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.

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.

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.

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.

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.

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.

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 .

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.

Intensive lifestyle intervention reduces urinary incontinence in overweight/obese men with type 2 diabetes: results from the Look AHEAD trial.

PURPOSE: We determined the effect of an intensive lifestyle intervention on the prevalence, incidence and resolution of bothersome nocturia, increased daytime urinary voiding and urinary incontinence in overweight/obese men with type 2 diabetes after 1 year in the Look AHEAD trial. MATERIALS AND METHODS: A subset of male Look AHEAD participants was selected for this secondary data analysis. Overall 1,910 men with an average (mean ± SD) age of 59.9 ± 6.7 years and body mass index of 35.2 ± 5.5 kg/m(2) were randomized to an intensive lifestyle intervention or diabetes support and education group. All participants self-reported information regarding incontinence, nocturia and daytime urinary voiding at entry and 1 year. RESULTS: After 1 year the intensive lifestyle intervention group lost significantly more weight than the diabetes support and education group (9.4% ± 7.0% vs 0.7% ± 4.5%, respectively; p <0.001). The odds of prevalent urinary incontinence at 1 year were reduced by 38% in the intensive lifestyle intervention group compared to the diabetes support and education group. The prevalence of urinary incontinence decreased from 11.3% to 9.0% in the intensive lifestyle intervention group and increased from 9.7% to 11.6% in the diabetes support and education group. The intensive lifestyle intervention group also had increased odds of urinary incontinence resolving (OR 1.93, 95% CI 1.04-3.59, p = 0.04 and 56.0% vs 40.7%, p = 0.03) and trend toward reduced odds of new onset, incident urinary incontinence (OR 0.66, 95% CI 0.42-1.02, p = 0.06) compared with the diabetes support and education arm. In contrast, no differences between intensive lifestyle intervention and diabetes support and education were seen at 1 year for frequency of nocturia or frequency of daytime voiding. CONCLUSIONS: Intensive lifestyle intervention should be considered for the treatment of urinary incontinence in overweight/obese men with type 2 diabetes.

The impact of multimorbidity on sexual function in middle-aged and older women: beyond the single disease perspective.

INTRODUCTION: Little is known about sexual activity and function in women with multiple chronic health conditions. AIM: To examine the impact of multimorbidity on sexual activity and function in middle-aged and older women. METHODS: Multiethnic cross-sectional cohort of 1,997 community-dwelling women (mean age of 60.2 [±9.5] years) in California. Structured questionnaires assessed prior diagnoses of common cardiometabolic, colorectal, neuropsychiatric, respiratory, musculoskeletal, and genitourinary conditions. MAIN OUTCOME MEASURES: Sexual desire, frequency of sexual activity, overall sexual satisfaction, and specific sexual problems (i.e., difficulty with arousal, lubrication, orgasm, and pain) were assessed by structured questionnaires. RESULTS: Seventy-one percent of women had two or more diagnosed chronic conditions. Fifty-nine percent reported low sexual desire, 53% reported less than monthly sexual activity, and 47% reported low overall sexual satisfaction. Multimorbidity was associated with increased odds of reporting low sexual desire (OR = 1.11, 95% CI = 1.06-1.17, per each additional chronic condition), less than monthly sexual activity (OR = 1.11, 95% CI = 1.05-1.17 per each additional condition), and low sexual satisfaction (OR = 1.10, 95% CI = 1.04-1.16 per each additional condition), adjusting for age, race/ethnicity, and partner status. Depression and urinary incontinence were each independently associated with low desire (OR = 1.53, 95% CI = 1.19-1.97, and OR = 1.23, 95% CI = 1.00-1.52, respectively), less than monthly sexual activity (OR = 1.39, 95% CI = 1.06-1.83, and OR = 1.29, 95% CI = 1.02-1.62, respectively), and low sexual satisfaction (OR = 1.49, 95% CI = 1.14-1.93, and OR = 1.38, 95% CI = 1.11-1.73, respectively), adjusting for other types of conditions. After adjustment for total number of chronic conditions, age remained a significant predictor of low desire and less than monthly sexual activity, but not sexual satisfaction. CONCLUSIONS: Women with multiple chronic health conditions are at increased risk for decreased sexual function. Depression and incontinence may have particularly strong effects on sexual desire, frequency of activity, and satisfaction in women, independent of other comorbid conditions. Women's overall sexual satisfaction may be more strongly influenced by multimorbidity than age.

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.

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.

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.

Smoking decreases the response of human lung macrophages to double-stranded RNA by reducing TLR3 expression.

BACKGROUND: Cigarette smoking is associated with increased frequency and duration of viral respiratory infections, but the underlying mechanisms are incompletely defined. We investigated whether smoking reduces expression by human lung macrophages (Mø) of receptors for viral nucleic acids and, if so, the effect on CXCL10 production. METHODS: We collected alveolar macrophages (AMø) by bronchoalveolar lavage of radiographically-normal lungs of subjects undergoing bronchoscopies for solitary nodules (n = 16) and of volunteers who were current or former smokers (n = 7) or never-smokers (n = 13). We measured expression of mRNA transcripts for viral nucleic acid receptors by real-time PCR in those AMø and in the human Mø cell line THP-1 following phorbol myristate acetate/vitamin D3 differentiation and exposure to cigarette smoke extract, and determined TLR3 protein expression using flow cytometry and immunohistochemistry. We also used flow cytometry to examine TLR3 expression in total lung Mø from subjects undergoing clinically-indicated lung resections (n = 25). Of these, seven had normal FEV1 and FEV1/FVC ratio (three former smokers, four current smokers); the remaining 18 subjects (14 former smokers; four current smokers) had COPD of GOLD stages I-IV. We measured AMø production of CXCL10 in response to stimulation with the dsRNA analogue poly(I:C) using Luminex assay. RESULTS: Relative to AMø of never-smokers, AMø of smokers demonstrated reduced protein expression of TLR3 and decreased mRNA for TLR3 but not TLR7, TLR8, TLR9, RIG-I, MDA-5 or PKR. Identical changes in TLR3 gene expression were induced in differentiated THP-1 cells exposed to cigarette smoke-extract in vitro for 4 hours. Among total lung Mø, the percentage of TLR3-positive cells correlated inversely with active smoking but not with COPD diagnosis, FEV1% predicted, sex, age or pack-years. Compared to AMø of never-smokers, poly(I:C)-stimulated production of CXCL10 was significantly reduced in AMø of smokers. CONCLUSIONS: Active smoking, independent of COPD stage or smoking duration, reduces both the percent of human lung Mø expressing TLR3, and dsRNA-induced CXCL10 production, without altering other endosomal or cytoplasmic receptors for microbial nucleic acids. This effect provides one possible mechanism for increased frequency and duration of viral lower respiratory tract infections in smokers. TRIAL REGISTRATION: ClinicalTrials.gov NCT00281190, NCT00281203 and NCT00281229.

Long-term efficacy and safety of questionnaire-based initiation of urgency urinary incontinence treatment.

OBJECTIVE: The objective of the study was to determine the longer-term efficacy and safety of initiating treatment for urgency-predominant urinary incontinence (UUI) in women diagnosed using a simple questionnaire rather than an extensive evaluation. STUDY DESIGN: Women completing a 12 week randomized controlled trial of fesoterodine therapy for UUI diagnosed by questionnaire were invited to participate in a 9 month, open-label continuation study. UUI and voiding episodes were collected using voiding diaries. Participant satisfaction was measured by questionnaire. Safety was assessed by the measurement of postvoid residual volume and adverse event monitoring; if necessary, women underwent a specialist evaluation. The longitudinal changes in UUI and voiding episodes were evaluated using linear mixed models adjusting for baseline. RESULTS: Of the 567 women completing the randomized trial, 498 (87.8%) took at least 1 dose of medication during this open-label study. Compared with the baseline visit in the randomized trial, fesoterodine was associated with a reduction in total incontinence episodes per day and urgency incontinence episodes per day at the end of the open-label study (adjusted mean [SE], 4.6 [0.12] to 1.2 [0.13] and 3.9 [0.11] to 0.9 [0.11], respectively, P < .0001 for both). Most women were satisfied with treatment (89%, 92%, and 93% at 3, 6, and 9 months, respectively). Twenty-six women experienced 28 serious adverse events, 1 of which was considered possibly treatment related. Twenty-two women had a specialist evaluation: 5 women's incontinence was misclassified by the 3 Incontinence Questions; none experienced harm because of misclassification. CONCLUSION: Using a simple validated questionnaire to diagnose and initiate treatment for UUI in community-dwelling women is safe and effective, allowing timely treatment by primary care practitioners.

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.

Weight loss prevents urinary incontinence in women with type 2 diabetes: results from the Look AHEAD trial.

PURPOSE: We determined the effect of weight loss on the prevalence, incidence and resolution of weekly or more frequent urinary incontinence in overweight/obese women with type 2 diabetes after 1 year of intervention in the Look AHEAD (Action for Health in Diabetes) trial. MATERIALS AND METHODS: Women in this substudy (2,739, mean ± SD age 57.9 ± 6.8 years, body mass index 36.5 ± 6.1 kg/m(2)) were randomized into an intensive lifestyle weight loss intervention or a diabetes support and education control condition. RESULTS: At baseline 27% of participants reported urinary incontinence on a validated questionnaire (no significant difference by intensive lifestyle intervention vs diabetes support and education). After 1 year of intervention the intensive lifestyle intervention group in this substudy lost 7.7 ± 7.0 vs 0.7 ± 5.0 kg in the diabetes support and education group. At 1 year fewer women in the intensive lifestyle intervention group reported urinary incontinence (25.3% vs 28.6% in the diabetes support and education group, p = 0.05). Among participants without urinary incontinence at baseline 10.5% of intensive lifestyle intervention and 14.0% of diabetes support and education participants experienced urinary incontinence after 1 year (p = 0.02). There were no significant group differences in the resolution of urinary incontinence (p >0.17). Each kg of weight lost was associated with a 3% reduction in the odds of urinary incontinence developing (p = 0.01), and weight losses of 5% to 10% reduced these odds by 47% (p = 0.002). CONCLUSIONS: Moderate weight loss reduced the incidence but did not improve the resolution rates of urinary incontinence at 1 year among overweight/obese women with type 2 diabetes. Weight loss interventions should be considered for the prevention of urinary incontinence in overweight/obese women with diabetes.

Pharmacologic treatment for urgency-predominant urinary incontinence in women diagnosed using a simplified algorithm: a randomized trial.

OBJECTIVE: The purpose of this study was to evaluate clinical outcomes associated with the initiation of treatment for urgency-predominant incontinence in women diagnosed by a simple 3-item questionnaire. STUDY DESIGN: We conducted a multicenter, double-blinded, 12-week randomized trial of pharmacologic therapy for urgency-predominant incontinence in ambulatory women diagnosed by the simple 3-item questionnaire. Participants (N = 645) were assigned randomly to fesoterodine therapy (4-8 mg daily) or placebo. Urinary incontinence was assessed with the use of voiding diaries; postvoid residual volume was measured after treatment. RESULTS: After 12 weeks, women who had been assigned randomly to fesoterodine therapy reported 0.9 fewer urgency and 1.0 fewer total incontinence episodes/day, compared with placebo (P ≤ .001). Four serious adverse events occurred in each group, none of which was related to treatment. No participant had postvoid residual volume of ≥ 250 mL after treatment. CONCLUSION: Among ambulatory women with urgency-predominant incontinence diagnosed with a simple 3-item questionnaire, pharmacologic therapy resulted in a moderate decrease in incontinence frequency without increasing significant urinary retention or serious adverse events, which provides support for a streamlined algorithm for diagnosis and treatment of female urgency-predominant incontinence.

Fecal incontinence decreases sexual quality of life, but does not prevent sexual activity in women.

BACKGROUND: The impact of anal incontinence on women's sexual function is poorly understood. OBJECTIVE: The aim of this study was to investigate the relationship between anal incontinence and sexual activity and functioning in women. DESIGN: This is a cross-sectional study. SETTINGS: This investigation was conducted in a community-based integrated health care delivery system. PATIENTS: Included were 2269 ethnically diverse women aged 40 to 80 years. MAIN OUTCOME MEASURES: Self-administered questionnaires assessed accidental leakage of gas (flatal incontinence) and fluid/mucus/stool (fecal incontinence) in the past 3 months. Additional questionnaires assessed sexual activity, desire and satisfaction, as well as specific sexual problems (difficulty with arousal, lubrication, orgasm, or pain). Multivariable logistic regression models compared sexual function in women with 1) isolated flatal incontinence, 2) fecal incontinence (with or without flatal incontinence), and 3) no fecal/flatal incontinence, controlling for potential confounders. RESULTS: Twenty-four percent of women reported fecal incontinence and 43% reported isolated flatal incontinence in the previous 3 months. The majority were sexually active (62% of women without fecal/flatal incontinence, 66% with isolated flatal incontinence, and 60% with fecal incontinence; p = 0.06). In comparison with women without fecal/flatal incontinence, women with fecal incontinence were more likely to report low sexual desire (OR: 1.41 (CI: 1.10-1.82)), low sexual satisfaction (OR: 1.56 (CI: 1.14-2.12)), and limitation of sexual activity by physical health (OR: 1.65 (CI: 1.19-2.28)) after adjustment for confounders. Among sexually active women, women with fecal incontinence were more likely than women without fecal/flatal incontinence to report difficulties with lubrication (OR: 2.66 (CI: 1.76-4.00)), pain (OR: 2.44 (CI: 1.52-3.91)), and orgasm (OR: 1.68 (CI: 1.12-2.51)). Women with isolated flatal incontinence reported sexual functioning similar to women without fecal/flatal incontinence. LIMITATIONS: The cross-sectional design prevented evaluation of causality. CONCLUSIONS: Although most women with fecal incontinence are at high risk for several aspects of sexual dysfunction, the presence of fecal incontinence does not prevent women from engaging in sexual activity. This indicates that sexual function is important to women with anal incontinence and should be prioritized during therapeutic management.