PMCID: PMC4340585  PMID: 25585330
4.  Community-Wide Cardiovascular Disease Prevention Programs and Health Outcomes in a Rural County, 1970–2010 
JAMA  2015;313(2):147-155.
IMPORTANCE
Few comprehensive cardiovascular risk reduction programs, particularly those in rural, low-income communities, have sustained community-wide interventions for more than 10 years and demonstrated the effect of risk factor improvements on reductions in morbidity and mortality.
OBJECTIVE
To document health outcomes associated with an integrated, comprehensive cardiovascular risk reduction program in Franklin County, Maine, a low-income rural community.
DESIGN, SETTING, AND PARTICIPANTS
Forty-year observational study involving residents of Franklin County, Maine, a rural, low-income population of 22 444 in 1970, that used the preceding decade as a baseline and compared Franklin County with other Maine counties and state averages.
INTERVENTIONS
Community-wide programs targeting hypertension, cholesterol, and smoking, as well as diet and physical activity, sponsored by multiple community organizations, including the local hospital and clinicians.
MAIN OUTCOMES AND MEASURES
Resident participation; hypertension and hyperlipidemia detection, treatment, and control; smoking quit rates; hospitalization rates from 1994 through 2006, adjusted for median household income; and mortality rates from 1970 through 2010, adjusted for household income and age.
RESULTS
More than 150 000 individual county resident contacts occurred over 40 years. Over time, as cardiovascular risk factor programs were added, relevant health indicators improved. Hypertension control had an absolute increase of 24.7%(95%CI, 21.6%–27.7%) from 18.3%to 43.0%, from 1975 to 1978; later, elevated cholesterol control had an absolute increase of 28.5% (95%CI, 25.3%-31.6%) from 0.4% to 28.9%, from 1986 to 2010. Smoking quit rates improved from 48.5% to 69.5%, better than state averages (observed − expected [O − E], 11.3%; 95% CI, 5.5%–17.7%; P < .001), 1996–2000; these differences later disappeared when Maine’s overall quit rate increased. Franklin County hospitalizations per capita were less than expected for the measured period, 1994–2006 (O − E, −17 discharges/1000 residents; 95% CI −20.1 to −13.9; P < .001). Franklin was the only Maine county with consistently lower adjusted mortality than predicted over the time periods 1970–1989 and 1990–2010 (O − E, −60.4 deaths/100 000; 95%CI, −97.9 to −22.8; P < .001, and −41.6/100 000; 95% CI, −77.3 to −5.8; P = .005, respectively).
CONCLUSIONS AND RELEVANCE
Sustained, community-wide programs targeting cardiovascular risk factors and behavior changes to improve a Maine county’s population health were associated with reductions in hospitalization and mortality rates over 40 years, compared with the rest of the state. Further studies are needed to assess the generalizability of such programs to other US county populations, especially rural ones, and to other parts of the world.
doi:10.1001/jama.2014.16969
PMCID: PMC4573538  PMID: 25585326
5.  International Research Ethics Education 
JAMA  2015;313(5):461-462.
doi:10.1001/jama.2015.203
PMCID: PMC4706163  PMID: 25647198
6.  Female Hormonal Factors and the Risk of Endometrial Cancer in Lynch Syndrome 
JAMA  2015;314(1):61-71.
Importance
Apart from hysterectomy, there is no consensus recommendation for reducing endometrial cancer risk for women with a mismatch repair (MMR) gene mutation (Lynch syndrome).
Objective
To investigate the association between hormonal factors and endometrial cancer risk in Lynch syndrome.
Design, Setting, and Participants
A retrospective cohort study including 1,128 women with a MMR gene mutation identified from the Colon Cancer Family Registry was conducted. Data were analyzed using a weighted cohort approach. Participants were recruited between 1997 and 2012, from centers across the United States, Australia, Canada, and New Zealand.
Exposures
Age at menarche, first and last live birth, and menopause, number of live births, hormonal contraceptive use, and postmenopausal hormone use.
Main Outcome and Measures
Self-reported diagnosis of endometrial cancer.
Results
Endometrial cancer was diagnosed in 133 women (incidence per 100 person-years, 0.29; 95% confidence interval [CI], 0.24 to 0.34). A lower risk of endometrial cancer was associated with later age at menarche (hazard ratio [HR] per year, 0.85 [95%CI, 0.73 to 0.99]; P=.04), parity (parous vs nulliparous: HR, 0.21 [95%CI, 0.10 to 0.42]; P<.001), and hormonal contraceptive use (≥1 year vs <1 year: HR, 0.39 [95%CI, 0.23 to 0.64]; P<.001). There was no statistically significant association between endometrial cancer and age at first and last live birth, age at menopause, and postmenopausal hormone use.
Conclusions and Relevance
For women with a MMR gene mutation, some endogenous and exogenous hormonal factors were associated with a lower risk of endometrial cancer. These directions and strengths of associations were similar to those for the general population. If replicated, these findings suggest that women with a MMR gene mutation may be counseled like the general population in regard to hormonal influences on endometrial cancer risk.
doi:10.1001/jama.2015.6789
PMCID: PMC4688894  PMID: 26151267
mismatch repair; endometrial cancer; reproductive factors; hormonal factors; pregnancy; contraceptives; Lynch syndrome
7.  Alignment of Do-Not-Resuscitate Status with Patients' Likelihood of Favorable Neurological Survival After In-hospital Cardiac Arrest 
JAMA  2015;314(12):1264-1271.
Importance
After patients survive an in-hospital cardiac arrest, discussions should occur about prognosis and preferences for future resuscitative efforts.
Objective
To assess whether patients' decisions for Do-Not-Resuscitate (DNR) orders after a successful resuscitation from in-hospital cardiac arrest are aligned with their expected prognosis.
Design, Setting, Participants
Within Get With The Guidelines®-Resuscitation, we 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 decile and the association between DNR status and actual favorable neurological survival were examined.
Exposure
DNR orders within 12 hours of ROSC.
Main Outcome
Likelihood of favorable neurological survival.
Results
Overall, 5,944 (22.6% [95% CI: 22.1%, 23.1%]) patients had DNR orders within 12 hours of ROSC. This group was older and had higher rates of comorbidities (all P <0.05) than patients without DNR orders. Among patients with the best prognosis (decile 1), 7.1% (95% CI: 6.1%, 8.1%) had DNR orders even though their predicted rate of favorable neurological survival was 64.7% (62.8%, 66.6%). Among patients with the worst expected prognosis (decile 10), 36.0% (34.2%, 37.8%) had DNR orders even though their predicted rate for favorable neurological survival was 4.0% (3.3%, 4.7%) (P for both trends <0.001). This pattern was similar when DNR orders were re-defined as within 24 hours, 72 hours, and 5 days of ROSC. The actual rate of favorable neurological survival was higher for patients without DNR orders (30.5% [95% CI: 29.9%, 31.1%]) compared with those with DNR orders (1.8% [95% CI: 1.6%, 2.0%]), and this pattern of lower survival among patients with DNR orders was seen in every decile of expected prognosis.
Conclusions and Relevance
Although DNR orders after in-hospital cardiac arrest were generally aligned with patients' likelihood of favorable neurological survival, only one-third of patients with the worst prognosis had DNR orders. Patients with DNR orders had lower survival than those without DNR orders, including among those with the best prognosis.
doi:10.1001/jama.2015.11069
PMCID: PMC4701196  PMID: 26393849
8.  Nonmyeloablative HLA-Matched Sibling Allogeneic Hematopoietic Stem Cell Transplantation for Severe Sickle Cell Phenotype 
JAMA  2014;312(1):48-56.
IMPORTANCE
Myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) is curative for children with severe sickle cell disease, but toxicity may be prohibitive for adults. Nonmyeloablative transplantation has been attempted with degrees of preparative regimen intensity, but graft rejection and graft-vs-host disease remain significant.
OBJECTIVE
To determine the efficacy, safety, and outcome on end-organ function with this low-intensity regimen for sickle cell phenotype with or without thalassemia.
DESIGN, SETTING, AND PARTICIPANTS
From July 16, 2004, to October 25, 2013, 30 patients aged 16–65 years with severe disease enrolled in this nonmyeloablative transplant study, consisting of alemtuzumab (1 mg/kg in divided doses), total-body irradiation (300 cGy), sirolimus, and infusion of unmanipulated filgrastim mobilized peripheral blood stem cells (5.5–31.7 × 106 cells/kg) from human leukocyte antigen–matched siblings.
MAIN OUTCOMES AND MEASURES
The primary end point was treatment success at 1 year after the transplant, defined as a full donor-type hemoglobin for patients with sickle cell disease and transfusion independence for patients with thalassemia. The secondary end points were the level of donor leukocyte chimerism; incidence of acute and chronic graft-vs-host disease; and sickle cell–thalassemia disease-free survival, immunologic recovery, and changes in organ function, assessed by annual brain imaging, pulmonary function, echocardiographic image, and laboratory testing.
RESULTS
Twenty-nine patients survived a median 3.4 years (range, 1–8.6), with no nonrelapse mortality. One patient died from intracranial bleeding after relapse. As of October 25, 2013, 26 patients (87%) had long-term stable donor engraftment without acute or chronic graft-vs-host disease. The mean donor T-cell level was 48% (95% CI, 34%–62%); the myeloid chimerism levels, 86% (95% CI, 70%–100%). Fifteen engrafted patients discontinued immunosuppression medication with continued stable donor chimerism and no graft-vs-host disease. The normalized hemoglobin and resolution of hemolysis among engrafted patients were accompanied by stabilization in brain imaging, a reduction of echocardiographic estimates of pulmonary pressure, and allowed for phlebotomy to reduce hepatic iron. The mean annual hospitalization rate was 3.23 (95%CI, 1.83–4.63) the year before, 0.63 (95% CI, 0.26–1.01) the first year after,0.19 (95% CI, 0–0.45) the second year after, and 0.11 (95%CI, 0.04–0.19) the third year after transplant. For patients taking long-term narcotics, the mean use per week was 639 mg (95%CI, 220–1058) of intravenous morphine–equivalent dose the week of their transplants and 140 mg (95% CI, 56–225) 6 months after transplant. There were 38 serious adverse events: pain and related management, infections, abdominal events, and sirolimus related toxic effects.
CONCLUSIONS AND RELEVANCE
Among 30 patients with sickle cell phenotype with or without thalassemia who underwent nonmyeloablative allogeneic HSCT, the rate of stable mixed-donor chimerism was high and allowed for complete replacement with circulating donor red blood cells among engrafted participants. Further accrual and follow-up are required to assess longer-term clinical outcomes, adverse events, and transplant tolerance.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT00061568
doi:10.1001/jama.2014.7192
PMCID: PMC4698790  PMID: 25058217
9.  Alternative Tobacco Products as a Second Front in the War on Tobacco 
JAMA  2015;314(14):1507-1508.
JAMA PEDIATRICS
Associations Between Initial Water Pipe Tobacco Smoking and Snus Use and Subsequent Cigarette Smoking: Results From a Longitudinal Study of US Adolescents and Young Adults Samir Soneji, PhD; James D. Sargent, MD; Susanne E. Tanski, MD, MPH; Brian A. Primack, MD, PhD
IMPORTANCE
Many adolescents and young adults use alternative tobacco products, such as water pipes and snus, instead of cigarettes.
OBJECTIVE
To assess whether prior water pipe tobacco smoking and snus use among never smokers are risk factors for subsequent cigarette smoking.
DESIGN, SETTING, AND PARTICIPANTS
We conducted a 2-wave national longitudinal study in the United States among 2541 individuals aged 15 to 23 years old. At baseline (October 25, 2010, through June 11, 2011), we ascertained whether respondents had smoked cigarettes, smoked water pipe tobacco, or used snus. At the 2-year follow-up (October 27, 2012, through March 31, 2013), we determined whether baseline non–cigarette smokers had subsequently tried cigarette smoking, were current (past 30 days) cigarette smokers, or were high-intensity cigarette smokers. We fit multivariable logistic regression models among baseline non–cigarette smokers to assess whether baseline water pipe tobacco smoking and baseline snus use were associated with subsequent cigarette smoking initiation and current cigarette smoking, accounting for established sociodemographic and behavioral risk factors. We fit similarly specified multivariable ordinal logistic regression models to assess whether baseline water pipe tobacco smoking and baseline snus use were associated with high-intensity cigarette smoking at follow-up.
EXPOSURES
Water pipe tobacco smoking and the use of snus at baseline.
MAIN OUTCOMES AND MEASURES
Among baseline non–cigarette smokers, cigarette smoking initiation, current (past 30 days) cigarette smoking at follow-up, and the intensity of cigarette smoking at follow-up.
RESULTS
Among 1596 respondents, 1048 had never smoked cigarettes at baseline, of whom 71 had smoked water pipe tobacco and 20 had used snus at baseline. At follow-up, accounting for behavioral and sociodemographic risk factors, baseline water pipe tobacco smoking and snus use were independently associated with cigarette smoking initiation (adjusted odds ratios: 2.56; 95% CI, 1.46–4.47 and 3.73; 95% CI, 1.43–9.76, respectively), current cigarette smoking (adjusted odds ratios: 2.48; 95%CI, 1.01–6.06 and 6.19; 95% CI, 1.86–20.56, respectively), and higher intensity of cigarette smoking (adjusted proportional odds ratios: 2.55; 95%CI, 1.48–4.38 and 4.45; 95%CI, 1.75–11.27, respectively).
CONCLUSIONS AND RELEVANCE
Water pipe tobacco smoking and the use of snus independently predicted the onset of cigarette smoking and current cigarette smoking at follow-up. Comprehensive Food and Drug Administration regulation of these tobacco products may limit their appeal to youth and curb the onset of cigarette smoking.
doi:10.1001/jama.2015.11394
PMCID: PMC4699172  PMID: 26461999
10.  Accountable Care Organizations and Health Care Disparities 
JAMA  2011;305(16):1706-1707.
doi:10.1001/jama.2011.533
PMCID: PMC4696383  PMID: 21521853
11.  Effect of Screening for Partner Violence on Women's Quality of Life 
JAMA  2012;308(7):681-689.
Context
Although partner violence screening has been endorsed by many health organizations, there is insufficient evidence that it has beneficial health outcomes.
Objective
To determine the effect of computerized screening for partner violence plus provision of a partner violence resource list vs provision of a partner violence list only on women's health in primary care settings, compared with a control group.
Design, Setting, and Participants
A 3-group blinded randomized controlled trial at 10 primary health care centers in Cook County, Illinois. Participants were enrolled from May 2009–April 2010 and reinterviewed 1 year (range, 48–56 weeks) later. Participants were English- or Spanish-speaking women meeting specific inclusion criteria and seeking clinical services at study sites. Of 3537 women approached, 2727 were eligible, 2708 were randomized (99%), and 2364 (87%) were recontacted 1 year later. Mean age of participants was 39 years. Participants were predominantly non-Latina African American (55%) or Latina (37%), had a high school education or less (57%), and were uninsured (57%).
Intervention
Randomization into 3 intervention groups: (1) partner violence screen (using the Partner Violence Screen instrument) plus a list of local partner violence resources if screening was positive (n=909); (2) partner violence resource list only without screen (n=893); and (3) no-screen, no-partner violence list control group (n=898).
Main Outcome Measures
Quality of life (QOL, physical and mental health components) was the primary outcome, measured on the 12-item Short Form (scale range 0–100, mean of 50 for US population).
Results
At 1-year follow-up, there were no significant differences in the QOL physical health component between the screen plus partner violence resource list group (n=801; mean score, 46.8; 95% CI, 46.1–47.4), the partner violence resource list only group (n=772; mean score, 46.4; 95% CI, 45.8–47.1), and the control group (n=791; mean score, 47.2; 95% CI, 46.5–47.8), or in the mental health component (screen plus partner violence resource list group [mean score, 48.3; 95% CI, 47.5–49.1], the partner violence resource list only group [mean score, 48.0; 95% CI, 47.2–48.9], and the control group [mean score, 47.8; 95% CI, 47.0–48.6]). There were also no differences between groups in days unable to work or complete housework; number of hospitalizations, emergency department, or ambulatory care visits; proportion who contacted a partner violence agency; or recurrence of partner violence.
Conclusions
Among women receiving care in primary care clinics, providing a partner violence resource list with or without screening did not result in improved health.
Trial Registration
clinicaltrials.gov Identifier: NCT00526994
doi:10.1001/jama.2012.6434
PMCID: PMC4689430  PMID: 22893165
12.  Assessing Value in Biomedical Research 
JAMA  2014;312(5):483-484.
doi:10.1001/jama.2014.6932
PMCID: PMC4687964  PMID: 24911291
13.  A Public Health Perspective on a National Precision Medicine Cohort 
JAMA  2015;313(21):2117-2118.
doi:10.1001/jama.2015.3382
PMCID: PMC4685667  PMID: 26034952
14.  Handling of Thermal Receipts as a Source of Exposure to Bisphenol A 
JAMA  2014;311(8):859-860.
doi:10.1001/jama.2013.283735
PMCID: PMC4685668  PMID: 24570250
15.  Copy number variations and cognitive phenotypes in unselected populations 
JAMA  2015;313(20):2044-2054.
Importance
The association of rare copy number variants (CNVs) with complex disorders is almost exclusively evaluated using clinically ascertained cohorts. As a result, the contribution of these genetic variants to cognitive phenotypes in the general population remains unclear.
Objectives
- To investigate the clinical features of genomic disorders in adult carriers without clinical pre-selection.
- To assess the genome-wide burden of rare CNVs on carriers’ educational attainment and intellectual disability prevalence in the general population.
Design, Setting, and Participants
The population biobank of Estonia (EGCUT) contains 52,000 participants, or 5% of the Estonian adults, enrolled in 2002-2010. General practitioners examined participants and filled out a questionnaire of health- and lifestyle-related questions, as well as reported diagnoses. As EGCUT is representative of the country's population, we investigated a random sample of 7877 individuals for CNV analysis and genotype-phenotype associations with education and disease traits.
Main Outcomes and Measures
Phenotypes of genomic disorders in the general population, prevalence of autosomal CNVs, and association of the latter variants with decreased educational attainment and increased prevalence of intellectual disability.
Results
We identified 56 carriers of genomic disorders. Their phenotypes are reminiscent of those described for carriers of identical rearrangements ascertained in clinical cohorts. We also generated a genome-wide map of rare (frequency ≤0.05%) autosomal CNVs and identified 10.5% of the screened general population (n=831) as carriers of CNVs ≥250kb. Carriers of deletions ≥250kb or duplications ≥1Mb show, compared to the Estonian population, a greater prevalence of intellectual disability (P=0.0015, OR=3.16, (95%CI: 1.51-5.98); P=0.0083, OR=3.67, (95%CI: 1.29-8.54), respectively), reduced mean education attainment (a proxy for intelligence; P=1.06e-04; P=5.024e-05, respectively) and an increased fraction of individuals not graduating from secondary school (P=0.005, OR=1.48 (95%CI: 1.12-1.95); P=0.0016, OR=1.89 (95%CI: 1.27-2.8), respectively). The deletions show evidence of enrichment for genes with a role in neurogenesis, cognition, learning, memory and behavior. Evidence for an association between rare CNVs and decreased educational attainment was confirmed by analyses in adult cohorts of Italian (HYPERGENES) and European American (Minnesota Center for Twin and Family Research) individuals, as well as in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort.
Conclusions and Relevance
Our results challenge the assumption that carriers of known syndromic CNVs identified in population cohorts are asymptomatic. They also indicate that individually rare but collectively common intermediate-size CNVs contribute to the variance in educational attainment. Refinements of these findings in additional population groups is warranted given the potential implications of this observation for genomics research, clinical care, and public health.
doi:10.1001/jama.2015.4845
PMCID: PMC4684269  PMID: 26010633
genomic disorders; CNV; 16p11.2; population biobanks; education; intelligence; EGCUT; ALSPAC
16.  The Diagnosis and Management of Mild Cognitive Impairment: A Clinical Review 
JAMA  2014;312(23):2551-2561.
Importance
Cognitive decline is a common and feared aspect of aging. Mild Cognitive Impairment (MCI) is defined as the “symptomatic pre-dementia stage” on the continuum of cognitive decline, characterized by objective impairment in cognition that is not severe enough to require help with usual activities of daily living.
Objective
To present evidence on the diagnosis,treatment, and prognosis of MCI, and to provide physicians with an evidence-based framework for caring for older MCI patients and their caregivers.
Evidence Acquisition
We searched PubMed for English-language articles in peer-reviewed journals and the Cochrane Library database through July 2014. Relevant references from retrieved articles were also evaluated.
Findings
The prevalence of MCI in adults aged ≥65 years is 10- 20%; risk increases with age, and men appear to be at higher risk than women. In older MCI patients, clinicians shouldconsider depression, polypharmacy, and uncontrolled cardiovascular risk factors, all of which may increase risk for cognitive impairment and other negative outcomes. Currently, no medications have proven effective for MCI; treatments and interventions should be aimed at reducing cardiovascular risk factors and prevention of stroke. Aerobic exercise, mental activity, and social engagement may help decrease risk of further cognitive decline. Although patients with MCI are at greater risk of developing dementia compared withthe general population, there is currently substantial variation in risk estimates (from <5% to 20% annual conversion rates), depending on the population studied.Current research is aimed at improving early detection and treatment of MCI, particularly in patients at high risk for progression to dementia.
Conclusions and Relevance
Cognitive decline and MCI have important implications for patients and their families, and will require that primary care clinicians be skilled in identifying and managing this common disorder as the number of older adults increases in coming decades. Current evidence supports aerobic exercise, mental activity, and cardiovascular risk factor control in patients with MCI.
doi:10.1001/jama.2014.13806
PMCID: PMC4269302  PMID: 25514304
17.  Could Behavioral Medicine Lead the Web Data Revolution? 
JAMA  2014;311(14):1399-1400.
doi:10.1001/jama.2014.1505
PMCID: PMC4670613  PMID: 24577162
18.  Intermittent Preventive Therapy for Malaria During Pregnancy Using 2 vs 3 or More Doses of Sulfadoxine-Pyrimethamine and Risk of Low Birth Weight in Africa 
JAMA  2013;309(6):594-604.
Importance
Intermittent preventive therapy with sulfadoxine-pyrimethamine to control malaria during pregnancy is used in 37 countries in sub-Saharan Africa, and 31 of those countries use the standard 2-dose regimen. However, 2 doses may not provide protection during the last 4 to 10 weeks of pregnancy, a pivotal period for fetal weight gain.
Objective
To perform a systematic review and meta-analysis of trials to determine whether regimens containing 3 or more doses of sulfadoxine-pyrimethamine for intermittent preventive therapy during pregnancy are associated with a higher birth weight or lower risk of low birth weight (LBW) (<2500 g) than standard 2-dose regimens.
Data Sources and Study Selection
ISI Web of Knowledge, EMBASE, SCOPUS, PubMed, LILACS, the Malaria in Pregnancy Library, Cochrane CENTRAL, and trial registries from their inception to December 2012, without language restriction. Eligible studies included randomized and quasi-randomized trials of intermittent preventive therapy during pregnancy with sulfadoxine-pyrimethamine monotherapy.
Data Extraction
Data were independently abstracted by 2 investigators. Relative risk (RR), mean differences, and 95% CIs were calculated with random-effects models.
Results
Of 241 screened studies, 7 trials of 6281 pregnancies were included. The median birth weight in the 2-dose group was 2870 g (range, 2722–3239 g) and on average 56 g higher (95% CI, 29–83 g; I2=0%) in the ≥3-dose group. Three or more doses were associated with fewer LBW births (RR,0.80; 95% CI, 0.69–0.94; I2=0%), with a median LBW risk per 1000 women in the 2-dose group (assumed control group risk) of 167 per 1000 vs 134 per 1000 in the ≥3-dose group (absolute risk reduction, 33 per 1000 [95% CI, 10–52]; number needed to treat=31). The association was consistent across a wide range of sulfadoxine-pyrimethamine resistance (0% to 96% dihydropteroate-synthase K540E mutations). There was no evidence of small-study bias. The ≥3-dose group had less placental malaria (RR,0.51; 95% CI, 0.38–0.68; I2=0%, in 6 trials, 63 vs 32 per 1000; absolute risk reduction,31 per 1000 [95% CI, 20–39]). In primigravid plus secundigravid women, the risk of moderate to severe maternal anemia was lower in the ≥3-dose group (RR,0.60; 95% CI, 0.36–0.99; I2=20%; in 6 trials, 36 vs 22 per 1000; absolute risk reduction,14 per 1000 [95% CI, 0.4–23]). There were no differences in rates of serious adverse events.
Conclusions and Relevance
Among pregnant women in sub-Saharan Africa, intermittent preventive therapy with 3 or more doses of sulfadoxine-pyrimethamine was associated with a higher birth weight and lower risk of LBW than the standard 2-dose regimens. These data provide support for the new WHO recommendations to provide at least 3 doses of intermittent preventive therapy during pregnancy at each scheduled antenatal care visit in the second and third trimester.
doi:10.1001/jama.2012.216231
PMCID: PMC4669677  PMID: 23403684
19.  Tadalafil for Prevention of Erectile Dysfunction After Radiotherapy for Prostate Cancer The Radiation Therapy Oncology Group [0831] Randomized Clinical Trial 
JAMA  2014;311(13):1300-1307.
IMPORTANCE
Tadalafil is used to treat erectile dysfunction after prostate cancer treatment, but its role as a preventive agent is undefined.
OBJECTIVES
To determine primarily whether tadalafil preserved erectile function in men treated with radiotherapy for prostate cancer, and secondarily to determine whether participant- or partner-reported overall sexual function and sexual and marital satisfaction were affected.
DESIGN, SETTING, AND PARTICIPANTS
Stratified, placebo-controlled, double-blind, parallel-group study with 1:1 randomization at 76 community-based and tertiary medical sites in the United States and Canada. Two hundred forty-two participants with intact erectile function scheduled to receive radiotherapy for prostate cancer were recruited between November 2009 and February 2012 with follow-up through March 2013.
INTERVENTIONS
One hundred twenty-one participants were assigned 5 mg of tadalafil daily and 121 were assigned placebo for 24 weeks starting with external radiotherapy (63%) or brachytherapy (37%). Participant-reported International Index of Erectile Function response before radiotherapy and at weeks 2 and 4, between weeks 20 and 24, between weeks 28 and 30, and 1 year thereafter. Participants and partners could respond also to the Sexual Adjustment Questionnaire and to the Locke Marital Adjustment Test before radiotherapy, between weeks 20 and 24 and weeks 28 and 30, and at 1 year.
MAIN OUTCOMES AND MEASURES
Primary outcome was off-drug spontaneous erectile function 28 to 30 weeks after radiotherapy started. Secondary end points were spontaneous erection at 1 year; overall sexual function and satisfaction; marital adjustment; and partner-reported satisfaction and marital adjustment at 28 to 30 weeks and 1 year, predictors of tadalafil response; and adverse events.
RESULTS
Among 221 evaluable participants, 80 (79%; 95% CI, 70%–88%) assigned to receive tadalafil retained erectile function between weeks 28 and 30 compared with 61 (74%; 95% CI, 63%–85%) assigned to receive placebo (P = .49); an absolute difference of 5% (95% CI, −9% to 19%). A significant difference was also not observed at 1 year (72%; 95% CI, 60%–84% vs 71%; 95% CI, 59%–84%; P = .93). Tadalafil was not associated with significantly improved overall sexual function or satisfaction; a significant difference was not observed in any domain subscale. Partners of men assigned tadalafil noted no significant effect on sexual satisfaction, and marital adjustment was not significantly improved in participants or partners.
CONCLUSIONS AND RELEVANCE
Amongmen undergoing radiotherapy for prostate cancer, daily use of tadalafil compared with placebo did not result in improved erectile function. These findings do not support daily use of tadalafil to prevent erectile dysfunction in these patients.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT00931528
doi:10.1001/jama.2014.2626
PMCID: PMC4669050  PMID: 24691606
20.  Screening and Brief Intervention for Drug Use in Primary Care 
JAMA  2014;312(5):502-513.
IMPORTANCE
The United States has invested substantially in screening and brief intervention for illicit drug use and prescription drug misuse, based in part on evidence of efficacy for unhealthy alcohol use. However, it is not a recommended universal preventive service in primary care because of lack of evidence of efficacy.
OBJECTIVE
To test the efficacy of 2 brief counseling interventions for unhealthy drug use (any illicit drug use or prescription drug misuse)—a brief negotiated interview (BNI) and an adaptation of motivational interviewing (MOTIV)—compared with no brief intervention.
DESIGN, SETTING, AND PARTICIPANTS
This 3-group randomized trial took place at an urban hospital-based primary care internal medicine practice; 528 adult primary care patients with drug use (Alcohol, Smoking, and Substance Involvement Screening Test [ASSIST] substance-specific scores of $4) were identified by screening between June 2009 and January 2012 in Boston, Massachusetts.
INTERVENTIONS
Two interventions were tested: the BNI is a 10- to 15-minute structured interview conducted by health educators; the MOTIV is a 30- to 45-minute intervention based on motivational interviewing with a 20- to 30-minute booster conducted by master’s-level counselors. All study participants received a written list of substance use disorder treatment and mutual help resources.
MAIN OUTCOMES AND MEASURES
Primary outcome was number of days of use in the past 30 days of the self-identified main drug as determined by a validated calendar method at 6 months. Secondary outcomes included other self-reported measures of drug use, drug use according to hair testing, ASSIST scores (severity), drug use consequences, unsafe sex, mutual help meeting attendance, and health care utilization.
RESULTS
At baseline, 63% of participants reported their main drug was marijuana, 19% cocaine, and 17% opioids. At 6 months, 98% completed follow-up. Mean adjusted number of days using the main drug at 6 months was 12 for no brief intervention vs 11 for the BNI group (incidence rate ratio [IRR], 0.97; 95% CI, 0.77-1.22) and 12 for the MOTIV group (IRR, 1.05; 95% CI, 0.84-1.32; P = .81 for both comparisons vs no brief intervention). There were also no significant effects of BNI or MOTIV on any other outcome or in analyses stratified by main drug or drug use severity.
CONCLUSIONS AND RELEVANCE
Brief intervention did not have efficacy for decreasing unhealthy drug use in primary care patients identified by screening. These results do not support widespread implementation of illicit drug use and prescription drug misuse screening and brief intervention.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT00876941
doi:10.1001/jama.2014.7862
PMCID: PMC4667772  PMID: 25096690
21.  Calorie Labeling on Menus and Menu Boards--Reply 
JAMA  2014;312(24):2689.
doi:10.1001/jama.2014.15078
PMCID: PMC4456671  PMID: 25536268
22.  Association of a Full-Day versus Part-Day Preschool Intervention with School Readiness, Attendance, and Parent Involvement 
JAMA  2014;312(20):2126-2134.
Importance
Early childhood interventions have demonstrated many positive effects on well-being. Whether attending for the full day vs part day improves outcomes is unknown.
Objective
To evaluate the association between a school-based full- and part-day early childhood development program and multiple indicators of school readiness, attendance, and parent involvement for a large cohort of low-income children.
Design, Setting, and Participants
End-of-preschool follow-up of a nonrandomized, matched-group cohort of predominantly low-income, ethnic minority children who enrolled in the Child-Parent Centers for the full school day (7 hours; n = 409) or part of the day (3 hours on average; n = 573) in the fall of 2012 in 11 schools in Chicago, Ill.
Interventions
The Midwest Child-Parent Center Education Program provides comprehensive education, family-support, and health services from preschool to third grade in high-poverty neighborhoods. In the preschool component assessed in this study, 3- and 4-year-olds in enrolled in the program for full- or part-day.
Main Outcomes and Measures
School readiness skills in 6 domains and on a total score at the end of the year, attendance and chronic absences, and parental involvement. Mean raw scores and the number of items for readiness domains were as follows: literacy (57.1, 12 items), language (37.8, 6), math (36.3, 7), cognitive (57.6, 10), socioemotional (55.4, 9), physical health (33.8, 5), and the total (278.0; 49).
Results
Full-day preschool participants had higher scores than part-day peers in the same schools on socioemotional development (58.6 vs. 54.5; diff. = 4.1; P = .025; 95% CI = 0.5, 7.6), language (39.9 vs. 37.3; diff = 2.6; P =.010; 95% CI = 0.6, 4.6), math (40.0 vs. 36.4; diff. = 3.6; P = .022; 95% CI = 0.5, 6.7), and physical health (35.5 vs. 33.6; diff. = 1.9; P = .006; 95% CI = 0.5, 3.2) but not parent involvement in school (3.95 vs. 4.65; diff. = -0.70; P = .170; 95% CI = -1.7, 3.0). The full-day group also had a higher mean total score (298.1 vs. 278.2; diff. = 19.9; P = .037; 95% CI = 1.2, 38.4) compared with the part-day group. For literacy, language, math, socioemotional development, and the total score, full-day participants met national assessment norms at rates that were 11 to 22 points higher (percentage change of 17-38%) than those in part-day classes. Standardized mean differences ranged from 0.16 (cognitive development score) to 0.65 (at/above national norm on 4 of 6 subscales). They also had significantly higher levels of attendance (85.9% vs. 80.4%; diff. = 5.5; P = .001; 95% CI = 2.6, 8.4) and lower rates of chronic absences measured at 10% (53.0% vs. 71.6%; diff. = -18.6; P = .001; 95% CI = -28.5, -8.7) and 20% or more of days missed (21.2% vs. 38.8%;diff. = -17.6; P < .001; 95% CI = -25.6, -9.7).
Conclusions and Relevance
In an expansion of the Child-Parent Center program in low-income Chicago communities, a full-day preschool intervention was associated with increased school readiness skills, attendance, and reduced chronic absences compared with a part-day program. These findings need to be replicated in other programs and contexts.
doi:10.1001/jama.2014.15376
PMCID: PMC4505551  PMID: 25423219
23.  In Reply 
JAMA  2015;313(20):2078-2079.
doi:10.1001/jama.2015.4427
PMCID: PMC4518852  PMID: 26010642
24.  Association Between Treated and Untreated Obstructive Sleep Apnea and Risk of Hypertension 
JAMA  2012;307(20):2169-2176.
Context
Systemic hypertension is prevalent among patients with obstructive sleep apnea (OSA). Short-term studies indicate that continuous positive airway pressure (CPAP) therapy reduces blood pressure in patients with hypertension and OSA.
Objective
To determine whether CPAP therapy is associated with a lower risk of incident hypertension.
Design, Setting, and Participants
A prospective cohort study of 1889 participants without hypertension who were referred to a sleep center in Zaragoza, Spain, for nocturnal polysomnography between January 1, 1994, and December 31, 2000. Incident hypertension was documented at annual follow-up visits up to January 1, 2011. Multivariable models adjusted for confounding factors, including change in body mass index from baseline to censored time, were used to calculate hazard ratios (HRs) of incident hypertension in participants without OSA (controls), with untreated OSA, and in those treated with CPAP therapy according to national guidelines.
Main Outcome Measure
Incidence of new-onset hypertension.
Results
During 21 003 person-years of follow-up (median, 12.2 years), 705 cases (37.3%) of incident hypertension were observed. The crude incidence of hypertension per 100 person-years was 2.19 (95% CI, 1.71–2.67) in controls, 3.34 (95% CI, 2.85–3.82) in patients with OSA ineligible for CPAP therapy, 5.84 (95% CI, 4.82–6.86) in patients with OSA who declined CPAP therapy, 5.12 (95% CI, 3.76–6.47) in patients with OSA nonadherent to CPAP therapy, and 3.06 (95% CI, 2.70–3.41) in patients with OSA and treated with CPAP therapy. Compared with controls, the adjusted HRs for incident hypertension were greater among patients with OSA ineligible for CPAP therapy (1.33; 95% CI, 1.01–1.75), among those who declined CPAP therapy (1.96; 95% CI, 1.44–2.66), and among those nonadherent to CPAP therapy (1.78; 95% CI, 1.23–2.58), whereas the HR was lower in patients with OSA who were treated with CPAP therapy (0.71; 95% CI, 0.53–0.94).
Conclusion
Compared with participants without OSA, the presence of OSA was associated with increased adjusted risk of incident hypertension; however, treatment with CPAP therapy was associated with a lower risk of hypertension.
doi:10.1001/jama.2012.3418
PMCID: PMC4657563  PMID: 22618924
25.  Efavirenz-Based Antiretroviral Therapy Among Nevirapine-Exposed HIV-Infected Children in South Africa: A Randomized Clinical Trial 
JAMA  2015;314(17):1808-1817.
Importance
Advantages of using efavirenz as part of treatment for HIV-infected children include once-daily dosing, simplification of co-treatment for tuberculosis, preserving ritonavir-boosted lopinavir for second-line treatment, and harmonization of adult and pediatric treatment regimens. However, there have been concerns about possible reduced viral efficacy of efavirenz in children exposed to nevirapine for prevention of mother-to-child transmission (PMTCT).
Objective
To evaluate whether nevirapine-exposed children, initially virally-suppressed on ritonavir-boosted lopinavir-based therapy, can transition to efavirenz-based therapy without risk of viral failure.
Design, Setting, Participants
Randomized, open-label, non-inferiority trial conducted at Rahima Moosa Mother and Child Hospital, Johannesburg, South Africa, June 2010 to December 2013. Three hundred HIV-infected children exposed to nevirapine for PMTCT, ≥ 3 years of age, and with plasma HIV RNA <50 copies/ml on ritonavir-boosted lopinavir-based therapy were enrolled; 298 were randomized, and 292 (98%) were followed to 48 weeks post-randomization.
Intervention
Switch to efavirenz-based therapy (n=150) or continue on ritonavir-boosted lopinavir-based therapy (n=148).
Main Outcomes and Measures
Risk difference (delta) between groups in (1) viral rebound; i.e., one or more HIV RNA >50 copies/ml, and (2) viral failure; i.e., confirmed HIV RNA >1000 copies/ml; with a non-inferiority bound for the delta of −0.10. Immunologic and clinical responses were secondary endpoints.
Results
The Kaplan-Meier probability of viral rebound by 48 weeks was 0.176 (n=26) in the efavirenz group and 0.284 (n=42) in the ritonavir-boosted lopinavir group. Probabilities of viral failure were 0.027 (n=4) in the efavirenz and 0.020 (n=3) in the ritonavir-boosted lopinavir group. The risk difference of viral rebound was 0.107 (1-sided 95% CI: 0.028,∞) and −0.007 (1-sided 95% CI: −0.036, ∞) for viral failure. We rejected the null hypothesis that efavirenz is inferior to ritonavir-boosted lopinavir (p<.001) for both endpoints. By 48 weeks, CD4 percentage was 2.88 (95% CI: 1.26, 4.49) units higher in the efavirenz than in the ritonavir-boosted lopinavir group.
Conclusions and Relevance
Among HIV-infected children exposed to nevirapine for PMTCT and initially virally-suppressed on ritonavir-boosted lopinavir-based therapy, switching to efavirenz-based therapy compared with continuing ritonavir-boosted lopinavir-based therapy did not result in significantly higher rates of viral rebound or viral failure. This therapeutic approach may offer advantages in children such as these.
doi:10.1001/jama.2015.13631
PMCID: PMC4655876  PMID: 26529159

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