Citations

Abstract Introduction Narcolepsy is a chronic neurologic condition associated with severe symptom burden, impaired functioning and reduced quality of life. Patients commonly report comorbid mood disorders. AXS-12 (reboxetine) is a selective norepinephrine reuptake inhibitor and cortical dopamine modulator under investigation for the treatment of narcolepsy. In the Phase 3 SYMPHONY trial, AXS-12 met the primary endpoint, a statistically significant reduction in weekly cataplexy attacks from baseline to Week 5 versus placebo. Here, we report secondary endpoints assessing symptom severity, daily functioning, and mood. Methods SYMPHONY was a randomized, double-blind, placebo-controlled trial in patients with narcolepsy type 1 (NT1). Participants (15-75 years) were randomized 1:1 to AXS-12 or placebo for 5 weeks. Stable, concurrent modafinil/armodafinil use was allowed. Secondary endpoints included: the Clinical Global Impression of Severity (CGI-S) for narcolepsy, the Functional Outcomes of Sleep Questionnaire short version (FOSQ-10), and the EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire anxiety/depression domain. Results Ninety participants were enrolled. At baseline, mean (SD) CGI-S for narcolepsy score was 5.2 (1.0) in the AXS-12 arm and 4.9 (1.0) in the placebo arm. AXS-12 led to a significant reduction versus placebo in CGI-S for narcolepsy at Week 5 (LS mean difference [95% CI]=0.72 [0.29, 1.16]; p=0.001). At baseline, mean FOSQ-10 total score was 11.1 (3.1) in the AXS-12 arm and 11.6 (3.2) in the placebo arm. AXS-12 led to a statistically significant improvement from baseline to Week 5 in FOSQ-10 total scores compared to placebo (1.66 [0.51, 2.82], p=0.005). At baseline, 47.8% of participants in the AXS-12 arm and 45.5% in the placebo arm reported anxiety/depression (EQ-5D-5L). A numerically greater proportion of participants achieved improvements on this domain with AXS-12 (55.0%) versus placebo (31.6%) at Week 5 (p=0.146). Conclusion AXS-12 demonstrated significant reductions in clinical impressions of narcolepsy symptom severity. Functional impairment due to EDS was also significantly reduced, in-line with previously reported improvement in clinician-rated assessments. Anxiety and depression-related symptoms showed trends favoring AXS-12. Combined with prior findings on cataplexy and cognitive improvements, these results highlight the potential of AXS-12 as a therapeutic option addressing multiple symptoms of narcolepsy which affect QoL and functioning. Support (if any) Axsome Therapeutics, Inc.

Abstract Introduction Persistent dyspnea increases the risk of disability and impairs quality of life in older patients with bronchiectasis. The impact of dyspnea and fatigue on patients with bronchiectasis in long term follow-up has not been adequately established. We sought to determine if fatigue and higher-grade dyspnea are associated with worse clinical outcomes in 5-years of longitudinal follow-up. Methods We analyzed data collected from a prospective cohort of adult patients with bronchiectasis enrolled in the US Bronchiectasis and Nontuberculous Mycobacteria Research Registry. Patients with a modified Medical Research Council (mMRC) dyspnea score collected at baseline and during 3-5 years of follow-up were included and stratified as mMRC<2 versus mMRC ≥2. Kruskal-Wallis, independent sample t-tests and chi-square tests were used to test the differences in medians and means for continuous variables and associations between categorical variables, respectively, between the baseline mMRC groups and bronchiectasis severity index (BSI) components at follow-up. A multivariable logistic regression analysis was performed to determine the association between dyspnea and clinical outcomes (exacerbations and hospitalizations) at follow-up. Results 1185 adult patients with bronchiectasis met the inclusion criteria. The median age (interquartile range) was 76 (68 to 83) years. At baseline, patients with mMRC ≥2 had a higher proportion of co-existing diagnoses such as asthma, chronic obstructive pulmonary disease (COPD), otitis/rhinosinusitis, rheumatologic disease, and pneumonia compared to patients with mMRC <2 (all p<0.05, data not shown). Furthermore, patients with mMRC > 2 compared to patients with mMRC <2 had higher prevalence of fatigue, acute exacerbations and pulmonary related hospitalizations, and lower mean percentage predicted forced expiratory volume in one second (FEV1) at follow-up (all p< 0.05) (Table 1). Interestingly, body mass index was slightly higher among those with baseline mMRC ≥2 compared to mMRC <2 (p=0.02). Among those with mMRC ≥2 at both baseline and follow-up (n=67, 42%), the odds of having ≥1 exacerbation was 2.4 times higher (odds ratio [OR] 2.45, 95% confidence interval [CI] 1.45-4.1) and 2.8 times higher for ≥1 hospitalization (OR 2.8, 95% CI 1.45-5.2) during follow-up after adjusting for fatigue. Conclusion Elevated dyspnea was associated with a greater proportion of patients with bronchiectasis exhibiting acute exacerbations and pulmonary related hospitalizations and lower lung function during follow-up. Research is still needed to understand the causes (drivers) of dyspnea to implement better treatment strategies and reduce adverse outcomes in bronchiectasis patients.

Abstract Introduction: Non-Cystic Fibrosis Bronchiectasis (NCFB) is an obstructive pulmonary disease associated with structural lung disease, altered mucociliary clearance, hyper mucus secretion, recurrent infection, and airway inflammation that results in significant morbidity and mortality. Aspergillus sp (Asp) is a common fungi isolated in respiratory specimens of those with lung disease and is associated with both infectious and allergic pulmonary diseases such as Asthma and Cystic Fibrosis. Despite individuals with NCFB having similar phenotypes as these conditions, the impact of Asp on this population is poorly understood. Methods: We performed a cross-sectional retrospective analysis from the US Bronchiectasis and NTM Research Registry (BRR). NCFB patients without a history of lung transplant who had at least one respiratory Asp culture were included. We compared patients with no history of Asp grown from respiratory culture to those with at least one positive respiratory culture for Asp during the available period. Patient demographics, bacterial culture history, lung function, comorbidities, modified Bronchiectasis Severity Index (mBSI), and sputum parameters were analyzed descriptively. Comparisons between groups were conducted using Kruskal-Wallis, independent sample t-tests, and chi-square tests for continuous and categorical variables as appropriate. Results: 3985 people with NCFB met inclusion criteria. 3359 (84.3%) individuals were Asp culture negative compared to 626 (15.7%) individuals with Asp. There were notable differences in race, showing higher proportions of non-Hispanic white (90.4 vs 82.2%) in this population. While the frequency of Chronic Obstructive Pulmonary Disease and Primary Ciliary Dyskinesia were similar, there were more individuals with Asthma (31.3 vs 24.7%, p<0.001) and Allergic Bronchopulmonary Aspergillosis (ABPA) (6.4 vs 2.4%, p<0.001) in the Asp positive group (Figure 1A). The Asp positive group had higher blood eosinophils (150.0 vs 124.0 cells/uL, p=0.026, Figure 1B), had nominally lower lung function (73.5 vs 75.3% ppFEV1, p=0.089), and were more likely to have at least one or more positive bacterial cultures (62.9 vs 51.9%, p<0.001, Figure 1C). There was no significant difference in sex, age, exacerbations, Pseudomonas aeruginosa or NTM positive cultures, sputum volume, or mBSI. Conclusion: Individuals with NCFB and history of one or more positive Asp cultures were more likely to be non-Hispanic white, have a diagnosis of Asthma and/or ABPA, higher blood eosinophils, and more positive airway bacterial cultures. Further work is needed to better understand how Asp contributes to bronchiectasis progression. More expansive analysis and multivariant modeling is underway to better understand the impact of Asp in people with NCFB.

Importance Few studies have assessed whether factors outside the workplace, such as support from a spouse or partner, are associated with work-life integration (WLI) satisfaction and burnout among physicians. Evaluating such an association may help with developing novel strategies to address burnout and improve WLI satisfaction among this group. Objectives To compare spousal support among female and male physicians and explore associations of spousal support with WLI satisfaction and burnout. Design, Setting, and Participants This cross-sectional, multispecialty survey study was conducted among 661 faculty physicians employed at an academic medical center from March 26 to May 22, 2024. Main Outcomes and Measures Survey items measured spousal support (5 items), WLI satisfaction (1 item), and burnout (2 Maslach Burnout Inventory items). Associations of spousal support and gender with WLI and burnout were assessed using logistic regression analyses adjusting for age, race and ethnicity, weekly work hours, and weekly hours spent on household or childcare duties. Results Overall, 739 of 2103 faculty physicians (response rate, 35.1%) completed the survey, of whom 661 (89.4%) were currently married or partnered (359 of 661 men [54.3%]). In this subset, 322 of 351 male physicians (91.7%) and 276 of 298 of female physicians (92.6%) reported frequent career support (defined as often, most of the time, or always) over the last year from their spouse or partner. Physicians reporting high levels of career support from their spouse or partner had higher odds of WLI satisfaction (odds ratio [OR], 1.50 [95% CI, 1.22-1.86]; P < .001) and lower odds of burnout (OR, 0.73 [95% CI, 0.61-0.87]; P < .001), independent of gender and adjusted for age, race and ethnicity, weekly work hours, and weekly hours spent on household or childcare duties. Male physicians had higher odds of WLI satisfaction than female physicians (OR, 1.95 [95% CI, 1.32-2.90]; P < .001), even after adjusting for spousal career support and other covariates listed, whereas odds of burnout did not significantly differ by gender (OR, 0.84 [95% CI, 0.57-1.23]; P = .37). Conclusions and Relevance This study suggests that the level of career support from a spouse or partner is associated with WLI satisfaction and burnout among physicians, independent of gender. Future studies should explore whether interventions designed to enhance career support can improve WLI and well-being among physicians.

Objectives: To determine associations between physician sex and use of postoperative healthcare resources among patients undergoing common surgeries in Ontario, Canada. Background: Prior studies have shown that patients of female physicians experience better outcomes and have lower healthcare costs compared with patients of male physicians. Understanding differences in resource utilization may offer insights into the care pathways and practice patterns contributing to these differences. Methods: We conducted a population-based, retrospective cohort study of adults (≥18 years of age) undergoing 1 of 25 common surgeries, between January 1, 2007, and December 31, 2019, in Ontario, Canada. The primary outcome was the utilization of one of the following: intensive care unit admission, other medical interventions (eg, tracheostomy, new dialysis starts, and home oxygen), and discharge care needs (eg inpatient rehab, long-term care, and home care use) within 30 days. The data were summarized using descriptive statistics and adjusted using multivariable generalized estimating equations. Results: This population-based study included 1,100,193 patients (61.8% female). Patients treated by male surgeons had higher use of postoperative resources versus those with female surgeons within 30 days (adjusted rate 33.1; 95% confidence interval [CI]: 28.0–39.2 versus 31.2; 95% CI: 25.8–37.7), 90 days, and 1 year. Consistent with these findings, following adjustment for patient, surgeon, procedural, and hospital characteristics, patients treated by male surgeons were significantly more likely to utilize postoperative resources within 30 days (adjusted odds ratio: 1.14; 95% CI: 1.03–1.27; P = 0.010) and at other time points. This difference was primarily driven by the higher use of home care among patients with a male versus female surgeon at all time points (30 days: adjusted odds ratio, 1.13; 95% CI: 1.05–1.21; P = 0.002). Conclusions: Patients with male surgeons had higher postoperative resource utilization when compared with those treated by female surgeons, which was almost entirely driven by the higher use of home care. Further mixed-methods investigation is needed to better understand other potentially relevant factors including surgical outcomes, individual patient preferences, and surgical team decision-making.

Abstract The pharmacological provocation test is a pivotal tool in cardiac electrophysiology for the diagnosis of potential causes of sudden cardiac death, sudden cardiac arrest (SCA), arrhythmias, symptoms, or ECG abnormalities. The 2022 European Society of Cardiology Guidelines for the Treatment of Ventricular Arrhythmias and Prevention of Sudden Cardiac Death offered guidance on provocation testing but did not describe the indications and requirements in depth. This clinical consensus statement, led by the European Heart Rhythm Association and approved by major international stakeholders, aims to advise the general cardiologist and the arrhythmia expert who to test and when, where, and how to do it. The statement focuses on current practice for the diagnosis of subclinical arrhythmia syndromes and the causes of SCA, building upon the recommendations of the Guidelines. We address the sodium channel blocker provocation test for patients suspected of Brugada syndrome as well as the use of epinephrine, isoproterenol, adenosine, ergonovine, and acetylcholine.

Background: Cognitive change is an important factor in understanding dementia. Estimating effects of exposures on cognitive change requires choosing an analytical timescale, typically time on study or current age. There is limited consensus regarding timescale choice in epidemiologic cognitive aging research. Methods: Using a coordinated analytic approach in 10 cohorts of older adults, we evaluated whether estimated effects of two exposures on memory change differed depending on timescale (time on study or current age). We modeled effects of apolipoprotein-E (APOE) ε4 genotype (a time-invariant exposure) and diabetes (a potentially time-varying/acquired exposure evaluated at baseline) using mixed-effects models with linear and nonlinear time specifications for both timescales. Results: Among APOE ε4 carriers, model-estimated memory scores at baseline (time on study timescale) or at each cohort’s median baseline age (current age timescale) were lower, and the average rate of decline was faster than among APOE ε4 noncarriers. Model-estimated memory scores at baseline or at median baseline age were generally similar across baseline diabetes status, with variability across cohorts in the diabetes-memory change association. In some cohorts, trends in diabetes-memory change associations differed in direction across timescales. Conclusions: Timescale was largely inconsequential for estimated effects of APOE genotype, but yielded differences in estimated diabetes effects, raising questions about the appropriate scale. The current age scale may be problematic because diabetes was measured heterogeneously in age across individuals, a common issue in aging cohorts. Our work demonstrates approaches to evaluate alternative timescales, including in multicohort analyses, and highlights potential implications for estimated exposure effects on cognitive change.

Abstract Objectives IBM is characterized by slowly progressive muscle weakness making it challenging to detect significant changes in weakness during a clinical trial. Trial participants receiving placebo may behave differently from in natural history studies. We aimed to quantify the change in muscle strength and IBM Functional Rating Scale (IBMFRS) of IBM patients receiving placebo during clinical trials. Methods Several databases were searched. Randomized, double-blinded, placebo-controlled trials without treatment intervention on the placebo group were included. Standardized mean differences (SMD) for change in muscle strength and mean differences for IBMFRS were used to calculate pooled effects, using DerSimonian-Laird continuous random effect models. Meta-regression determined change in muscle strength. Heterogeneity was evaluated using the I2 indicator. Results Eleven eligible trials were identified with 257 participants receiving placebo and a low risk of bias per the Cochrane Collaboration Risk of Bias 2 (RoB2) tool. Participants receiving placebo on average had a measurable decline in muscle strength with a mean effect size of –0.398 (95% CI –0.652, –0.144) (P = 0.002). SMD changed by –0.009 (–0.016, –0.002) points per week (P = 0.015). Manual muscle testing was associated with higher heterogeneity (I2 = 67.68%) compared with quantitative muscle testing (I2 = 0%). Only three studies reported IBMFRS results. The pooled change in IBMFRS at 12 months was –2.189 points (–3.893, –0.485) on this 0 to 40-point scale (P = 0.012), with relatively high heterogeneity. Conclusion Participants with IBM displayed a measurable decline in their muscle strength and IBMFRS during clinical trials, in keeping with the disease’s slowly progressive nature. These estimates can inform sample size calculations in future studies.