Predictors of Nerve Stimulator Success in Patients With Overactive Bladder

Purpose To identify factors associated with successful sacral nerve stimulator (SNS) trial after SNS implantation for the treatment of medication refractory overactive bladder (OAB). Methods Patients undergoing treatment for OAB at Lahey Hospital and Medical Center between 2004 and 2016 were identified. Patients undergoing SNS placement were identified; SNS success was defined as permanent implantation of the SNS. Demographic, clinical and treatment data were extracted from patient charts; uni- and multivariate analyses were conducted to identify factors associated with SNS treatment success. Results A total of 128 patients were included. On univariate analysis, male sex, prior diagnosis of benign prostatic hyperplasia, and lower volume at first urge on urodynamics (UDS) were associated with unsuccessful SNS trial. On multivariate analysis, male sex (odds ratio [OR], 0.145; 95% confidence interval [CI], 0.036–0.530) and lower volume at first urge on UDS (OR, 0.982; 95% CI, 0.967–0.995) were associated with unsuccessful SNS trial. A threshold value of 100 mL at first urge during preoperative UDS had a specificity of 0.86 in predicting SNS success in men. Conclusions SNS is frequently successful at relieving OAB symptoms. Male patients and those with lower volumes at first urge on UDS, particularly below 100 mL, are more likely to have an unsuccessful SNS trial. Patients in these groups should be counseled on the lower likelihood of SNS success

Dissecting the shared genetic basis of migraine and mental disorders using novel statistical tools

Migraine is three times more prevalent in people with bipolar disorder or depression. The relationship between schizophrenia and migraine is less certain although glutamatergic and serotonergic neurotransmission are implicated in both. A shared genetic basis to migraine and mental disorders has been suggested but previous studies have reported weak or non-significant genetic correlations and five shared risk loci. Using the largest samples to date and novel statistical tools, we aimed to determine the extent to which migraine’s polygenic architecture overlaps with bipolar disorder, depression and schizophrenia beyond genetic correlation, and to identify shared genetic loci. Summary statistics from genome-wide association studies were acquired from large-scale consortia for migraine (n cases = 59 674; n controls = 316 078), bipolar disorder (n cases = 20 352; n controls = 31 358), depression (n cases = 170 756; n controls = 328 443) and schizophrenia (n cases = 40 675, n controls = 64 643). We applied the bivariate causal mixture model to estimate the number of disorder-influencing variants shared between migraine and each mental disorder, and the conditional/conjunctional false discovery rate method to identify shared loci. Loci were functionally characterized to provide biological insights. Univariate MiXeR analysis revealed that migraine was substantially less polygenic (2.8 K disorder-influencing variants) compared to mental disorders (8100–12 300 disorder-influencing variants). Bivariate analysis estimated that 800 (SD = 300), 2100 (SD = 100) and 2300 (SD = 300) variants were shared between bipolar disorder, depression and schizophrenia, respectively. There was also extensive overlap with intelligence (1800, SD = 300) and educational attainment (2100, SD = 300) but not height (1000, SD = 100). We next identified 14 loci jointly associated with migraine and depression and 36 loci jointly associated with migraine and schizophrenia, with evidence of consistent genetic effects in independent samples. No loci were associated with migraine and bipolar disorder. Functional annotation mapped 37 and 298 genes to migraine and each of depression and schizophrenia, respectively, including several novel putative migraine genes such as L3MBTL2, CACNB2 and SLC9B1. Gene-set analysis identified several putative gene sets enriched with mapped genes including transmembrane transport in migraine and schizophrenia. Most migraine-influencing variants were predicted to influence depression and schizophrenia, although a minority of mental disorder-influencing variants were shared with migraine due to the difference in polygenicity. Similar overlap with other brain-related phenotypes suggests this represents a pool of ‘pleiotropic’ variants that influence vulnerability to diverse brain-related disorders and traits. We also identified specific loci shared between migraine and each of depression and schizophrenia, implicating shared molecular mechanisms and highlighting candidate migraine genes for experimental validation

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders 1 . They are heritable 2,3 and etiologically related 4,5 behaviors that have been resistant to gene discovery efforts 6–11 . In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

Evolving a national clinical trials learning health system

Abstract Clinical trials generate key evidence to inform decision making, and also benefit participants directly. However, clinical trials frequently fail, often struggle to enroll participants, and are expensive. Part of the problem with trial conduct may be the disconnected nature of clinical trials, preventing rapid data sharing, generation of insights and targeted improvement interventions, and identification of knowledge gaps. In other areas of healthcare, a learning health system (LHS) has been proposed as a model to facilitate continuous learning and improvement. We propose that an LHS approach could greatly benefit clinical trials, allowing for continuous improvements to trial conduct and efficiency. A robust trial data sharing system, continuous analysis of trial enrollment and other success metrics, and development of targeted trial improvement interventions are potentially key components of a Trials LHS reflecting the learning cycle and allowing for continuous trial improvement. Through the development and use of a Trials LHS, clinical trials could be treated as a system, producing benefits to patients, advancing care, and decreasing costs for stakeholders

Exploring implementation outcomes in the clinical trial context: a qualitative study of physician trial stakeholders

Abstract Introduction Cancer clinical trials can be considered evidence-based interventions with substantial benefits, but suffer from poor implementation leading to low enrollment and frequent failure. Applying implementation science approaches such as outcomes frameworks to the trial context could aid in contextualizing and evaluating trial improvement strategies. However, the acceptability and appropriateness of these adapted outcomes to trial stakeholders are unclear. For these reasons, we interviewed cancer clinical trial physician stakeholders to explore how they perceive and address clinical trial implementation outcomes. Methods We purposively selected 15 cancer clinical trial physician stakeholders from our institution representing different specialties, trial roles, and trial sponsor types. We performed semi-structured interviews to explore a previous adaptation of Proctor’s Implementation Outcomes Framework to the clinical trial context. Emergent themes from each outcome were developed. Results The implementation outcomes were well understood and applicable (i.e., appropriate and acceptable) to clinical trial stakeholders. We describe cancer clinical trial physician stakeholder understanding of these outcomes and current application of these concepts. Trial feasibility and implementation cost were felt to be most critical to trial design and implementation. Trial penetration was most difficult to measure, primarily due to eligible patient identification. In general, we found that formal methods for trial improvement and trial implementation evaluation were poorly developed. Cancer clinical trial physician stakeholders referred to some design and implementation techniques used to improve trials, but these were infrequently formally evaluated or theory-based. Conclusion Implementation outcomes adapted to the trial context were acceptable and appropriate to cancer clinical trial physician stakeholders. Use of these outcomes could facilitate the evaluation and design of clinical trial improvement interventions. Additionally, these outcomes highlight potential areas for the development of new tools, for example informatics solutions, to improve the evaluation and implementation of clinical trials

Comparative Effectiveness of Treatment Strategies for Squamous Cell Carcinoma of the Bladder.

BACKGROUND: While there is established evidence supporting the use of radical cystectomy (RC) and perioperative chemotherapy for muscle-invasive urothelial carcinoma of the bladder, such evidence does not exist for squamous cell carcinoma. OBJECTIVE: We present the largest study to date of patients with squamous cell carcinoma and compare the effectiveness of possible treatment regimens for overall survival. DESIGN, SETTING, AND PARTICIPANTS: The National Cancer Data Base was queried for cases of localized, muscle-invasive pure squamous cell bladder cancer, classified as clinical stage T2/3N0M0. Permutations of surgery (RC), chemotherapy, and external beam radiation were selected. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A multinomial propensity score method was used to create treatment weights based on clinical characteristics predicting the probability of treatment receipt. These were then applied in weighted Cox proportional hazards models to assess the comparative effectiveness of treatments for overall survival, adjusting for age, TNM clinical stage, Charlson comorbidity index, race, sex, and facility and county level variables. RESULTS AND LIMITATIONS: A total of 828 cases were included, comprising 465 RC alone, 53 neoadjuvant chemotherapy+RC, 48 RC+adjuvant chemotherapy, 72 chemotherapy alone, 88 radiation alone, and 102 chemoradiation cases. On weighted regression, RC treatment with or without perioperative chemotherapy was associated with significantly better overall survival compared to the other treatment modalities; chemotherapy alone, radiation alone, and chemoradiation were associated with a hazard ratio (HR) of death of 2.43 (95% confidence interval [CI] 1.65-3.59), 4.78 (95% CI 3.33-6.86), and 1.61 (95% CI 1.16-2.25), respectively, compared to RC alone (all p CONCLUSIONS: RC with or without perioperative chemotherapy should be considered an upfront therapy for squamous cell carcinoma of the bladder. PATIENT SUMMARY: Using a national database, we compared treatments for muscle-invasive squamous cell bladder cancer. Patients undergoing radical cystectomy with or without chemotherapy had longer survival. Radical cystectomy with or without chemotherapy should be the standard of care for this disease

Considerations in the Triage of Urologic Surgeries During the COVID-19 Pandemic

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156076/1/PIIS0302283820302025.pdfSEL