PLoS Medicine最新文献

Elvin Hsing Geng and colleagues discuss mechanism mapping and its utility in conceptualizing and understanding how implementation strategies produce desired effects.

Background: Preclinical data suggest circadian variation in ischemic stroke progression, with more active cell death and infarct growth in rodent models with inactive phase (daytime) than active phase (nighttime) stroke onset. We aimed to examine the association of stroke onset time with presenting severity, early neurological deterioration (END), and long-term functional outcome in human ischemic stroke.

Methods and findings: In a Korean nationwide multicenter observational cohort study from May 2011 to July 2020, we assessed circadian effects on initial stroke severity (National Institutes of Health Stroke Scale [NIHSS] score at admission), END, and favorable functional outcome (3-month modified Rankin Scale [mRS] score 0 to 2 versus 3 to 6). We included 17,461 consecutive patients with witnessed ischemic stroke within 6 hours of onset. Stroke onset time was divided into 2 groups (day-onset [06:00 to 18:00] versus night-onset [18:00 to 06:00]) and into 6 groups by 4-hour intervals. We used mixed-effects ordered or logistic regression models while accounting for clustering by hospitals. Mean age was 66.9 (SD 13.4) years, and 6,900 (39.5%) were women. END occurred in 2,219 (12.7%) patients. After adjusting for covariates including age, sex, previous stroke, prestroke mRS score, admission NIHSS score, hypertension, diabetes, hyperlipidemia, smoking, atrial fibrillation, prestroke antiplatelet use, prestroke statin use, revascularization, season of stroke onset, and time from onset to hospital arrival, night-onset stroke was more prone to END (adjusted incidence 14.4% versus 12.8%, p = 0.006) and had a lower likelihood of favorable outcome (adjusted odds ratio, 0.88 [95% CI, 0.79 to 0.98]; p = 0.03) compared with day-onset stroke. When stroke onset times were grouped by 4-hour intervals, a monotonic gradient in presenting NIHSS score was noted, rising from a nadir in 06:00 to 10:00 to a peak in 02:00 to 06:00. The 18:00 to 22:00 and 22:00 to 02:00 onset stroke patients were more likely to experience END than the 06:00 to 10:00 onset stroke patients. At 3 months, there was a monotonic gradient in the rate of favorable functional outcome, falling from a peak at 06:00 to 10:00 to a nadir at 22:00 to 02:00. Study limitations include the lack of information on sleep disorders and patient work/activity schedules.

Conclusions: Night-onset strokes, compared with day-onset strokes, are associated with higher presenting neurologic severity, more frequent END, and worse 3-month functional outcome. These findings suggest that circadian time of onset is an important additional variable for inclusion in epidemiologic natural history studies and in treatment trials of neuroprotective and reperfusion agents for acute ischemic stroke.

Background: Pre-gestational diabetes mellitus (PGDM) has been known to be a risk factor for congenital heart defects (CHDs) for decades. However, the associations between maternal PGDM and gestational diabetes mellitus (GDM) and the risk of specific types of CHDs and congenital anomalies (CAs) in other systems remain under debate. We aimed to investigate type-specific CAs in offspring of women with diabetes and to examine the extent to which types of maternal diabetes are associated with increased risk of CAs in offspring.

Methods and findings: We searched PubMed and Embase from database inception to 15 October 2021 for population-based studies reporting on type-specific CAs in offspring born to women with PGDM (combined type 1 and 2) or GDM, with no limitation on language. Reviewers extracted data for relevant outcomes and performed random effects meta-analyses, subgroup analyses, and multivariable meta-regression. Risk of bias appraisal was performed using the Cochrane Risk of Bias Tool. This study was registered in PROSPERO (CRD42021229217). Primary outcomes were overall CAs and CHDs. Secondary outcomes were type-specific CAs. Overall, 59 population-based studies published from 1990 to 2021 with 80,437,056 participants met the inclusion criteria. Of the participants, 2,407,862 (3.0%) women had PGDM and 2,353,205 (2.9%) women had GDM. The meta-analyses showed increased risks of overall CAs/CHDs in offspring born to women with PGDM (for overall CAs, relative risk [RR] = 1.99, 95% CI 1.82 to 2.17, P < 0.001; for CHDs, RR = 3.46, 95% CI 2.77 to 4.32, P < 0.001) or GDM (for overall CAs, RR = 1.18, 95% CI 1.13 to 1.23, P < 0.001; for CHDs, RR = 1.50, 95% CI 1.38 to 1.64, P < 0.001). The results of the meta-regression analyses showed significant differences in RRs of CAs/CHDs in PGDM versus GDM (all P < 0.001). Of the 23 CA categories, excluding CHD-related categories, in offspring, maternal PGDM was associated with a significantly increased risk of CAs in 21 categories; the corresponding RRs ranged from 1.57 (for hypospadias, 95% CI 1.22 to 2.02) to 18.18 (for holoprosencephaly, 95% CI 4.03 to 82.06). Maternal GDM was associated with a small but significant increase in the risk of CAs in 9 categories; the corresponding RRs ranged from 1.14 (for limb reduction, 95% CI 1.06 to 1.23) to 5.70 (for heterotaxia, 95% CI 1.09 to 29.92). The main limitation of our analysis is that some high significant heterogeneity still persisted in both subgroup and sensitivity analyses.

Conclusions: In this study, we observed an increased rate of CAs in offspring of women with diabetes and noted the differences for PGDM versus GDM. The RRs of overall CAs and CHDs in offspring of women with PGDM were higher than those in offspring of women with GDM. Screening for diabetes in pregnant women may enable better glycemic control, and may enable identification of offspring at risk for CAs.

Background: Pictorial warnings on tobacco products are promising for motivating behavior change, but few studies have examined pictorial warnings for sugary drinks, especially in naturalistic environments. This study aimed to examine the impact of pictorial warnings on parents' purchases of sugary drinks for their children in a naturalistic store laboratory.

Methods and findings: Parents of children ages 2 to 12 (n = 325, 25% identifying as Black, 20% Hispanic) completed a shopping task in a naturalistic store laboratory in North Carolina. Participants were randomly assigned to a pictorial warnings arm (sugary drinks displayed pictorial health warnings about type 2 diabetes and heart damage) or a control arm (sugary drinks displayed a barcode label). Parents selected 1 beverage and 1 snack for their child, as well as 1 household good; one of these items was selected for them to purchase and take home. The primary outcome was whether parents purchased a sugary drink for their child. Secondary outcomes included reactions to the trial labels, attitudes toward sugary drinks, and intentions to serve their child sugary drinks. Pictorial warnings led to a 17-percentage point reduction in purchases of sugary drinks (95% CI for reduction: 7% to 27%), with 45% of parents in the control arm buying a sugary drink for their child compared to 28% in the pictorial warning arm (p = 0.002). The impact of pictorial warnings on purchases did not differ by any of the 13 participant characteristics examined (e.g., race/ethnicity, income, education, and age of child). Pictorial warnings also led to lower calories (kcal), purchased from sugary drinks (82 kcal in the control arm versus 52 kcal in the pictorial warnings arm, p = 0.003). Moreover, pictorial warnings led to lower intentions to serve sugary drinks to their child, feeling more in control of healthy eating decisions, greater thinking about the harms of sugary drinks, stronger negative emotional reactions, greater anticipated social interactions, lower perceived healthfulness of sugary drinks for their child, and greater injunctive norms to limit sugary drinks for their child (all p < 0.05). There was no evidence of difference between trial arms on noticing of the labels, appeal of sugary drinks, perceived amount of added sugar in sugary drinks, risk perceptions, or perceived tastiness of sugary drinks (all p > 0.05).

Conclusions: Pictorial warnings reduced parents' purchases of sugary drinks for their children in this naturalistic trial. Warnings on sugary drinks are a promising policy approach to reduce sugary drink purchasing in the US.

Trial registration: The trial design, measures, power calculation, and analytic plan were registered before data collection at www.clinicaltrials.gov NCT04223687.

Background: Obesity is observationally associated with altered risk of many female reproductive conditions. These include polycystic ovary syndrome (PCOS), abnormal uterine bleeding, endometriosis, infertility, and pregnancy-related disorders. However, the roles and mechanisms of obesity in the aetiology of reproductive disorders remain unclear. Thus, we aimed to estimate observational and genetically predicted causal associations between obesity, metabolic hormones, and female reproductive disorders.

Methods and findings: Logistic regression, generalised additive models, and Mendelian randomisation (MR) (2-sample, non-linear, and multivariable) were applied to obesity and reproductive disease data on up to 257,193 women of European ancestry in UK Biobank and publicly available genome-wide association studies (GWASs). Body mass index (BMI), waist-to-hip ratio (WHR), and WHR adjusted for BMI were observationally (odds ratios [ORs] = 1.02-1.87 per 1-SD increase in obesity trait) and genetically (ORs = 1.06-2.09) associated with uterine fibroids (UF), PCOS, heavy menstrual bleeding (HMB), and pre-eclampsia. Genetically predicted visceral adipose tissue (VAT) mass was associated with the development of HMB (OR [95% CI] per 1-kg increase in predicted VAT mass = 1.32 [1.06-1.64], P = 0.0130), PCOS (OR [95% CI] = 1.15 [1.08-1.23], P = 3.24 × 10-05), and pre-eclampsia (OR [95% CI] = 3.08 [1.98-4.79], P = 6.65 × 10-07). Increased waist circumference posed a higher genetic risk (ORs = 1.16-1.93) for the development of these disorders and UF than did increased hip circumference (ORs = 1.06-1.10). Leptin, fasting insulin, and insulin resistance each mediated between 20% and 50% of the total genetically predicted association of obesity with pre-eclampsia. Reproductive conditions clustered based on shared genetic components of their aetiological relationships with obesity. This study was limited in power by the low prevalence of female reproductive conditions among women in the UK Biobank, with little information on pre-diagnostic anthropometric traits, and by the susceptibility of MR estimates to genetic pleiotropy.

Conclusions: We found that common indices of overall and central obesity were associated with increased risks of reproductive disorders to heterogenous extents in a systematic, large-scale genetics-based analysis of the aetiological relationships between obesity and female reproductive conditions. Our results suggest the utility of exploring the mechanisms mediating the causal associations of overweight and obesity with gynaecological health to identify targets for disease prevention and treatment.

Background: Women prescribed antidepressants face the dilemma of whether or not to continue their treatment during pregnancy. Currently, limited evidence is available on the efficacy of continuing versus discontinuing antidepressant treatment during pregnancy to aid their decision. We aimed to estimate whether antidepressant discontinuation before or during pregnancy was associated with an increased risk of psychiatric emergency (ascertained by psychiatric admission or emergency room visit), a proxy measure of severe exacerbation of symptoms/mental health crisis.

Methods and findings: We carried out a propensity score-matched cohort study of women who gave birth to live-born singletons between January 1, 1997 and June 30, 2016 in Denmark and who redeemed an antidepressant prescription in the 90 days before the pregnancy, identified by Anatomical Therapeutic Chemical (ATC) code N06A. We constructed 2 matched cohorts, matching each woman who discontinued antidepressants before pregnancy (N = 2,669) or during pregnancy (N = 5,467) to one who continued antidepressants based on propensity scores. Maternal characteristics and variables related to disease severity were used to generate the propensity scores in logistic regression models. We estimated hazard ratios (HRs) of psychiatric emergency in the perinatal period (pregnancy and 6 months postpartum) using stratified Cox regression. Psychiatric emergencies were observed in 76 women who discontinued antidepressants before pregnancy and 91 women who continued. There was no evidence of higher risk of psychiatric emergency among women who discontinued antidepressants before pregnancy (cumulative incidence: 2.9%, 95% confidence interval [CI]: 2.3% to 3.6% for discontinuation versus 3.4%, 95% CI: 2.8% to 4.2% for continuation; HR = 0.84, 95% CI: 0.61 to 1.16, p = 0.298). Overall, 202 women who discontinued antidepressants during pregnancy and 156 who continued had psychiatric emergencies (cumulative incidence: 5.0%, 95% CI: 4.2% to 5.9% versus 3.7%, 95% CI: 3.1% to 4.5%). Antidepressant discontinuation during pregnancy was associated with increased risk of psychiatric emergency (HR = 1.25, 95% CI: 1.00 to 1.55, p = 0.048). Study limitations include lack of information on indications for antidepressant treatment and reasons for discontinuing antidepressants.

Conclusions: In this study, we found that discontinuing antidepressant medication during pregnancy (but not before) is associated with an apparent increased risk of psychiatric emergency compared to continuing treatment throughout pregnancy.