Post-Acute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) After Infection During Pregnancy.

OBJECTIVE: To estimate the prevalence of post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) after infection with SARS-CoV-2 during pregnancy and to characterize associated risk factors. METHODS: In a multicenter cohort study (NIH RECOVER [Researching COVID to Enhance Recovery]-Pregnancy Cohort), individuals who were pregnant during their first SARS-CoV-2 infection were enrolled across the United States from December 2021 to September 2023, either within 30 days of their infection or at differential time points thereafter. The primary outcome was PASC, defined as score of 12 or higher based on symptoms and severity as previously published by the NIH RECOVER-Adult Cohort, at the first study visit at least 6 months after the participant's first SARS-CoV-2 infection. Risk factors for PASC were evaluated, including sociodemographic characteristics, clinical characteristics before SARS-CoV-2 infection (baseline comorbidities, trimester of infection, vaccination status), and acute infection severity (classified by need for oxygen therapy). Multivariable logistic regression models were fitted to estimate associations between these characteristics and presence of PASC. RESULTS: Of the 1,502 participants, 61.1% had their first SARS-CoV-2 infection on or after December 1, 2021 (ie, during Omicron variant dominance); 51.4% were fully vaccinated before infection; and 182 (12.1%) were enrolled within 30 days of their acute infection. The prevalence of PASC was 9.3% (95% CI, 7.9-10.9%) measured at a median of 10.3 months (interquartile range 6.1-21.5) after first infection. The most common symptoms among individuals with PASC were postexertional malaise (77.7%), fatigue (76.3%), and gastrointestinal symptoms (61.2%). In a multivariable model, the proportion PASC positive with vs without history of obesity (14.9% vs 7.5%, adjusted odds ratio [aOR] 1.65, 95% CI, 1.12-2.43), depression or anxiety disorder (14.4% vs 6.1%, aOR 2.64, 95% CI, 1.79-3.88) before first infection, economic hardship (self-reported difficulty covering expenses) (12.5% vs 6.9%, aOR 1.57, 95% CI, 1.05-2.34), and treatment with oxygen during acute SARS-CoV-2 infection (18.1% vs 8.7%, aOR 1.86, 95% CI, 1.00-3.44) were associated with increased prevalence of PASC. CONCLUSION: The prevalence of PASC at a median time of 10.3 months after SARS-CoV-2 infection during pregnancy was 9.3% in the NIH RECOVER-Pregnancy Cohort. The predominant symptoms were postexertional malaise, fatigue, and gastrointestinal symptoms. Several socioeconomic and clinical characteristics were associated with PASC after infection during pregnancy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT05172024.

Promoting End-of-Life Care and Healthcare Worker Well-Being: Implementing the 3 Wishes Project in an Oncology Intensive Care Unit.

This scholarly project implemented the 3 Wishes Project (3WP), which aims to fulfill the final wishes of dying critically ill patients, in a 16-bed tertiary intensive care unit (ICU). The project assessed outcomes through sur.

The Role of Obstructive Sleep Apnea in Hypercapnic Respiratory Failure Identified in Critical Care, Inpatient, and Outpatient Settings.

An emerging body of literature describes the prevalence and consequences of hypercapnic respiratory failure. While device qualifications, documentation practices, and previously performed clinical studies often encourage conceptualizing patients as having a single "cause" of hypercapnia, many patients encountered in practice have several contributing conditions. Physiologic and epidemiologic data suggest that sleep-disordered breathing-particularly obstructive sleep apnea (OSA)-often contributes to the development of hypercapnia. In this review, the authors summarize the frequency of contributing conditions to hypercapnic respiratory failure among patients identified in critical care, emergency, and inpatient settings with an aim toward understanding the contribution of OSA to the development of hypercapnia.

Burning questions: Current practices and critical gaps in evaluating removal of per- and polyfluoroalkyl substances (PFAS) during pyrolysis treatments of biosolids.

Concerns surrounding potential health and environmental impacts of per- and polyfluoroalkyl substances (PFAS) are growing at tremendous rates because adverse health impacts are expected with trace-level exposures. Extreme measures are required to mitigate potential PFAS contamination and minimize exposures. Extensive PFAS use results in the release of diverse PFAS species from domestic, industrial, and municipal effluents to wastewater, which partition to biosolids throughout secondary treatment. Biosolids generated during municipal wastewater treatment are a major environmental source of PFAS due to prevailing disposal practices as fertilizers. Pyrolysis is emerging as a viable, scalable technology for PFAS removal from biosolids while retaining nutrients and generating renewable, raw materials for energy generation. Despite early successes of pyrolysis in PFAS removal, significant unknowns remain about PFAS and transformation product fates in pyrolysis products and emissions. Applicable PFAS sampling methods, analytical workflows, and removal assessments are currently limited to a subset of high-interest analytes and matrices. Further, analysis of exhaust gases, particulate matter, fly ashes, and other pyrolysis end-products remain largely unreported or limited due to cost and sampling limitations. This paper identifies critical knowledge gaps on the pyrolysis of biosolids that must be addressed to assess the effectiveness of PFAS removal during pyrolysis treatment.

Tracheostomy to Noninvasive Ventilation: From Acute Care to Home.

The number of patients experiencing prolonged mechanical ventilation is increasing over time. Patients who have a tracheostomy placed in a critical care setting have been described as having an average of 4 separate transitions between the acute care setting, long-term acute care (LTAC), and home. Transition points can be problematic if not addressed adequately; however, proactive planning can optimize patient care. Individual patient factors will determine if the patient will require long-term tracheostomy, transitioned to noninvasive positive pressure ventilation, or able to be decannulated. Patients and caregivers should be included in transition planning to optimize outcomes.

A founder noncoding GALT variant interfering with splicing causes galactosemia.

Galactosemia is a rare, treatable hereditary disorder of carbohydrate metabolism. We investigated the etiology of decreased GALT enzyme activity in a cohort of newborns referred by the Florida Newborn Screening Program with no detectable GALT variants in diagnostic molecular tests. Six affected individuals from four families with Guatemalan heritage were included. GALT enzyme activity ranged from 20% to 34% of normal. Clinical findings were unremarkable except for speech delay in two children. Via genome sequencing followed by Sanger confirmation we showed that all affected individuals were homozygous for a deep intronic GALT variant, c.1059+390A>G, which segregated as an autosomal recessive trait in all families. The intronic variant disrupts splicing and leads to a premature termination and is associated with a single haplotype flanking GALT, suggesting a founder effect. In conclusion, we present a deep intronic GALT variant leading to a biochemical variant form of galactosemia. This variant remains undiagnosed until it is specifically targeted in molecular testing.

Positive airway pressure therapy for sleep-disordered breathing confers short-term benefits to patients with spinal cord injury despite widely ranging patterns of use.

STUDY DESIGN: Prospective, cohort study. OBJECTIVES: To evaluate the effectiveness of bi-level positive airway pressure (PAP) therapy and the patterns of use for sleep-disordered breathing (SDB) in individuals with spinal cord injury (SCI). SETTING: Academic tertiary care center, USA. METHODS: Overall, 91 adults with C1-T6 SCI for ≥3 months were recruited and 74 remained in the study to be evaluated for SDB and follow-up. Individuals with SDB but no nocturnal hypercapnia (NH) were prescribed auto-titrating PAP. Those with NH were prescribed PAP with volume-assured pressure support. Device downloads and overnight transcutaneous capnography were performed at 3, 6, and 12 months to quantify PAP use and effectiveness. Participants kept daily event logs, and quality of life (QOL) questionnaires were performed after 3, 6, and 12 months. RESULTS: Overall, 45% of 91 participants completed the study. There was great diversity among SCI patients in PAP utilization; after 3 months, 37.8% of participants used PAP for ≥70% nights and ≥240 min per night, whereas 42.2% seldom used PAP and 20% used PAP sporadically or for short periods. PAP therapy was effective in improving OSA in 89% and nocturnal hypercapnia in 77%. Higher PAP pressures predicted higher levels of device use. There were marked reductions in symptoms of autonomic dysreflexia (AD) and orthostatic hypotension as well as some improved indices of QOL. CONCLUSIONS: Despite widely diverse patterns of use, PAP therapy may have short-term benefits with regard to QOL and reducing episodes of dizziness and autonomic dysreflexia.

Association of Pharmacologic Treatment of Urgency Urinary Incontinence With Sleep Quality and Daytime Sleepiness.

OBJECTIVE: To evaluate the association between pharmacologic therapy for urgency urinary incontinence (UUI) and sleep quality. METHODS: We conducted a planned secondary data analysis of sleep outcomes in a previously conducted multicenter, double-blind, 12-week randomized trial of pharmacologic therapy for urgency-predominant incontinence among community-dwelling women self-diagnosed using the 3-Incontinence Questions questionnaire. Participants (N=645) were assigned randomly to 4-8 mg antimuscarinic therapy daily or placebo. At baseline and 12 weeks, participants completed a validated voiding diary to evaluate incontinence and voiding symptoms, the Pittsburgh Sleep Quality Index to evaluate sleep quality, and the Epworth Sleepiness Scale to evaluate daytime sleepiness. RESULTS: Mean (SD) age was 56 (±14) years, 68% were white, and 57% had poor sleep quality (Pittsburgh Sleep Quality Index score greater than 5). Mean frequency of any urinary incontinence and UUI was 4.6 and 3.9 episodes/d, respectively. After 12 weeks, women randomized to the antimuscarinic group reported greater decrease compared with the placebo group in UUI frequency (0.9 episodes/d; P<.001) and diurnal and nocturnal voiding frequency (P<.05). As compared with the placebo group, women in the antimuscarinic group also reported greater improvement in sleep quality (total Pittsburgh Sleep Quality Index score 0.48; P=.02) with greater improvement in sleep duration and sleep efficiency subscales (P<.05). The intervention did not affect daytime sleepiness. CONCLUSION: Pharmacologic treatment of UUI is associated with decreased incontinence frequency and nocturia and improvement in overall sleep quality, sleep duration, and sleep efficiency. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00862745.

Sleep Quality and Daytime Sleepiness Among Women With Urgency Predominant Urinary Incontinence.

OBJECTIVE: The objective of this study was to examine the strength and direction of the association between urinary symptoms and both poor quality sleep and daytime sleepiness among women with urgency urinary incontinence. METHODS: A planned secondary analysis of baseline characteristics of participants in a multicenter, double-blinded, 12-week randomized controlled trial of pharmacologic therapy for urgency-predominant urinary incontinence in ambulatory women self-diagnosed by the 3 Incontinence Questions was performed. Urinary symptoms were assessed by 3-day voiding diaries. Quality of sleep was assessed using the Pittsburgh Sleep Quality Index (PSQI) and daytime sleepiness using the Epworth Sleepiness Scale. RESULTS: Of the 640 participants, mean (SD) age was 56 (±14) years and 68% were white. Participants reported an average of 3.9 (±3.0) urgency incontinence episodes per day and 1.3 (±1.3) episodes of nocturia per night. At baseline, 57% had poor sleep quality (PSQI score, >5) and 17% reported daytime sleepiness (Epworth Sleepiness Scale score, >10). Most women (69%) did not use sleeping medication during the prior month, whereas 13% reported use of sleeping medication 3 or more times per week. An increase in total daily incontinence episodes, total daily urgency incontinence episodes, total daily micturitions, and moderate to severe urge sensations were all associated with higher self-report of poor sleep quality according to the PSQI (all P ≤ 0.01). Higher scores on the Bother Scale and the Health-Related Quality of Life for overactive bladder on the Overactive Bladder Questionnaire were similarly associated with higher rates of poor sleep quality (both P ≤ 0.01). In subgroup analysis of those who took sleeping medications less than twice a week, there was still a significant relationship between incontinence measures and quality of sleep as measured by the PSQI. In multivariable analyses, greater frequency of nighttime urgency incontinence was associated with poor sleep quality (P = 0.03). CONCLUSIONS: Among ambulatory women with urgency urinary incontinence, poor sleep quality is common and greater frequency of incontinence is associated with a greater degree of sleep dysfunction. Women seeking urgency urinary incontinence treatment should be queried about their sleeping habits so that they can be offered appropriate interventions.

Glycemic Control and Urinary Tract Infections in Women with Type 1 Diabetes: Results from the DCCT/EDIC.

PURPOSE: We examined the relationship between glycemic control and urinary tract infections in women with type 1 diabetes mellitus. MATERIALS AND METHODS: Women enrolled in the Epidemiology of Diabetes Interventions and Complications study, the observational followup of the Diabetes Control and Complications Trial, were surveyed to assess the rate of physician diagnosed urinary tract infections in the preceding 12 months. The relationship between glycated hemoglobin levels and number of urinary tract infections in the previous 12 months was assessed using a multivariable Poisson regression model. RESULTS: A total of 572 women were evaluated at year 17. Mean age was 50.7 ± 7.2 years, mean body mass index was 28.6 ± 5.9 kg/m(2), mean type 1 diabetes duration was 29.8 ± 5.0 years and mean glycated hemoglobin was 8.0% ± 0.9%. Of these women 86 (15.0%) reported at least 1 physician diagnosed urinary tract infection during the last 12 months. Higher glycated hemoglobin levels were significantly associated with number of urinary tract infections such that for every unit increase (1%) in recent glycated hemoglobin level, there was a 21% (p=0.02) increase in urinary tract infection frequency in the previous 12 months after adjusting for race, hysterectomy status, urinary incontinence, sexual activity in the last 12 months, peripheral and autonomic neuropathy, and nephropathy. CONCLUSIONS: The frequency of urinary tract infections increases with poor glycemic control in women with type 1 diabetes. This relationship is independent of other well described predictors of urinary tract infections and suggests that factors directly related to glycemic control may influence the risk of lower urinary tract infections.

Chronic obstructive pulmonary disease comorbidities.

PURPOSE OF REVIEW: Classic descriptions of chronic obstructive pulmonary disease (COPD) centered on its impact on respiratory function. It is currently recognized that comorbidities contribute to the severity of symptoms and COPD progression. Understanding COPD-comorbidities associations could provide innovative treatment strategies and identify new mechanistic pathways to be targeted. RECENT FINDINGS: Some comorbidities are clustered with specific COPD phenotypes. There are stronger associations between airway-predominant disease and cardio-metabolic comorbidities, whereas in emphysema-predominant COPD sarcopenia and osteoporosis are frequent. These patterns suggest different inflammatory pathways acting by COPD phenotype. Osteoporosis is a major concern in COPD, particularly among men. Although ß-blockers use for cardiac indications in COPD remains low, recent evidence suggests that this medication group could decrease COPD exacerbations. Gastroesophageal reflux is consistently associated with poor COPD outcomes, but mechanisms and impact of treatment are still unclear. Nontraditional comorbid conditions, such as cognitive impairment, anxiety, and depression have significant impact in COPD outcomes. SUMMARY: Clinicians should screen their COPD patients for the presence of cardiovascular disease, diabetes, osteoporosis, sleep apnea, and sarcopenia, comorbidities for which specific treatments are available and associated with better COPD outcomes. The impact of interventions to treat gastroesophageal reflux disease, anxiety and depression is still to be defined.

Bladder Symptoms in the Early Menopausal Transition.

PURPOSE: Bladder symptoms are common in women and result in use of healthcare resources and poor quality of life. Bladder symptoms have been linked to age and menopause, but debate exists in the literature. This article examines factors associated with bladder symptoms and compares women in late reproductive stage with those in menopausal transition. MATERIALS AND METHODS: We analyzed cross-sectional data from a prospective cohort study of midlife women (mean age, 48; range, 44-54 years) in northern California. The sample consisted of 158 women in late reproductive stage or menopause transition. Assessments included anthropometrics, menstrual cycle lengths and symptoms, urine samples for follicle-stimulating hormone level, and self-reported health perception and depressive symptoms. Analyses included descriptive bivariate statistics, group comparisons, and regression models. RESULTS: The most common bladder symptoms were nocturia (72%) at least once per night and urinary incontinence (50%) at least once per week. Incontinence was less prevalent in African American women compared to European Americans and Latinas (p = 0.001) and more prevalent in late reproductive stage than in menopause transition (p = 0.024). Controlling for age, women in late reproductive stage were more likely to report nocturia compared to those in menopause transition. Reproductive stage (p = 0.016), higher body mass index (p = 0.007), and race (p = 0.017) contributed to the variance in weekly nighttime urinary frequency. CONCLUSION: Bladder symptoms were associated with reproductive stage. Women in late reproductive stage were more likely to experience nocturia and incontinence than those in menopause transition. The higher rates of nocturia and incontinence in late reproductive stage are intriguing. Future studies should include analysis of pelvic organ prolapse degree and other structural differences.

Exposure to methylphenidate during peri-adolescence affects endocrine functioning and sexual behavior in female Long-Evans rats.

The present study was designed to test the effects of methylphenidate (MPH) exposure on the maturation of endocrine functioning and sexual behavior. Female rat pups received either MPH (2.0mg/kg, i.p.) or saline twice daily between postnatal days 20-35. This period of exposure represents the time just prior to puberty as well as puberty onset. Approximately five weeks after the last injection of MPH or saline, female subjects were hormone-primed and tested during their first sexual experience. Subjects were given the choice to interact with a sexually active male or a sexually receptive female rat (i.e., the partner-preference test). The partner-preference paradigm allows us to assess multiple aspects of female sexual behavior. MPH exposure during peri-adolescence delayed puberty and, when mated for the first time, affected sexual behavior (e.g., increased time spent with the male stimulus and decreased the likelihood of leaving after mounts) during the test of partner preference. When monitoring estrous cyclicity, female subjects treated with MPH during peri-adolescence frequently experienced irregular estrous cycles. The results of the present study suggest that chronic exposure to a therapeutic dose of MPH around the onset of puberty alters long-term endocrine functioning, but with hormone priming, increases sensitivity to sexual stimuli.

Bridging the gap: determinants of undiagnosed or untreated urinary incontinence in women.

BACKGROUND: More than a third of middle-aged or older women suffer from urinary incontinence, but less than half undergo evaluation or treatment for this burdensome condition. With national organizations now including an assessment of incontinence as a quality performance measure, providers and health care organizations have a growing incentive to identify and engage these women who are undiagnosed and untreated. OBJECTIVE: We sought to identify clinical and sociodemographic determinants of patient-provider discussion and treatment of incontinence among ethnically diverse, community-dwelling women. STUDY DESIGN: We conducted an observational cohort study from 2003 through 2012 of 969 women aged 40 years and older enrolled in a Northern California integrated health care delivery system who reported at least weekly incontinence. Clinical severity, type, treatment, and discussion of incontinence were assessed by structured questionnaires. Multivariable regression evaluated predictors of discussion and treatment. RESULTS: Mean age of the 969 participants was 59.9 (±9.7) years, and 55% were racial/ethnic minorities (171 black, 233 Latina, 133 Asian or Native American). Fifty-five percent reported discussing their incontinence with a health care provider, 36% within 1 year of symptom onset, and with only 3% indicating that their provider initiated the discussion. More than half (52%) reported being at least moderately bothered by their incontinence. Of these women, 324 (65%) discussed their incontinence with a clinician, with 200 (40%) doing so within 1 year of symptom onset. In a multivariable analysis, women were less likely to have discussed their incontinence if they had a household income < $30,000/y vs ≥ $120,000/y (adjusted odds ratio [AOR], 0.49, 95% confidence interval [CI], 0.28-0.86) or were diabetic (AOR, 0.71, 95% CI, 0.51-0.99). They were more likely to have discussed incontinence if they had clinically severe incontinence (AOR, 3.09, 95% CI, 1.89-5.07), depression (AOR, 1.71, 95% CI, 1.20-2.44), pelvic organ prolapse (AOR, 1.98, 95% CI, 1.13-3.46), or arthritis (AOR, 1.44, 95% CI, 1.06-1.95). Among the subset of women reporting at least moderate subjective bother from incontinence, black race (AOR, 0.45, 95% CI, 0.25-0.81, vs white race) and income < $30,000/y (AOR, 0.37, 95% CI, 0.17-0.81, vs ≥ $120,000/y) were associated with a reduced likelihood of discussing incontinence. Those with clinically severe incontinence (AOR, 2.93, 95% CI, 1.53-5.61, vs low to moderate incontinence by the Sandvik scale) were more likely to discuss it with a clinician. CONCLUSION: Even in an integrated health care system, lower income was associated with decreased rates of patient-provider discussion of incontinence among women with at least weekly incontinence. Despite being at increased risk of incontinence, diabetic women were also less likely to have discussed incontinence or received care. Findings provide support for systematic screening of women to overcome barriers to evaluation and treatment.

Glucocorticoid-Augmented Efferocytosis Inhibits Pulmonary Pneumococcal Clearance in Mice by Reducing Alveolar Macrophage Bactericidal Function.

Inhaled corticosteroids (ICS) increase community-acquired pneumonia (CAP) incidence in patients with chronic obstructive pulmonary disease (COPD) by unknown mechanisms. Apoptosis is increased in the lungs of COPD patients. Uptake of apoptotic cells (ACs) ("efferocytosis") by alveolar macrophages (AMøs) reduces their ability to combat microbes, including Streptococcus pneumoniae, the most common cause of CAP in COPD patients. Having shown that ICS significantly increase AMø efferocytosis, we hypothesized that this process, termed glucocorticoid-augmented efferocytosis, might explain the association of CAP with ICS therapy in COPD. To test this hypothesis, we studied the effects of fluticasone, AC, or both on AMøs of C57BL/6 mice in vitro and in an established model of pneumococcal pneumonia. Fluticasone plus AC significantly reduced TLR4-stimulated AMø IL-12 production, relative to either treatment alone, and decreased TNF-α, CCL3, CCL5, and keratinocyte-derived chemoattractant/CXCL1, relative to AC. Mice treated with fluticasone plus AC before infection with viable pneumococci developed significantly more lung CFUs at 48 h. However, none of the pretreatments altered inflammatory cell recruitment to the lungs at 48 h postinfection, and fluticasone plus AC less markedly reduced in vitro mediator production to heat-killed pneumococci. Fluticasone plus AC significantly reduced in vitro AMø killing of pneumococci, relative to other conditions, in part by delaying phagolysosome acidification without affecting production of reactive oxygen or nitrogen species. These results support glucocorticoid-augmented efferocytosis as a potential explanation for the epidemiological association of ICS therapy of COPD patients with increased risk for CAP, and establish murine experimental models to dissect underlying molecular mechanisms.

The burden of nocturia among middle-aged and older women.

OBJECTIVE: To examine the prevalence, predictors, and effects of nocturia in women and evaluate overlaps with established urinary tract disorders. METHODS: This was a cross-sectional analysis of 2,016 women, aged 40 years and older, recruited from Kaiser Permanente Northern California from 2008 to 2012. Nocturia and other urinary symptoms were assessed using structured interviewer-administered questionnaires. Nocturia was defined as patient-reported nocturnal voiding of two or more times per night over a typical week. RESULTS: Thirty-four percent (n=692) reported nocturia, and 40% of women with nocturia reported no other urinary tract symptom. Women with nocturia were older (mean age 58 compared with 55 years) (odds ratio [OR] per 5-year increase 1.21, 95% confidence interval [CI] 1.12-1.31), more likely black (45%) (OR 1.75, 95% CI 1.30-2.35) or Latina (37%) (OR 1.36, 95% CI 1.02-1.83) compared with non-Latina white (30%), have worse depression (mean Hospital Anxiety and Depression Scale score 3.8 compared with 2.8) (OR per 1-point increase in Hospital Anxiety and Depression Scale score 1.08, 95% CI 1.04-1.12), and worse mobility (mean Timed Up-and-Go 11.3 compared with 10 seconds) (OR per 5-second increase in Timed Up-and-Go 1.29, 95% CI 1.05-1.58). Nocturia occurred more among women with hysterectomy (53% compared with 33%) (OR 1.78, 95% CI 1.08-2.94), hot flushes (38% compared with 32%) (OR 1.49, 95% CI 1.19-1.87), and vaginal estrogen use (42% compared with 34%) (OR 1.50, 95% CI 1.04-2.18). CONCLUSION: Nocturia is common in women and not necessarily attributable to other urinary tract disorders. Factors not linked to bladder function may contribute to nocturia risk, underlining the need for multiorgan prevention and treatment strategies. LEVEL OF EVIDENCE: II.

Design of a multi-center immunophenotyping analysis of peripheral blood, sputum and bronchoalveolar lavage fluid in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS).

BACKGROUND: Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS) is a multi-center longitudinal, observational study to identify novel phenotypes and biomarkers of chronic obstructive pulmonary disease (COPD). In a subset of 300 subjects enrolled at six clinical centers, we are performing flow cytometric analyses of leukocytes from induced sputum, bronchoalveolar lavage (BAL) and peripheral blood. To minimize several sources of variability, we use a "just-in-time" design that permits immediate staining without pre-fixation of samples, followed by centralized analysis on a single instrument. METHODS: The Immunophenotyping Core prepares 12-color antibody panels, which are shipped to the six Clinical Centers shortly before study visits. Sputum induction occurs at least two weeks before a bronchoscopy visit, at which time peripheral blood and bronchoalveolar lavage are collected. Immunostaining is performed at each clinical site on the day that the samples are collected. Samples are fixed and express shipped to the Immunophenotyping Core for data acquisition on a single modified LSR II flow cytometer. Results are analyzed using FACS Diva and FloJo software and cross-checked by Core scientists who are blinded to subject data. RESULTS: Thus far, a total of 152 sputum samples and 117 samples of blood and BAL have been returned to the Immunophenotyping Core. Initial quality checks indicate useable data from 126 sputum samples (83%), 106 blood samples (91%) and 91 BAL samples (78%). In all three sample types, we are able to identify and characterize the activation state or subset of multiple leukocyte cell populations (including CD4+ and CD8+ T cells, B cells, monocytes, macrophages, neutrophils and eosinophils), thereby demonstrating the validity of the antibody panel. CONCLUSIONS: Our study design, which relies on bi-directional communication between clinical centers and the Core according to a pre-specified protocol, appears to reduce several sources of variability often seen in flow cytometric studies involving multiple clinical sites. Because leukocytes contribute to lung pathology in COPD, these analyses will help achieve SPIROMICS aims of identifying subgroups of patients with specific COPD phenotypes. Future analyses will correlate cell-surface markers on a given cell type with smoking history, spirometry, airway measurements, and other parameters. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov as NCT01969344 .

Transforming growth factor-ß induces microRNA-29b to promote murine alveolar macrophage dysfunction after bone marrow transplantation.

Hematopoietic stem cell transplantation (HSCT) is complicated by pulmonary infections that manifest posttransplantation. Despite engraftment, susceptibility to infections persists long after reconstitution. Previous work using a murine bone marrow transplant (BMT) model implicated increased cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) in promoting impaired alveolar macrophage (AM) responses. However, mechanisms driving COX-2 overexpression remained elusive. Previously, transforming growth factor-ß (TGF-ß) signaling after BMT was shown to promote hypomethylation of the COX-2 gene. Here, we provide mechanistic insight into how this occurs and show that TGF-ß induces microRNA (miR)-29b while decreasing DNA methyltransferases (DNMT)1, DNMT3a, and DNMT3b in AMs after BMT. De novo DNMT3a and DNMT3b were decreased upon transient transfection of miR-29b, resulting in decreased methylation of the COX-2 promoter and induction of COX-2. As a consequence, miR-29b-driven upregulation of COX-2 promoted AM dysfunction, and transfection of BMT AMs with a miR-29b inhibitor rescued the bacterial-killing defect. MiR-29b-mediated defects in BMT AMs were dependent on increased levels of PGE2, as miR-29b-transfected AMs treated with a novel E prostanoid receptor 2 antagonist abrogated the impaired bacterial killing. We also demonstrate that patients that have undergone HSCT exhibit increased miR-29b; thus these studies highlight miR-29b in driving defective AM responses and identify this miRNA as a potential therapeutic target.

Long-term prevalence and predictors of urinary incontinence among women in the Diabetes Prevention Program Outcomes Study.

OBJECTIVES: To examine the long-term prevalence and predictors of weekly urinary incontinence in the Diabetes Prevention Program Outcomes Study, a follow-up study of the Diabetes Prevention Program randomized clinical trial of overweight adults with impaired glucose tolerance. METHODS: This analysis included 1778 female participants of the Diabetes Prevention Program Outcomes Study who had been randomly assigned during the Diabetes Prevention Program to intensive lifestyle intervention (n = 582), metformin (n = 589) or placebo (n = 607). The study participants completed semi-annual assessments after the final Diabetes Prevention Program visit and for 6 years until October 2008. RESULTS: At the study entry, the prevalence of weekly urinary incontinence was lower in the intensive lifestyle intervention group compared with the metformin and placebo groups (44.2% vs 51.8%, 48.0% urinary incontinence/week, P = 0.04); during the 6-year follow-up period, these lower rates in intensive lifestyle intervention were maintained (46.7%, 53.1%, 49.9% urinary incontinence/week; P = 0.03). Statistically adjusting for urinary incontinence prevalence at the end of the Diabetes Prevention Program, the treatment arm no longer had a significant impact on urinary incontinence during the Diabetes Prevention Program Outcomes Study. Independent predictors of lower urinary incontinence during the Diabetes Prevention Program Outcomes Study included lower body mass index (odds ratio 0.988, 95% confidence interval 0.982-0.994) and greater physical activity (odds ratio 0.999, 95% confidence interval 0.998-1.000) at the Diabetes Prevention Program Outcomes Study entry, and greater reductions in body mass index (odds ratio 0.75, 95% confidence interval 0.60-0.94) and waist circumference (odds ratio 0.998, 95% confidence interval 0.996-1.0) during the Diabetes Prevention Program Outcomes Study. Diabetes was not significantly related to urinary incontinence. CONCLUSIONS: Intensive lifestyle intervention has a modest positive and enduring impact on urinary incontinence, and should be considered for the long-term prevention and treatment of urinary incontinence in overweight/obese women with glucose intolerance.