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PURPOSE: Although maternal depression is associated with adverse outcomes in women and children, its relationship with lower urinary tract symptoms (LUTS) in offspring is less well-characterized. We examined the association between prenatal and postpartum maternal depression and LUTS in primary school-age daughters. DESIGN: Observational cohort study. SUBJECTS AND SETTING: The sample comprised 7148 mother-daughter dyads from the Avon Longitudinal Study of Parents and Children. METHOD: Mothers completed questionnaires about depressive symptoms at 18 and 32 weeks gestation and 21 months postpartum and their childrens LUTS (urinary urgency, nocturia, and daytime and nighttime wetting) at 6, 7, and 9 years of age. Multivariable logistic regression models were used to estimate the association between maternal depression and LUTS in daughters. RESULTS: Compared to daughters of mothers without depression, those born to mothers with prenatal and postpartum depression had higher odds of LUTS, including urinary urgency (adjusted odds ratio [aOR] range = 1.99-2.50) and nocturia (aOR range = 1.67-1.97) at 6, 7, and 9 years of age. Additionally, daughters born to mothers with prenatal and postpartum depression had higher odds of daytime wetting (aOR range = 1.81-1.99) and nighttime wetting (aOR range = 1.63-1.95) at 6 and 7 years of age. Less consistent associations were observed for depression limited to the prenatal or postpartum periods only. CONCLUSIONS: Exposure to maternal depression in the prenatal and postpartum periods was associated with an increased likelihood of LUTS in daughters. This association may be an important opportunity for childhood LUTS prevention. Prevention strategies should reflect an understanding of potential biological and environmental mechanisms through which maternal depression may influence childhood LUTS.

INTRODUCTION AND HYPOTHESIS: Lower urinary tract symptoms (LUTS) are common among adolescent girls. Physical activity (PA) has been implicated as both a risk (high-impact PA) and protective factor (low-impact, moderate to vigorous intensity PA) for LUTS in adult women, but its role in adolescent girls is unclear. This study investigated the prospective association between physical activity and LUTS risk in adolescent girls. METHODS: The sample comprised 3,484 female participants in the Avon Longitudinal Study of Parents and Children. Multivariate logistic regression models were used to examine daily minutes of moderate to vigorous PA (MVPA) at ages 11 and 15 years in relation to LUTS at ages 14 and 19 respectively. MVPA was assessed by 7-day accelerometer data. LUTS were assessed by questionnaire. MVPA were analyzed as continuous (minutes/day) and categorical variables (

BACKGROUND: Post-COVID-19 condition (also known as long COVID) is an emerging chronic illness potentially affecting millions of people. We aimed to evaluate whether outpatient COVID-19 treatment with metformin, ivermectin, or fluvoxamine soon after SARS-CoV-2 infection could reduce the risk of long COVID. METHODS: We conducted a decentralised, randomised, quadruple-blind, parallel-group, phase 3 trial (COVID-OUT) at six sites in the USA. We included adults aged 30-85 years with overweight or obesity who had COVID-19 symptoms for fewer than 7 days and a documented SARS-CoV-2 positive PCR or antigen test within 3 days before enrolment. Participants were randomly assigned via 2 × 3 parallel factorial randomisation (1:1:1:1:1:1) to receive metformin plus ivermectin, metformin plus fluvoxamine, metformin plus placebo, ivermectin plus placebo, fluvoxamine plus placebo, or placebo plus placebo. Participants, investigators, care providers, and outcomes assessors were masked to study group assignment. The primary outcome was severe COVID-19 by day 14, and those data have been published previously. Because the trial was delivered remotely nationwide, the a priori primary sample was a modified intention-to-treat sample, meaning that participants who did not receive any dose of study treatment were excluded. Long COVID diagnosis by a medical provider was a prespecified, long-term secondary outcome. This trial is complete and is registered with ClinicalTrials.gov, NCT04510194. FINDINGS: Between Dec 30, 2020, and Jan 28, 2022, 6602 people were assessed for eligibility and 1431 were enrolled and randomly assigned. Of 1323 participants who received a dose of study treatment and were included in the modified intention-to-treat population, 1126 consented for long-term follow-up and completed at least one survey after the assessment for long COVID at day 180 (564 received metformin and 562 received matched placebo; a subset of participants in the metformin vs placebo trial were also randomly assigned to receive ivermectin or fluvoxamine). 1074 (95%) of 1126 participants completed at least 9 months of follow-up. 632 (56·1%) of 1126 participants were female and 494 (43·9%) were male; 44 (7·0%) of 632 women were pregnant. The median age was 45 years (IQR 37-54) and median BMI was 29·8 kg/m2 (IQR 27·0-34·2). Overall, 93 (8·3%) of 1126 participants reported receipt of a long COVID diagnosis by day 300. The cumulative incidence of long COVID by day 300 was 6·3% (95% CI 4·2-8·2) in participants who received metformin and 10·4% (7·8-12·9) in those who received identical metformin placebo (hazard ratio [HR] 0·59, 95% CI 0·39-0·89; p=0·012). The metformin beneficial effect was consistent across prespecified subgroups. When metformin was started within 3 days of symptom onset, the HR was 0·37 (95% CI 0·15-0·95). There was no effect on cumulative incidence of long COVID with ivermectin (HR 0·99, 95% CI 0·59-1·64) or fluvoxamine (1·36, 0·78-2·34) compared with placebo. INTERPRETATION: Outpatient treatment with metformin reduced long COVID incidence by about 41%, with an absolute reduction of 4·1%, compared with placebo. Metformin has clinical benefits when used as outpatient treatment for COVID-19 and is globally available, low-cost, and safe. FUNDING: Parsemus Foundation; Rainwater Charitable Foundation; Fast Grants; UnitedHealth Group Foundation; National Institute of Diabetes, Digestive and Kidney Diseases; National Institutes of Health; and National Center for Advancing Translational Sciences.

PURPOSE: We examined how antecedent sexual health factors affect lower urinary tract symptoms (LUTS) in adolescent women. METHODS: We analyzed 1,941 adolescent women from the Avon Longitudinal Study of Parents and Children at age 19. At ages 15 and 17, participants reported use of oral contraceptives (OCs), history of sexual intercourse, number of sexual partners, and condom use. At age 19, The Bristol Female Lower Urinary Tract Symptoms questionnaire quantified the frequency over the past month: stress incontinence, any incontinence, urgency, sensation of incomplete emptying, bladder pain, and urinary tract infection. Multivariable regression models examined associations between sexual health behaviors reported at ages 15 and 17 and six LUTS reported at age 19, after controlling for covariates. RESULTS: Commonly reported LUTS at age 19 were past-month stress incontinence (26.8%), bladder pain (26.3%), any urine leakage (22.1%), and urinary tract infection (15.4%). OC use by age 17 was associated with urgency (odds ratio [OR] = 1.62, 95% confidence interval [CI] 1.19-2.20), incomplete emptying (OR = 1.62, 95% CI = 1.17-2.26), bladder pain (OR = 1.45, 95% CI = 1.15-1.83), and urinary tract infections (OR = 1.68, 95% CI = 1.28-2.21) at age 19 after adjustment for covariates. However, associations were attenuated after adjustment for condom use and number of sexual partners. Sexual intercourse by age 17 was associated with 1.53-2.65 increased odds of LUTs categories except incontinence, with lower confidence interval boundaries > 1.0. Associations were stronger among women with ≥ 3 sexual partners (vs. 0) by age 17. DISCUSSION: We found longitudinally assessed associations between OC use, sexual intercourse, and number of sexual partners during adolescence and LUTS at age 19.

BackgroundObservational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials.MethodsIn this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol.ResultsA total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV1) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P = 0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group.ConclusionsAmong patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol. (Funded by the Department of Defense; BLOCK COPD ClinicalTrials.gov number, NCT02587351.).

Background: Little research to date has focused on lower urinary tract symptom (LUTS) prevention and bladder health promotion in women. To address this gap, the Prevention of LUTS Research Consortium developed the following working bladder health definition: "A complete state of physical, mental, and social well-being related to bladder function [that] permits daily activities [and] allows optimal well-being." To begin to inform and quantify this definition, we used data from the Boston Area Community Health Survey, drawing upon its rare collection of information on LUTS and LUTS-specific interference with activities. Methods: At baseline, participants reported their frequency of 15 LUTS and interference with 7 activities. Prevalence ratios (PRs) were calculated by generalized linear models with robust variance estimation, adjusting for LUTS risk factors and individual LUTS. Results: Of the 3169 eligible participants, 17.5% reported no LUTS or interference, whereas the remaining 82.5% reported some frequency of LUTS/interference: 15.1% rarely; 21.7% a few times; 22.6% fairly often/usually; and 22.9% almost always. LUTS independently associated with interference were urgency incontinence, any incontinence, urgency, nocturia, perceived frequency, and urinating again after

Key Points: Question: Does adding sigh breaths to the usual care of trauma patients receiving mechanical ventilation increase ventilator-free days? Findings: In this randomized clinical trial among 524 trauma patients with risk factors for developing acute respiratory distress syndrome, the addition of sigh breaths did not significantly increase ventilator-free days compared with usual care alone (median ventilator-free days, 18.4 vs 16.1, respectively). Although not adjusted for multiple testing, sigh breaths were associated with improvement in secondary outcomes including all-cause mortality. There was no evidence of harm. Meaning: Sigh breaths added to usual care did not significantly increase ventilator-free days among trauma patients who received mechanical ventilation but may improve clinical outcomes. Importance: Among patients receiving mechanical ventilation, tidal volumes with each breath are often constant or similar. This may lead to ventilator-induced lung injury by altering or depleting surfactant. The role of sigh breaths in reducing ventilator-induced lung injury among trauma patients at risk of poor outcomes is unknown. Objective: To determine whether adding sigh breaths improves clinical outcomes. Design, Setting, and Participants: A pragmatic, randomized trial of sigh breaths plus usual care conducted from 2016 to 2022 with 28-day follow-up in 15 academic trauma centers in the US. Inclusion criteria were age older than 18 years, mechanical ventilation because of trauma for less than 24 hours, 1 or more of 5 risk factors for developing acute respiratory distress syndrome, expected duration of ventilation longer than 24 hours, and predicted survival longer than 48 hours. Interventions: Sigh volumes producing plateau pressures of 35 cm H2O (or 40 cm H2O for inpatients with body mass indexes >35) delivered once every 6 minutes. Usual care was defined as the patient's physician(s) treating the patient as they wished. Main Outcomes and Measures: The primary outcome was ventilator-free days. Prespecified secondary outcomes included all-cause 28-day mortality. Results: Of 5753 patients screened, 524 were enrolled (mean [SD] age, 43.9 [19.2] years; 394 [75.2%] were male). The median ventilator-free days was 18.4 (IQR, 7.0-25.2) in patients randomized to sighs and 16.1 (IQR, 1.1-24.4) in those receiving usual care alone (P =.08). The unadjusted mean difference in ventilator-free days between groups was 1.9 days (95% CI, 0.1 to 3.6) and the prespecified adjusted mean difference was 1.4 days (95% CI, −0.2 to 3.0). For the prespecified secondary outcome, patients randomized to sighs had 28-day mortality of 11.6% (30/259) vs 17.6% (46/261) in those receiving usual care (P =.05). No differences were observed in nonfatal adverse events comparing patients with sighs (80/259 [30.9%]) vs those without (80/261 [30.7%]). Conclusions and Relevance: In a pragmatic, randomized trial among trauma patients receiving mechanical ventilation with risk factors for developing acute respiratory distress syndrome, the addition of sigh breaths did not significantly increase ventilator-free days. Prespecified secondary outcome data suggest that sighs are well-tolerated and may improve clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02582957 This randomized clinical trial compares the efficacy of sighs in addition to usual care vs usual care alone in improving clinical outcomes among trauma patients receiving mechanical ventilation and are at risk for developing acute respiratory distress syndrome. [ABSTRACT FROM AUTHOR]

Background: Traditional models to predict intensive care outcomes do not perform well in COVID‐19. We undertook a comprehensive study of factors affecting mortality and functional outcome after severe COVID‐19. Methods: In this prospective multicentre cohort study, we enrolled laboratory‐confirmed, critically ill COVID‐19 patients at six ICUs in the Skåne Region, Sweden, between May 11, 2020, and May 10, 2021. Demographics and clinical data were collected. ICU burden was defined as the total number of ICU‐treated COVID‐19 patients in the region on admission. Surviving patients had a follow‐up at 90 days for assessment of functional outcome using the Glasgow Outcome Scale‐Extended (GOSE), an ordinal scale (1–8) with GOSE ≥5 representing a favourable outcome. The primary outcome was 90‐day mortality; the secondary outcome was functional outcome at 90 days. Results: Among 498 included patients, 74% were male with a median age of 66 years and a median body mass index (BMI) of 30 kg/m2. Invasive mechanical ventilation was employed in 72%. Mortality in the ICU, in‐hospital and at 90 days was 30%, 38% and 39%, respectively. Mortality increased markedly at age 60 and older. Increasing ICU burden was independently associated with a two‐fold increase in mortality. Higher BMI was not associated with increased mortality. Besides age and ICU burden, smoking status, cortisone use, PaCO2 >7 kPa, and inflammatory markers on admission were independent factors of 90‐day mortality. Lower GOSE at 90 days was associated with a longer stay in the ICU. Conclusion: In critically ill COVID‐19 patients, the 90‐day mortality was 39% and increased considerably at age 60 or older. The ICU burden was associated with mortality, whereas a high BMI was not. A longer stay in the ICU was associated with unfavourable functional outcomes at 90 days. [ABSTRACT FROM AUTHOR]

Objective: Self-monitoring is recommended following brief alcohol intervention (BI). We have previously demonstrated that self-monitoring with an automated telephone system (interactive voice response; IVR) is associated with a steady reduction in alcohol consumption in the absence of BI. In this study we explore the feasibility and efficacy of IVR as a possible therapeutic enhancement for BI. Method: We updated all providers (N = 112) in 15 primary care clinics about BI and encouraged them to do a BI with their patients whenever appropriate and to invite those patients to participate in the research project. Interested patients (N = 338) were randomized to one of four study conditions including no IVR and three groups who self-monitored for 6 months using an IVR: no feedback, feedback, and feedback plus a monetary calling incentive. Results: The IVR proved to be a feasible method for self-monitoring. Of those invited to use the IVR, 90% initiated use and made 95% of the calls while they remained engaged with the system; more than half continued calling for the entire 6 months. Reported impact of the IVR and associated feedback on drinking awareness was high. Therapeutic results were mixed. Overall, the IVR groups reported higher consumption on the Timeline Followback (TLFB) at the 3- and 6-month follow-ups than did the no IVR group. However, because of a potential measurement confound, the TLFB may not have operated in an unbiased fashion across the four study conditions. A comparison of the feedback and no feedback IVR groups, which is independent of this confound, shows a significant therapeutic advantage of IVR with feedback. Conclusions: IVR is a feasible technology for behavioral self-monitoring in primary care clinics. IVR with regular feedback may be an effective therapeutic enhancement to BI., THE EFFICACY OF BRIEF INTERVENTION (BI) for heavy and problem drinking in the primary care office is now well established (Bertholet et al., 2005; Bien et al., 1993; Kahan et [...]

Objective: Randomized trials examining the effects of brief alcohol interventions by primary care providers have consistently excluded individuals with alcohol dependence. The purpose of this study was to examine whether a diagnosis of alcohol dependence, according to the criteria in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, predicted differential effectiveness of a brief intervention (BI). Method: Retrospective analyses were performed on participants (N = 326) enrolled in a randomized trial designed to examine the impact of interactive voice response following BI. All participants had received a BI from their primary care provider before enrolling in the study. Daily consumption data were collected using the Timeline Followback for the period before the BI (mean = 71days) and for 6 months following the BI. We compared nondependent and dependent participants on a number of consumption-based outcomes. Results: Dependent participants had significantly higher pre-BI consumption. At the index assessment (median = 15 days after BI), both dependent and nondependent participants reported significant reductions in total drinks per week and drinking days per week after BI. Dependent participants significantly reduced their drinks per drinking day. After BI, dependent participants no longer differed significantly from nondependent participants on these measures. Similar decreases from before BI were observed in both groups through 6 months, although dependent participants drank on fewer days and significantly more on days on which they drank than did nondependent participants. Regression analyses showed that baseline consumption was the only significant predictor of post-BI consumption. Conclusions: We found no evidence that dependent participants realized less benefit on measures of alcohol consumption following a BI than nondependent participants., BRIEF INTERVENTIONS (BIs) performed in primary care settings repeatedly have been found to be efficacious in assisting patients in reducing their alcohol consumption. A number of randomized, controlled trials (Chick [...]

Introduction: A substantial majority of chronic obstructive pulmonary disease (COPD)-related morbidity, mortality and healthcare costs are due to acute exacerbations, but existing medications have only a modest effect on reducing their frequency, even when used in combination. Observational studies suggest β-blockers may reduce the risk of COPD exacerbations; thus, we will conduct a randomised, placebo-controlled trial to definitively assess the impact of metoprolol succinate on the rate of COPD exacerbations. Methods and analyses: This is a multicentre, placebo-controlled, double-blind, prospective randomised trial that will enrol 1028 patients with at least moderately severe COPD over a 3-year period. Participants with at least moderate COPD will be randomised in a 1:1 fashion to receive metoprolol or placebo; the cohort will be enriched for patients at high risk for exacerbations. Patients will be screened and then randomised over a 2-week period and will then undergo a dose titration period for the following 6 weeks. Thereafter, patients will be followed for 42 additional weeks on their target dose of metoprolol or placebo followed by a 4-week washout period. The primary end point is time to first occurrence of an acute exacerbation during the treatment period. Secondary end points include rates and severity of COPD exacerbations; rate of major cardiovascular events; all-cause mortality; lung function (forced expiratory volume in 1 s (FEV1)); dyspnoea; quality of life; exercise capacity; markers of cardiac stretch (pro-NT brain natriuretic peptide) and systemic inflammation (high-sensitivity C reactive protein and fibrinogen). Analyses will be performed on an intentto- treat basis. Ethics and dissemination: The study protocol has been approved by the Department of Defense Human Protection Research Office and will be approved by the institutional review board of all participating centres. Study findings will be disseminated through presentations at national and international conferences and publications in peer-reviewed journals. [ABSTRACT FROM AUTHOR]

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination has decreasing protection from acquiring any infection with emergence of new variants; however, vaccination continues to protect against progression to severe coronavirus disease 2019 (COVID-19). The impact of vaccination status on symptoms over time is less clear., Methods: Within a randomized trial on early outpatient COVID-19 therapy testing metformin, ivermectin, and/or fluvoxamine, participants recorded symptoms daily for 14 days. Participants were given a paper symptom diary allowing them to circle the severity of 14 symptoms as none (0), mild (1), moderate (2), or severe (3). This is a secondary analysis of clinical trial data on symptom severity over time using generalized estimating equations comparing those unvaccinated, SARS-CoV-2 vaccinated with primary vaccine series only, or vaccine-boosted., Results: The parent clinical trial prospectively enrolled 1323 participants, of whom 1062 (80%) prospectively recorded some daily symptom data. Of these, 480 (45%) were unvaccinated, 530 (50%) were vaccinated with primary series only, and 52 (5%) vaccine-boosted. Overall symptom severity was least for the vaccine-boosted group and most severe for unvaccinated at baseline and over the 14 days (P < .001). Individual symptoms were least severe in the vaccine-boosted group including cough, chills, fever, nausea, fatigue, myalgia, headache, and diarrhea, as well as smell and taste abnormalities. Results were consistent over Delta and Omicron variant time periods., Conclusions: SARS-CoV-2 vaccine-boosted participants had the least severe symptoms during COVID-19, which abated the quickest over time. Clinical Trial Registration. NCT04510194., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)