Safety profile of pembrolizumab monotherapy based on an aggregate safety evaluation of 8937 patients.

BACKGROUND: Pembrolizumab has a manageable safety profile as described in its label, which was primarily based on 2799 patients who participated in clinical trials for melanoma or non-small cell lung cancer. Here, we evaluated the safety of pembrolizumab in a broader population of patients from 31 advanced cancer clinical trials across 19 cancer types. METHODS: Safety was analyzed in patients who received at least one dose of pembrolizumab (200 mg every 3 weeks [Q3W], 10 mg/kg Q2W or Q3W, or 2 mg/kg Q3W). Adverse events (AEs) and immune-mediated AEs and infusion reactions were evaluated. RESULTS: Safety data from 8937 patients in 31 trials of pembrolizumab monotherapy were pooled (median, seven administrations; range, 1-59). Median duration on treatment was 4.1 months (range, 0.03-40.1). AEs occurred in 96.6% of patients. Grade 3-5 AEs occurred in 50.6% of patients. AEs led to pembrolizumab discontinuation in 12.7% of patients and death in 5.9%. Immune-mediated AEs and infusion reactions occurred in 23.7% of patients (4.6% experienced multiple immune-mediated AEs/infusion reactions) and led to pembrolizumab discontinuation in 3.6% and death in 0.2%. Grade 3-5 immune-mediated AEs occurred in 6.3% of patients. Serious immune-mediated AEs and infusion reactions occurred in 6.0% of patients. Median time to immune-mediated AE onset was 85 days (range, 13-163). Of 2657 immune-mediated AEs, 22.3% were initially treated with prednisone ≥ 40 mg/day or equivalent, and 8.3% were initially treated with lower steroid doses. CONCLUSIONS: This pooled analysis of 31 clinical trials showed that pembrolizumab has a consistent safety profile across indications.

Safety signal detection with control of latent factors.

Postmarket drug safety database like vaccine adverse event reporting system (VAERS) collect thousands of spontaneous reports annually, with each report recording occurrences of any adverse events (AEs) and use of vaccines. We hope to identify signal vaccine-AE pairs, for which certain vaccines are statistically associated with certain adverse events (AE), using such data. Thus, the outcomes of interest are multiple AEs, which are binary outcomes and could be correlated because they might share certain latent factors; and the primary covariates are vaccines. Appropriately accounting for the complex correlation among AEs could improve the sensitivity and specificity of identifying signal vaccine-AE pairs. We propose a two-step approach in which we first estimate the shared latent factors among AEs using a working multivariate logistic regression model, and then use univariate logistic regression model to examine the vaccine-AE associations after controlling for the latent factors. Our simulation studies show that this approach outperforms current approaches in terms of sensitivity and specificity. We apply our approach in analyzing VAERS data and report our findings.

Transverse Maxillary Deficiency Predicts Increased Upper Airway Collapsibility during Drug-Induced Sleep Endoscopy.

OBJECTIVE: To examine the relationship between craniofacial skeletal anatomy and objective measures of pharyngeal collapse obtained during drug-induced sleep endoscopy. We hypothesized that transverse maxillary deficiency and an increased pharyngeal length will be associated with higher levels of pharyngeal collapsibility. STUDY DESIGN: Cross-sectional analysis in a prospective cohort. SETTING: University Hospital. METHODS: A cross-sectional analysis was conducted in a cohort of consecutive patients from the positive airway pressure (PAP) alternatives clinic who underwent computed tomography (CT) analysis and drug-induced sleep endoscopy for characterization of upper airway collapsibility. PAP titration was used to determine pharyngeal critical pressure (PCRIT ) and pharyngeal opening pressure (PhOP). CT metrics included: Transverse maxillary dimensions (interpremolar and intermolar distances) and pharyngeal length (posterior nasal spine to hyoid distance). RESULTS: The cohort (n = 103) of severe obstructive sleep apnea (Apnea and Hipopnea Index 32.1 ± 21.3 events/h) was predominantly male (71.8%), Caucasian (81.6%), middle-aged (54.4 ± 14.3 years), and obese (body mass index [BMI] = 30.0 ± 4.9 kg/m2 ). Reduced transverse maxillary dimensions were associated with higher PCRIT (intermolar distance: ß [95% confidence interval, CI] = -.25 [-0.14, -0.36] cmH2 O/mm; p = .03) and PhOP (Interpremolar distance: ß = -.25 [-0.14, -0.36] cmH2 O/mm; p = .02). Longer pharyngeal length was also associated with higher PCRIT (ß = .11 [0.08, 0.14] cmH2 O/mm, p = .04) and PhOP (ß [95% CI] = .06 [0.03, 0.09] cmH2 O/mm, p = .04). These associations persisted after adjustments for sex, age, height, and BMI. CONCLUSION: Our results further the concept that skeletal restriction in the transverse dimension and hyoid descent are associated with elevations in pharyngeal collapsibility during sleep, suggesting a role of transverse deficiency in the pathogenesis of airway obstruction.

Facial and Intraoral Photographic Traits Related to Sleep Apnea in a Clinical Sample with Genetic Ancestry Analysis.

Rationale: Craniofacial and pharyngeal morphology influences risk for obstructive sleep apnea (OSA). Quantitative photography provides phenotypic information about these anatomical factors and is feasible in large samples. However, whether associations between morphology and OSA severity differ among populations is unknown. Objectives: The aim of this study was to examine this question in a large sample encompassing people from different ancestral backgrounds. Methods: Participants in SAGIC (Sleep Apnea Global Interdisciplinary Consortium) with genotyping data were included (N = 2,393). Associations between photography-based measures and OSA severity were assessed using linear regression, controlling for age, sex, body mass index, and genetic ancestry. Subgroups (on the basis of 1000 Genomes reference populations) were identified: European (EUR), East Asian, American, South Asian, and African (AFR). Interaction tests were used to assess if genetically determined ancestry group modified these relationships. Results: Cluster analysis of genetic ancestry proportions identified four ancestrally defined groups: East Asia (48.3%), EUR (33.6%), admixed (11.7%; 46% EUR, 27% Americas, and 22% AFR), and AFR (6.4%). Multiple anatomical traits were associated with more severe OSA independent of ancestry, including larger cervicomental angle (standardized ß [95% confidence interval (CI)] = 0.11 [0.06-0.16]; P < 0.001), mandibular width (standardized ß [95% CI] = 0.15 [0.10-0.20]; P < 0.001), and tongue thickness (standardized ß [95% CI] = 0.06 [0.02-0.10]; P = 0.001) and smaller airway width (standardized ß [95% CI] = -0.08 [-0.15 to -0.002]; P = 0.043). Other traits, including maxillary and mandibular depth angles and lower face height, demonstrated different associations with OSA severity on the basis of ancestrally defined subgroups. Conclusions: We confirm that multiple facial and intraoral photographic measurements are associated with OSA severity independent of ancestral background, whereas others differ in their associations among the ancestrally defined subgroups.

The Medical Home Initiative in Italy: an Analysis of Changes in Healthcare Utilization.

BACKGROUND: Seventeen medical homes (MHs) were established in the Local Health Authority (LHA) of Parma (about 450,000 residents), Emilia Romagna, Italy, between 2011 and 2016. OBJECTIVE: To estimate the effects of MH implementation on healthcare utilization. DESIGN: We conducted a longitudinal cohort study (01/2011-12/2017) using the Parma LHA administrative healthcare database. PARTICIPANTS: Residents for ≥1 year and older than 14 years of age with a documented primary care physician (PCP) in Parma LHA. INTERVENTION: MH exposure status was classified for each resident as either receiving care from a PCP that (1) eventually practices in an MH (pre-MH), (2) is currently in an MH (post-MH), or (3) does not join an MH (non-MH). MAIN OUTCOME MEASURES: Risks of ordinary inpatient hospital admissions, day hospital admissions, admissions for ambulatory care sensitive conditions (ACSCs), all-cause emergency department (ED) visits, and deferrable ED visits were compared using Cox proportional hazards regression and risks of all-cause 30- and 90-day readmissions for congestive heart failure (CHF) or chronic obstructive pulmonary disease (COPD) were compared using logistic regression. KEY RESULTS: Prior to MH implementation, the risk of all-cause ED visits for pre-MH residents was 0.93 (95% CI: 0.92-0.94) that of non-MH residents. After MH implementation, the relative risk for post-MH versus non-MH was 0.86 (95% CI: 0.85-0.87) and, over time, post-MH versus pre-MH was 0.93 (95% CI: 0.92-0.94). Hospitalization risks were generally lower among the pre-MH and post-MH, compared to non-MH. However, hospitalizations and HF or COPD readmissions were not generally lower post-MH compared to pre-MH. CONCLUSIONS: This MH initiative was associated with a 7% reduction in risk of ED visits. More research is necessary to understand if ED visit risk will continue to improve and how other aspects of healthcare utilization might change as more MHs open and the length of exposure to MHs increases.

Motivated displacement assay distinguishes ALA neuron mutants from RIS neuron mutants during recovery from heat stress in Caenorhabditis elegans.

The interneurons ALA and RIS both regulate stress induced sleep in C. elegans but their roles in awake animal movement has been reported to differ. We describe the development of a motivated mobility-based assay that distinguishes between animals mutant for ALA function and those mutant for RIS function.

Preparing for the MD: How Long, at What Cost, and With What Outcomes?

PURPOSE: To assess educational and professional outcomes of an accelerated combined bachelor of science-doctor of medicine (BS-MD) program using data collected from 1968 through 2018. METHOD: Participants of this longitudinal study included 2,235 students who entered medical school between 1968 and 2014: 1,134 in the accelerated program and 1,101 in the regular curriculum (control group)-matched by year of entrance to medical school, gender, and Medical College Admission Test (MCAT) scores. Outcome measures included performance on medical licensing examinations, academic progress, satisfaction with medical school, educational debt, first-year residency program directors' ratings on clinical competence, specialty choice, board certification, and faculty appointments. RESULTS: The authors found no practically important differences between students in the accelerated program and those in the control group on licensing examination performance, academic progress, specialty choice, board certification, and faculty appointments. Accelerated students had lower mean educational debt (P < .01, effect sizes = 0.81 and 0.45 for, respectively, their baccalaureate debt and medical school debt), lower satisfaction with their second year of medical school (P < .01, effect size = 0.21), and lower global satisfaction with their medical school education (P < .01, effect size = 0.35). Residency program directors' ratings in 6 postgraduate competency areas showed no practically important differences between the students in the accelerated program and those in the control group. The proportion of Asian students was higher among program participants (P < .01, effect size = 0.43). CONCLUSIONS: Students in the accelerated program earned BS and MD degrees at a faster pace and pursued careers that were comparable to students in a matched control who were in a regular MD program. Findings indicate that shortening the length of medical education does not compromise educational and professional outcomes.