Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19.

BACKGROUND: Early treatment to prevent severe coronavirus disease 2019 (Covid-19) is an important component of the comprehensive response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. METHODS: In this phase 3, double-blind, randomized, placebo-controlled trial, we used a 2-by-3 factorial design to test the effectiveness of three repurposed drugs - metformin, ivermectin, and fluvoxamine - in preventing serious SARS-CoV-2 infection in nonhospitalized adults who had been enrolled within 3 days after a confirmed diagnosis of infection and less than 7 days after the onset of symptoms. The patients were between the ages of 30 and 85 years, and all had either overweight or obesity. The primary composite end point was hypoxemia (≤93% oxygen saturation on home oximetry), emergency department visit, hospitalization, or death. All analyses used controls who had undergone concurrent randomization and were adjusted for SARS-CoV-2 vaccination and receipt of other trial medications. RESULTS: A total of 1431 patients underwent randomization; of these patients, 1323 were included in the primary analysis. The median age of the patients was 46 years; 56% were female (6% of whom were pregnant), and 52% had been vaccinated. The adjusted odds ratio for a primary event was 0.84 (95% confidence interval [CI], 0.66 to 1.09; P = 0.19) with metformin, 1.05 (95% CI, 0.76 to 1.45; P = 0.78) with ivermectin, and 0.94 (95% CI, 0.66 to 1.36; P = 0.75) with fluvoxamine. In prespecified secondary analyses, the adjusted odds ratio for emergency department visit, hospitalization, or death was 0.58 (95% CI, 0.35 to 0.94) with metformin, 1.39 (95% CI, 0.72 to 2.69) with ivermectin, and 1.17 (95% CI, 0.57 to 2.40) with fluvoxamine. The adjusted odds ratio for hospitalization or death was 0.47 (95% CI, 0.20 to 1.11) with metformin, 0.73 (95% CI, 0.19 to 2.77) with ivermectin, and 1.11 (95% CI, 0.33 to 3.76) with fluvoxamine. CONCLUSIONS: None of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19. (Funded by the Parsemus Foundation and others; COVID-OUT ClinicalTrials.gov number, NCT04510194.).

Association Between Maternal Depression and Lower Urinary Tract Symptoms in Their Primary School-Age Daughters: A Birth Cohort Study.

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 children's 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.

Impact of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccination and Booster on Coronavirus Disease 2019 (COVID-19) Symptom Severity Over Time in the COVID-OUT Trial.

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.

Is there an association between physical activity and lower urinary tract symptoms in adolescent girls? Results from the Avon Longitudinal Study of Parents and Children.

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 (<10th percentile, 10-89th percentile, ≥90th percentile). RESULTS: Prevalence of LUTS ranged from 2.0% for bedwetting to 9.5% for nocturia at age 14 and from 2.0% for straining to urinate to 35.5% for interrupted urine flow at age 19. Physical activity was not associated with LUTS at either time-point. CONCLUSIONS: Given the prevalence of LUTS in female adolescent populations, although this study did not find an association with accelerometer-measured MVPA, other aspects of PA that may serve as risk or protective factors deserve investigation.

Intensive care unit burden is associated with increased mortality in critically ill COVID-19 patients.

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, Pa CO2 >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.

Sigh Ventilation in Patients With Trauma: The SiVent Randomized Clinical Trial.

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.

Metoprolol for the Prevention of Acute Exacerbations of COPD.

BACKGROUND: Observational 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. METHODS: In 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. RESULTS: A 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. CONCLUSIONS: Among 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.).

Diagnosis and management of duodenal perforations: a narrative review.

Duodenal perforation is a rare, but potentially life-threatening injury. Multiple etiologies are associated with duodenal perforations such as peptic ulcer disease, iatrogenic causes and trauma. Computed tomography with intravenous and oral contrast is the most valuable imaging technique to identify duodenal perforation. In some cases, surgical exploration may be necessary for diagnosis. Specific treatment depends upon the nature of the disease process that caused the perforation, the timing, location and extent of the injury and the clinical condition of the patient. Conservative management seems to be feasible in stable patients with sealed perforations. Immediate surgery is required for patients presenting with peritonitis and/or intra-abdominal sepsis. Minimally invasive techniques are safe and effective alternatives to conventional open surgery in selected patients with duodenal perforations. Here we review the current literature on duodenal perforations and discuss the outcomes of different treatment strategies.

ß-Blocker Use and Clinical Outcomes in Patients With COPD Following Acute Myocardial Infarction.

Importance: While ß-blockers are associated with decreased mortality in cardiovascular disease (CVD), exacerbation-prone patients with chronic obstructive pulmonary disease (COPD) who received metoprolol in the Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease (BLOCK-COPD) trial experienced increased risk of exacerbations requiring hospitalization. However, the study excluded individuals with established indications for the drug, raising questions about the overall risk and benefit in patients with COPD following acute myocardial infarction (AMI). Objective: To investigate whether ß-blocker prescription at hospital discharge is associated with increased risk of mortality or adverse cardiopulmonary outcomes in patients with COPD and AMI. Design, Setting, and Participants: This prospective, longitudinal cohort study with 6 months of follow-up enrolled patients aged 35 years or older with COPD who underwent cardiac catheterization for AMI at 18 BLOCK-COPD network hospitals in the US from June 2020 through May 2022. Exposure: Prescription for any ß-blocker at hospital discharge. Main Outcomes and Measures: The primary outcome was time to the composite outcome of death or all-cause hospitalization or revascularization. Secondary outcomes included death, hospitalization, or revascularization for CVD events, death or hospitalization for COPD or respiratory events, and treatment for COPD exacerbations. Results: Among 3531 patients who underwent cardiac catheterization for AMI, prevalence of COPD was 17.1% (95% CI, 15.8%-18.4%). Of 579 total patients with COPD and AMI, 502 (86.7%) were prescribed a ß-blocker at discharge. Among the 562 patients with COPD included in the final analysis, median age was 70.0 years (range, 38.0-94.0 years) and 329 (58.5%) were male; 553 of the 579 patients (95.5%) had follow-up information. Among those discharged with ß-blockers, there was no increased risk of the primary end point of all-cause mortality, revascularization, or hospitalization (hazard ratio [HR], 1.01; 95% CI, 0.66-1.54; P = .96) or of cardiovascular events (HR, 1.11; 95% CI, 0.65-1.92; P = .69), COPD-related or respiratory events (HR, 0.75; 95% CI, 0.34-1.66; P = .48), or treatment for COPD exacerbations (rate ratio, 1.01; 95% CI, 0.53-1.91; P = .98). Conclusions and Relevance: In this cohort study, ß-blocker prescription at hospital discharge was not associated with increased risk of adverse outcomes in patients with COPD and AMI. These findings support use of ß-blockers in patients with COPD and recent AMI.

Sexual Health Behaviors by Age 17 and Lower Urinary Tract Symptoms at Age 19: PLUS Research Consortium Analysis of ALSPAC Data.

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.

Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial.

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.

Outpatient treatment of Covid-19 with metformin, ivermectin, and fluvoxamine and the development of Long Covid over 10-month follow-up.

Background: Long Covid is an emerging chronic illness potentially affecting millions, sometimes preventing the ability to work or participate in normal daily activities. COVID-OUT was an investigator-initiated, multi-site, phase 3, randomized, quadruple-blinded placebo-controlled clinical trial (NCT04510194). The design simultaneously assessed three oral medications (metformin, ivermectin, fluvoxamine) using two by three parallel treatment factorial assignment to efficiently share placebo controls and assessed Long Covid outcomes for 10 months to understand whether early outpatient treatment of SARS-CoV-2 with metformin, ivermectin, or fluvoxamine prevents Long Covid. Methods: This was a decentralized, remotely delivered trial in the US of 1,125 adults age 30 to 85 with overweight or obesity, fewer than 7 days of symptoms, and enrolled within three days of a documented SARS-CoV-2 infection. Immediate release metformin titrated over 6 days to 1,500mg per day 14 days total; ivermectin 430mcg/kg/day for 3 days; fluvoxamine, 50mg on day one then 50mg twice daily through 14 days. Medical-provider diagnosis of Long Covid, reported by participant by day 300 after randomization was a pre-specified secondary outcome; the primary outcome of the trial was severe Covid by day 14. Result: The median age was 45 years (IQR 37 to 54), 56% female of whom 7% were pregnant. Two percent identified as Native American; 3.7% as Asian; 7.4% as Black/African American; 82.8% as white; and 12.7% as Hispanic/Latino. The median BMI was 29.8 kg/m2 (IQR 27 to 34); 51% had a BMI >30kg/m2. Overall, 8.4% reported having received a diagnosis of Long Covid from a medical provider: 6.3% in the metformin group and 10.6% in the metformin control; 8.0% in the ivermectin group and 8.1% in the ivermectin control; and 10.1% in the fluvoxamine group and 7.5% in the fluvoxamine control. The Hazard Ratio (HR) for Long Covid in the metformin group versus control was 0.58 (95% CI 0.38 to 0.88); 0.99 (95% CI 0.592 to 1.643) in the ivermectin group; and 1.36 in the fluvoxamine group (95% CI 0.785 to 2.385). Conclusions: There was a 42% relative decrease in the incidence of Long Covid in the metformin group compared to its blinded control in a secondary outcome of this randomized phase 3 trial.

School Toileting Environment, Bullying, and Lower Urinary Tract Symptoms in a Population of Adolescent and Young Adult Girls: Preventing Lower Urinary Tract Symptoms Consortium Analysis of Avon Longitudinal Study of Parents and Children.

OBJECTIVES: To examine whether the school toilet environment at age 13, including bullying at toilets, is associated with female lower urinary tract symptoms (LUTS) at ages 13 and 19, as little is known about the association among school toilet environment, voiding behaviors, and LUTS in adolescent girls. METHODS: The sample comprised 3962 female participants from the Avon Longitudinal Study of Parents and Children. At age 13, participants reported on 7 school toilet environment characteristics and a range of LUTS items. At age 19, participants completed the Bristol Female Lower Urinary Tract Symptoms questionnaire. RESULTS: All toilet environmental factors were associated with at least 1 LUTS outcome at age 13. Holding behavior was associated with all school toilet environmental factors, with odds ratios ranging from 1.36 (95% confidence interval [CI]: 1.05, 1.76) for dirty toilets to 2.38 (95% CI: 1.60, 3.52) for feeling bullied at toilets. Bullying was associated with all daytime LUTS symptoms and nocturia; odds ratios ranged from 1.60 (95% CI: 1.04, 2.07) for nocturia to 2.90 (95% CI: 1.77, 4.75) for urgency. Associations between age 13 school toilets and age 19 LUTS were in the same direction as age 13 LUTS. CONCLUSION: This is the first examination of associations between school toilets and LUTS. Toileting environments were cross-sectionally associated with LUTS in adolescent girls. While further work is needed to determine whether these associations are causal, school toilet environments are modifiable and thus a promising target for LUTS prevention.

Prevalence of DSM/ICD-defined nicotine dependence.

We conducted a qualitative review to estimate for adults (1) the lifetime and current prevalence of DSM/ICD-defined nicotine dependence and (2) the prevalence of individual DSM/ICD dependence criteria. Systematic computer searches and other methods located eleven population-based surveys of adults (>or=18 year olds) and two of young adults (18-30 year olds). In the USA and Germany, about 25% of adults had been dependent on nicotine in their lifetime, including 15% who were currently dependent. Similar or higher rates were seen in Asian men but <5% of Asian women had been dependent. About a third of ever-smokers and half of current smokers either had been or were currently dependent on nicotine and this did not consistently differ by age, country or sex. Impaired control over tobacco use was the most commonly endorsed criteria and giving up activities to use and spending lots of time with nicotine were the least commonly endorsed. Nicotine dependence is one of the most common mental disorders; however, about half of current smokers do not meet DSM/ICD dependence criterion.

Inflammatory markers associated with abdominal aortic aneurysm.

PURPOSE: Inflammation with leukocytic infiltration, degradation of extracellular matrix (ECM), and depletion of vascular smooth muscle cells (VSMC) are pathological hallmarks of abdominal aortic aneurysm (AAA). The aim of this study was to further evaluate relationships between AAA and inflammatory biomarkers, interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), endothelin-1 (ET-1) and soluble urokinase-type plasminogen activator receptor (suPAR), by comparing levels in 65-year-old men with and without AAA at ultrasound screening. We also evaluated whether any biomarker can independently predict AAA at screening, and clarified potential correlations between aortic diameter and blood levels of these biomarkers. RESULTS: There were significant (p ≤ 0.05) differences between subjects with and without AAA for the following variables: p-leukocyte count (TLC) (p<0.001), p-homocysteine (p<0.001), p-TNF-α (p = 0.023), p-IL-6 (p<0.001), p-ET-1 (p = 0.002), p-suPAR (p<0.001), ankle brachial index (ABI) (p<0.001), plasma (p)-creatinine (p = 0.049), p-total cholesterol (p<0.001), p-high density lipoprotein (HDL) (p<0.001) and low density lipoprotein (LDL) cholesterol (p = 0.001), smoking habits (p<0.001), and use of antihypertensive (p<0.001) and lipid-lowering (p = 0.001) drugs. When the above variables were stepwise excluded in a logistic regression model, only p-IL-6 (p = 0.002), p-homocysteine (p = 0.015), p-HDL (p = 0.004), ABI in the right (p = 0.005) and left (p = 0.094) leg, smoking habits (p = 0.003), and antihypertensive drug use (p = 0.045), differed between groups. Significant correlations with aortic diameter existed for p-TNF-α (p = 0.028), p-IL-6 (p<0.001), p-ET-1 (p = 0.002) and p-suPAR (p<0.001) in the entire study population, and for p-TNF-α (p = 0.023), p-ET-1 (p = 0.009) and p-suPAR (p = 0.001) among men with AAA. CONCLUSIONS: Several inflammatory biomarkers were significantly elevated and correlated with aortic diameter among 65-year old men with AAA at ultrasound screening. IL-6, homocysteine and use of antihypertensive medication remained elevated in the logistic regression model, together with known risk markers for AAA such as smoking and signs of atherosclerosis.

ß-Blockers for the prevention of acute exacerbations of chronic obstructive pulmonary disease (ßLOCK COPD): a randomised controlled study protocol.

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 ß-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 intent-to-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. TRIAL REGISTRATION NUMBER: NCT02587351; Pre-results.

Self-reported alcohol intake and risk of acute exacerbations of chronic obstructive pulmonary disease: a prospective cohort study.

OBJECTIVE: To evaluate the relationship between alcohol consumption and the risk of acute exacerbation of COPD (AECOPD). METHODS AND MEASUREMENTS: We conducted a secondary analysis of data previously collected in a large, multicenter trial of daily azithromycin in COPD. To analyze the relationship between amount of baseline self-reported alcohol consumption in the past 12 months and subsequent AECOPD, we categorized the subjects as minimal (<1 drink/month), light-to-moderate (1-60 drinks/month), or heavy alcohol users (>60 drinks/month). The primary outcome was time to first AECOPD and the secondary outcome was AECOPD rate during the 1-year study period. RESULTS: Of the 1,142 enrolled participants, 1,082 completed baseline alcohol questionnaires and were included in this analysis. Six hundred and forty-five participants reported minimal alcohol intake, 363 reported light-to-moderate intake, and 74 reported heavy intake. There were no statistically significant differences in median time to first AECOPD among minimal (195 days), light-to-moderate (241 days), and heavy drinkers (288 days) (P=0.11). The mean crude rate of AECOPD did not significantly differ between minimal (1.62 events per year) and light-to-moderate (1.44 events per year) (P=0.095), or heavy drinkers (1.68 events per year) (P=0.796). There were no significant differences in hazard ratios for AECOPD after adjustment for multiple covariates. CONCLUSION: Among persons with COPD at high risk of exacerbation, we found no significant relationship between self-reported baseline alcohol intake and subsequent exacerbations. The number of patients reporting heavy alcohol intake was small and further study is needed to determine the effect of heavy alcohol intake on AECOPD risk.

Self-reported sleep quality and acute exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: Many patients with chronic obstructive pulmonary disease (COPD) suffer from poor sleep quality. We hypothesized that poor sleep quality in otherwise stable patients predicted exacerbations in these patients. METHODS: This is a secondary analysis of the results of a previously published randomized trial of azithromycin in 1,117 patients with moderate to severe COPD who were clinically stable on enrollment. Sleep quality was measured using the Pittsburgh Sleep Quality Index. Other quality of life indices included the Medical Outcome Study 36-item Short Form Health Survey and the St Georges Respiratory Questionnaire. Outcomes included time to first exacerbation and exacerbation rate. RESULTS: Sleep quality was "poor" (Pittsburgh Sleep Quality Index >5) in 53% of participants but was not related to age or severity of airflow obstruction. Quality of life scores were worse in "poor" sleepers than in "good" sleepers. Major classes of comorbid conditions, including psychiatric, neurologic, and musculoskeletal disease, were more prevalent in the "poor" sleepers. Unadjusted time to first exacerbation was shorter (190 versus 239 days) and exacerbation rate (1.7 versus 1.37 per year) was greater in the poor sleepers, but no differences were observed after adjusting for medications and comorbid conditions associated with poor sleep. CONCLUSION: Poor sleepers had greater exacerbation rates than did good sleepers. This appeared to be due largely to them having more, or more severe, concomitant medical conditions and taking more medications.

Azithromycin and COPD Exacerbations in the Presence or Absence of Symptoms or Active Treatment for Gastroesophageal Reflux.

Introduction: Gastroesophageal reflux disease (GERD) is common in chronic obstructive pulmonary disease (COPD) and is associated with COPD exacerbations. Since macrolides have prokinetic effects and consequently may decrease GERD, we hypothesized that azithromycin may decrease exacerbations by decreasing GERD. Methods: We conducted a retrospective review of data collected in a prospective, randomized, controlled trial of azithromycin for preventing COPD exacerbations. Participants were classified as having GERD on the basis of having a history of GERD or having a history or being treated for GERD. Results: We analyzed 1116 participants, 478 (43%) and 568 (51%) had GERD on the basis of history and history or treatment respectively. Individuals with GERD developed exacerbations sooner and more frequently, and were more likely to be hospitalized than those without GERD but the difference only reached significance when GERD was defined by history or treatment (P = 0.02, 0.02, and 0.03, respectively). Azithromycin reduced exacerbations regardless of the presence of GERD, but had a greater effect in those without GERD. Conclusions: GERD is associated with more frequent and severe COPD exacerbations. Azithromycin reduces COPD exacerbations regardless of the presence or absence of GERD but does so to a greater degree in individuals without GERD.

Brief intervention in alcohol-dependent versus nondependent individuals.

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 = 71 days) 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.