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Background Cumulative exposure to one or more anticholinergic medications (“anticholinergic burden”) is associated with an increased risk of adverse outcomes, particularly among older individuals. Mirabegron, an oral selective β3-adrenergic receptor agonist, has demonstrated efficacy in managing the symptoms of overactive bladder without contributing to anticholinergic burden. However, it is not known whether the favorable safety profile of mirabegron relative to antimuscarinics varies with increasing age among a patient population who may have a high anticholinergic burden. Objective The primary objective of this study was to indirectly compare the safety and efficacy profile of mirabegron relative to antimuscarinics in older adults with overactive bladder. Methods A systematic literature review was conducted to identify randomized controlled trials that reported safety and efficacy endpoints among patients aged ≥ 65 years. Identified randomized controlled trials were subsequently synthesized via a network meta-analysis. Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines in designing, performing, and reporting the literature review were followed. In line with current best practices, the network meta-analysis was conducted using a Bayesian approach and according to the overall general guidance for evidence synthesis developed by the National Institute for Health and Care Excellence decision support unit. Estimates of relative safety were assessed via the odds ratio and estimates of relative efficacy were assessed via means and credible intervals. Results A total of 3078 abstracts, 300 of which underwent full-text screening, were identified using the search criteria. Twenty articles reporting on 21 randomized controlled trials were eligible for data extraction and synthesis. Following review, five safety and five efficacy endpoints were considered for inclusion in the network meta-analysis. Regarding findings typical of anticholinergic exposure in older adults, mirabegron was not associated with an increased odds of dry mouth (odds ratio 95% credible interval 0.76 [0.26–2.37]) or constipation (1.08 [0.39–3.02]) relative to placebo, whereas antimuscarinics were strongly associated with these events (odds ratio range 3.78–7.85 and 2.12–4.66, respectively). In this older population, mirabegron was associated with a similar odds of experiencing adverse event-related treatment discontinuations relative to placebo (0.99 [0.57–1.70]), while the odds of experiencing an adverse event-related treatment discontinuation for antimuscarinics had a range of 1.14–3.03 (in most cases, the association was mild). No increased odds of experiencing overall treatment-emergent adverse events was observed for mirabegron or antimuscarinics (odds ratio range 1.25–1.55), apart from fesoterodine (2.23 [1.37–3.37]). Finally, a similar treatment effect was observed across all efficacy endpoints between mirabegron and antimuscarinics in this older population. Conclusions This study indicates that the safety and efficacy profile of mirabegron remains favorable compared with antimuscarinics among older adults. This includes safety outcomes typically associated with anticholinergic burden, which were less frequently observed in patients treated with mirabegron.

Objective To understand factors guiding overactive bladder (OAB) therapy selection and experience with combination therapy (antimuscarinics and beta-3 agonists). Methods Cross-sectional surveys of OAB patients and OAB-treating physicians in the USA were conducted. Patients receiving monotherapy with antimuscarinics were categorized by OAB treatment history: monotherapy only; third-line procedures (e.g., onabotulinumtoxinA injections) and combination therapy; third-line therapy only; and combination therapy only. The patient survey assessed therapy choice drivers and barriers, treatment satisfaction and sociodemographic/clinical characteristics. The physician survey assessed drivers of and barriers to OAB treatment choices. Results Of 200 patients, 86.5% reported involvement in treatment decision-making; doctor’s recommendation was the most frequently considered factor (84.4%). Most patients (71%) were unaware of combination therapy. The primary reason why those patients aware of combination therapy had not used it (N = 43/200; 21%) was physician recommendation of other treatments (69.8%). For physicians (N = 50), the most frequently considered factors when prescribing OAB treatment were effectiveness (92.0%) and side effects (84.0%); 70% prescribed combination therapy, primarily for symptom severity (82.9%). The main reasons for not prescribing combination therapy were cost/insurance coverage (80%) and lack of information (53.3%). Conclusions Shared decision-making guided treatment decisions; the main considerations were treatment safety and efficacy.

Background Overactive bladder (OAB) is common and morbid. Medication and diagnosis claims may be specific, but lack sensitivity to identify patients with overactive bladder. We used an “electronic health record (EHR) phenotype” to identify cases and describe treatment choices and anticholinergic burden for OAB. Methods We conducted a retrospective cohort study in a large, integrated health delivery system between July 2011 and June 2012 (2-year follow-up). We examined care from primary care and specialty clinics, medication and procedure use, and anticholinergic burden for each patient. Results There were 7362 patients with an EHR OAB phenotype; 50% of patients were > 65 years old, 74% were female, and 83% were white. The distribution of care included primary care physician (PCP)/specialty co-management (25% of patients); PCP care only (18%); urology only (13%); or some other combination of specialty care (33%). Only 40% of patients were prescribed at least 1 OAB medication during the study. The mean duration of prescribed medication was 1.5 months (95% confidence interval [CI], 1.4 to 1.6 months; range, < 1 month to 24 months). Independent predictors of receipt of an OAB medication included increasing age (odds ratio [OR], 1.4 for every 10 years; 95% CI, 1.4 to 1.5), women (OR, 1.6 compared with men; 95% CI, 1.4 to 1.8), diabetes (OR, 1.3; 95% CI, 1.1 to 1.5), and certain sources of care compared with PCP-only care: PCP/specialty co-management (OR, 1.8; 95% CI, 1.5 to 2.0), urology (OR, 2.2; 95% CI, 1.8 to 2.6), and multiple specialists (OR, 1.4; 95% CI, 1.2 to 1.8). Very few patients received other treatments: biofeedback (< 1%), onabotulinumtoxinA (2%), or sacral nerve stimulation (1%). Patients who received OAB medications had significantly higher anticholinergic burden than patients who did not (anticholinergic total standardized daily dose, 125 versus 46; P  < .001). Conclusions Although OAB is common and morbid, in a longitudinal study using an EHR OAB phenotype 40% of patients were treated with OAB medication and only briefly.

Background and Objective Given that a high intrapatient variability (IPV) of tacrolimus whole blood concentration increases the risk for a poor kidney transplant outcome, some experts advocate routine IPV monitoring for detection of high-risk patients. However, attempts to estimate the variance of tacrolimus trough concentrations (TTC) are limited by the need for patients to receive a fixed dose over time and/or the use of linear statistical models. A goal of this study is to overcome the current limitations through the novel application of statistical methodology generalizing the relationship between TTC and dose through the use of nonparametric functional regression modeling. Methods With TTC as a response and dose as a covariate, the model employs an unknown bivariate function, allowing for the potentially complex, nonlinear relationship between the two parameters. A dose-adjusted variance of TTC is then derived based on standard functional principal component analysis (FPCA). To assess the model, it was compared against an FPCA-based model and linear mixed-effects models using prediction error, bias, and coverage probabilities for simulated data as well as phase III data from the Astellas new drug application studies for extended-release tacrolimus. Results Our numerical investigation indicates that the new model better predicts dose-adjusted TTCs compared with the prediction of linear mixed effects models. Estimated coverage probabilities also indicate that the new model accurately accounts for the variance of TTC during the periods of large fluctuation in dose, whereas the linear mixed effects model consistently underestimates the coverage probabilities because of the inaccurate characterization of TTC fluctuation. Conclusion This is the first known application of a functional regression model to assess complex relationships between TTC and dose in a real clinical setting. This new method has applicability in future clinical trials including real-world data sets due to flexibility of the nonparametric modeling approach.

Background In older patients with overactive bladder (OAB), mirabegron, a β 3 -adrenoreceptor agonist, represents an alternative treatment that may have a favorable risk–benefit profile. Objectives Our objective was to further examine the safety and tolerability of mirabegron versus placebo treatment in patients aged ≥ 65 years with OAB-wet. Methods We conducted a 12-week, double-blind, randomized, placebo-controlled phase IV study to compare mirabegron with placebo. Community-dwelling patients aged ≥ 65 years with OAB-wet (one or more incontinence episode and three or more urgency episodes, and an average of eight or more micturitions/24 h over a 3-day diary) were randomized to receive placebo or mirabegron 25 mg/day (optional dose escalation to 50 mg/day at week 4 or 8). Safety analyses were performed for adverse events (AEs) and vital signs on all randomized patients who received one or more dose of study drug. Results Treatment-emergent AEs (TEAEs), the majority mild or moderate in severity, were reported in 39.4% of placebo patients and 44.2 and 49.8% of those who received mirabegron 25 mg or 50 mg, respectively. The most common TEAEs in mirabegron-treated patients were urinary tract infection, headache, and diarrhea. The incidence of TEAEs was slightly higher in mirabegron patients aged ≥ 75 years than in those aged < 75 years. There were no clinically meaningful differences in changes in vital signs from baseline to end of treatment for any treatment group, and no differences were observed between mirabegron and placebo treatment groups. TEAEs tended to occur early post exposure and were not dose related. Conclusions Mirabegron treatment was well-tolerated in older adults with OAB-wet. Safety and tolerability were consistent with the known mirabegron safety profile. Trial Registration This study is registered at ClinicalTrials.gov: NCT02216214.

Background Missing data in costs and/or health outcomes and in confounding variables can create bias in the inference of health economics and outcomes research studies, which in turn can lead to inappropriate policies. Most of the literature focuses on handling missing data in randomized controlled trials, which are not necessarily always the data used in health economics and outcomes research. Objectives We aimed to provide an overview on missing data issues and how to address incomplete data and report the findings of a systematic literature review of methods used to deal with missing data in health economics and outcomes research studies that focused on cost, utility, and patient-reported outcomes. Methods A systematic search of papers published in English language until the end of the year 2020 was carried out in PubMed. Studies using statistical methods to handle missing data for analyses of cost, utility, or patient-reported outcome data were included, as were reviews and guidance papers on handling missing data for those outcomes. The data extraction was conducted with a focus on the context of the study, the type of missing data, and the methods used to tackle missing data. Results From 1433 identified records, 40 papers were included. Thirteen studies were economic evaluations. Thirty studies used multiple imputation with 17 studies using multiple imputation by chained equation, while 15 studies used a complete-case analysis. Seventeen studies addressed missing cost data and 23 studies dealt with missing outcome data. Eleven studies reported a single method while 20 studies used multiple methods to address missing data. Conclusions Several health economics and outcomes research studies did not offer a justification of their approach of handling missing data and some used only a single method without a sensitivity analysis. This systematic literature review highlights the importance of considering the missingness mechanism and including sensitivity analyses when planning, analyzing, and reporting health economics and outcomes research studies.

The Henry Ford Hospital (HFH) regadenoson (REG) registry includes patients with a variety of comorbidities allowing for the evaluation of outcomes in a large, unselected population. Using a database of electronic medical records and nuclear cardiology reports, patients aged > 18 years who underwent REG-facilitated single-photon emission computed tomography (SPECT) testing at HFH between January 2009 and August 2012 were identified. The primary objective was to describe the clinical and demographic characteristics of patients who had undergone REG only vs REG WALK (REG + low-level exercise) SPECT. A total of 2104 patients were included in the analysis (mean age 65.3 years; 50% women; 51% African American, 43% Caucasian). For the REG only (n = 1318) and REG WALK (n = 786) cohorts, SPECT was abnormal in 37% of patients (REG only, 39%; REG WALK, 34%; P < 0.01). No differences in diagnostic modalities or interventions in 90 days after SPECT were observed. Immediate safety analysis showed no deaths 48 h after REG SPECT testing. Although they guide invasive therapy, abnormal scans do not automatically lead to invasive testing. This demonstrates the focus on initial medical management, which reflects the existing evidence of initial goal-directed medical management of stable coronary disease.

Background Clinical guidelines provide clinicians with substantial discretion in the use of noninvasive cardiac testing for patients with suspected coronary artery disease. Repeat testing, frequent emergency department (ED) visits, and increases in other cardiac-related procedures can be a burden on patients and payers and can complicate treatment planning. We assessed downstream healthcare resource utilization (HCRU) for patients undergoing initial single-photon emission computed tomography (SPECT), myocardial perfusion imaging (MPI), stress echocardiography (ECHO), or exercise treadmill testing (ETT) with probable type I myocardial infarction (MI). Methods Electronic medical records data from 12,130 patients with probable type I MI presenting to EDs within a large healthcare system comprised of 11 adult hospitals were retrospectively analyzed. Logistic and linear regression determined the individual contribution of SPECT-MPI, ETT, and ECHO on repeat cardiovascular (CV) testing, inpatient visits, outpatient visits, and cardiac-related costs within 12 months of the index visit. Results The majority of patients received SPECT-MPI for the index-testing event (56.5%), followed by ETT (29.2%) and ECHO (14.3%). Patients who had SPECT-MPI at the index visit were less likely to have a repeat CV testing visit (odds ratio [OR] 0.77, 95% confidence interval [CI] 0.62‒0.96; p  = 0.020) or an inpatient visit (OR 0.70, 95% CI 0.49‒0.98; p  = 0.039) than those who underwent ETT or ECHO. ETT and ECHO were not predictive of any outcome. Conclusions SPECT-MPI does not result in more downstream HCRU than ETT or ECHO and is associated with a lower likelihood of repeat non-invasive CV testing and inpatient visits.

The current paper, using data from the National Longitudinal Survey of Youth 1979 (NLSY) and the NLSY Child Survey, reports results from a test designed to determine if impulsiveness is associated with credit card behavior, and whether a mother's time preference, socioeconomic status, and risk attitude transmit to her children in shaping credit card behavior. In addition to certain demographic factors, individuals who exhibited self-control/low impulsivity were more likely to possess a credit card, as were those whose mothers had a high socioeconomic status. Men, those with higher income, and those who were raised by mothers with high financial impatience were more likely to hold a credit card balance. [PUBLICATION ABSTRACT]

A large-effect QTL for divergence in sex-comb tooth number between Drosophila simulans and D. mauritiana was previously mapped to 73A–84AB. Here we identify genes that are likely contributors to this divergence. We first improved the mapping resolution in the 73A–84AB region using 12 introgression lines and 62 recombinant nearly isogenic lines. To further narrow the list of candidate genes, we assayed leg-specific expression and identified genes with transcript-level evolution consistent with a potential role in sex-comb divergence. Sex combs are formed on the prothoracic (front) legs, but not on the mesothoracic (middle) legs of Drosophila males. We extracted RNA from the prothoracic and mesothoracic pupal legs of two species to determine which of the genes expressed differently between leg types were also divergent for gene expression. Two good functional candidate genes, Scr and dsx, are located in one of our fine-scale QTL regions. In addition, three previously uncharacterized genes (CG15186, CG2016, and CG2791) emerged as new candidates. These genes are located in regions strongly associated with sex-comb tooth number differences and are expressed differently between leg tissues and between species. Further supporting the potential involvement of these genes in sex-comb divergence, we found a significant difference in sex-comb tooth number between co-isogenic D. melanogaster lines with and without P-element insertions at CG2791.