Citations

Chloroquine is an antimalarial agent commonly used as an autophagy inhibitor by preventing autolysosomal fusion. Autophagy is an important cellular process through which defective cytoplasmic structures are recycled and degraded that has been implicated in aging neuromuscular effects. We recently showed that acute chloroquine treatment blunts the maximal forces generated by the diaphragm muscle, likely by impairing neuromuscular transmission generally consistent with aging effects in the diaphragm muscle. In addition, old mice show increased accumulation of autophagy proteins in phrenic motor neurons, consistent with impaired autophagy flux. In the present study, we hypothesized that chloroquine treatment results in accumulation of bulk endosomes pre-synaptically. Each hemidiaphragm with attached phrenic nerve was excised from 24-month-old male and female C57BL/6 mice to evaluate frequency dependent (0 vs 80 Hz stimulation) uptake of the styryl dye FM4-64, given that 80-Hz stimulation frequency induces bulk endocytosis after synaptic vesicle retrieval. Diaphragm-phrenic nerve preparations were incubated in 5 μM FM4-64 for 1 h prior to 6-min nerve stimulation (0.5 ms supramaximal pulses in 80 Hz, 200 ms trains delivered at 40% duty cycle) followed by a 5-min post-stimulation incubation. FM4-64 uptake at diaphragm neuromuscular junctions (NMJs) was measured using confocal microscopy. Preparations were randomly assigned to co-incubation with chloroquine (50 μM) or vehicle (Rees-Simpson solution). There was minimal FM4-64 uptake in the absence of phrenic nerve stimulation, consistent with the activity-dependent uptake of the styryl dye. With 80 Hz stimulation, high levels of FM4-64 uptake were evident in both the chloroquine and vehicle-treated groups without significant differences across groups. FM4-64 fluorescence was evident throughout the presynpatic terminal with few areas of dense accumulation, consistent with retention of endosomes. There was no evidence of greater endosome accumulation with chloroquine treatment. Of note, a slight increase in FM4-64 uptake was evident in the chloroquine treated groups compared to vehicle in the non-stimulated NMJs. These results are consistent with FM4-64 uptake reflecting bulk endocytosis that mainly occurs during high frequency stimulation. The impairment in autophagy flux following chloroquine treatment is expected to result in endosome accumulation but it is possible that the stimulation protocol was insuffcient to elucidate this possibility. Collectively, the findings of this study are consistent with impaired autophagy at diaphragm presynaptic terminals which may underlie neuromuscular deficits observed in old age. Supported by NIH grant R01 AG057052 and the Mayo Clinic. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

PURPOSE To report the results of OPAL (ClinicalTrials.gov identifier: NCT03574779 ) cohort A, a single-arm substudy of niraparib plus dostarlimab and bevacizumab for the treatment of advanced, platinum-resistant ovarian cancer (PROC). METHODS Participants with PROC who received 1-2 previous lines of therapy were treated with niraparib (200 or 300 mg once daily), dostarlimab (500 mg once every 3 weeks for four 21-day cycles, followed by 1,000 mg once every 6 weeks), and bevacizumab (15 mg/kg once every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1. Safety was also assessed. Exploratory biomarker end points included evaluation of changes in the tumor molecular profile and microenvironment using baseline and on-treatment tumor samples. RESULTS Of 41 enrolled participants (median age, 66.0 years [range, 37-83 years]), 9.8% had tumors that were BRCA-mutated, 19.5% were homologous recombination (HR)–deficient, and 17.1% were HR repair (HRR)–mutated. As of the cutoff date, all participants discontinued treatment. The ORR was 17.1% (80% CI, 9.8 to 27.0), including one complete response (2.4%); the disease control rate was 73.2% (80% CI, 62.3 to 82.2). Two participants withdrew before first postbaseline scan because of adverse events (AEs). Grade ≥3 treatment-emergent AEs were reported in 92.7% of participants, with the most common being hypertension (26.8%). Response was not correlated with BRCA, HRR, HR deficiency (HRD), or PD-L1 status. Changes suggesting immune activation were observed in on-treatment samples after triplet therapy. CONCLUSION Results demonstrated modest activity of niraparib, dostarlimab, and bevacizumab in participants with PROC, many of whom had prognostic factors for poor treatment response. Most participants with response were bevacizumab-naïve. No association was found with HRD, BRCA, or PD-L1 status. AEs were consistent with previous monotherapy reports, except that hypertension was reported more frequently.

Abstract Background and Aims Presentation, outcome, and management of females with degenerative mitral regurgitation (DMR) are undefined. We analysed sex-specific baseline clinical and echocardiographic characteristics at referral for DMR due to flail leaflets and subsequent management and outcomes. Methods In the Mitral Regurgitation International Database (MIDA) international registry, females were compared with males regarding presentation at referral, management, and outcome (survival/heart failure), under medical treatment, post-operatively, and encompassing all follow-up. Results At referral, females (n = 650) vs. males (n = 1660) were older with more severe symptoms and higher MIDA score. Smaller cavity diameters belied higher cardiac dimension indexed to body surface area. Under conservative management, excess mortality vs. expected was observed in males [standardized mortality ratio (SMR) 1.45 (1.27–1.65), P < .001] but was higher in females [SMR 2.00 (1.67–2.38), P < .001]. Female sex was independently associated with mortality [adjusted hazard ratio (HR) 1.29 (1.04–1.61), P = .02], cardiovascular mortality [adjusted HR 1.58 (1.14–2.18), P = .007], and heart failure [adjusted HR 1.36 (1.02–1.81), P = .04] under medical management. Females vs. males were less offered surgical correction (72% vs. 80%, P < .001); however, surgical outcome, adjusted for more severe presentation in females, was similar (P ≥ .09). Ultimately, overall outcome throughout follow-up was worse in females who displayed persistent excess mortality vs. expected [SMR 1.31 (1.16–1.47), P < .001], whereas males enjoyed normal life expectancy restoration [SMR 0.92 (0.85–0.99), P = .036]. Conclusions Females with severe DMR were referred to tertiary centers at a more advanced stage, incurred higher mortality and morbidity under conservative management, and were offered surgery less and later after referral. Ultimately, these sex-related differences yielded persistent excess mortality despite surgery in females with DMR, while males enjoyed restoration of life expectancy, warranting imperative re-evaluation of sex-specific DMR management.

Objectives: In hemodialysis patients, central hemodynamics, stiffness, and wave reflections assessed through ambulatory blood pressure monitoring (ABPM) showed superior prognostic value for cardiovascular (CV) events than peripheral blood pressures (BPs). No such evidence is available for lower-risk hypertensive patients. Methods: In 591 hypertensive patients (mean age 58 ± 14 years, 49% males), ambulatory brachial and central BP, pulse wave velocity (PWV), and augmentation index (AIx) were obtained with a validated upper arm cuff-based pulse wave analysis technology. Information on treatment for hypertension (73% of patients), dyslipidemia (27%), diabetes (8%), CV disease history (25%), was collected. Patients were censored for CV events or all-cause death over 4.2 years. Results: One hundred and four events (24 fatal) were recorded. Advanced age [hazard ratio and 95% confidence interval: 1.03 (1.01, 1.05), P = 0.0001], female sex [1.57 (1.05, 2.33), P = 0.027], CV disease [2.22 (1.50, 3.29), P = 0.0001], increased 24-h central pulse pressure (PP) [1.56 (1.05, 2.31), P = 0.027], PWV [1.59 (1.07, 2.36), P = 0.022], or AIx [1.59 (1.08, 2.36), P = 0.020] were significantly associated with a worse prognosis (univariate Cox regression analysis). The prognostic power of peripheral and central BPs was lower. However, PWV [1.02 (0.64, 1.63), P = 0.924], AIx [1.06 (0.66, 1.69), P = 0.823], and central PP [1.18 (0.76, 1.82), P = 0.471], were not significant predictors in multivariate analyses. Conclusions: In hypertensive patients, ambulatory central PP, PWV, and AIx are associated with an increased risk of CV morbidity and all-cause mortality. However, this association is not independent of other patient characteristics.

AbstractBackgroundDespite the overall safety and efficacy of COVID‐19 vaccinations, rare cases of systemic autoimmune diseases (SAIDs) have been reported post‐vaccination. This study used a global survey to analyze SAIDs in susceptible individuals' post‐vaccination.MethodsA cross‐sectional study was conducted among participants with self‐reported new‐onset SAIDs using the COVID‐19 Vaccination in Autoimmune Diseases (COVAD) 2 study dataset—a validated, patient‐reported e‐survey—to analyze the long‐term safety of COVID‐19 vaccines. Baseline characteristics of patients with new‐onset SAIDs and vaccinated healthy controls (HCs) were compared after propensity score matching based on age and sex in a 1:4 ratio.ResultsOf 16 750 individuals, 74 (median age 52 years, 79.9% females, and 76.7% Caucasians) had new‐onset SAID post‐vaccination, mainly idiopathic inflammatory myopathies (IIMs) (n = 23, 31.51%), arthritis (n = 15; 20.53%), and polymyalgia rheumatica (PMR) (n = 12, 16.40%). Higher odds of new‐onset SAIDs were noted among Caucasians (OR = 5.3; 95% CI = 2.9–9.7; p < .001) and Moderna vaccine recipients (OR = 2.7; 95% CI = 1.3–5.3; p = .004). New‐onset SAIDs were associated with AID multimorbidity (OR = 1.4; 95% CI = 1.1–1.7; p < .001), mental health disorders (OR = 1.6; 95% CI = 1.3–1.9; p < .001), and mixed race (OR = 2.2; 95% CI = 1.2–4.2; p = .010), where those aged >60 years (OR = 0.6; 95% CI = 0.4–0.8; p = .007) and from high/medium human development index (HDI) countries (compared to very high HDI) reported fewer events than HCs.ConclusionThis study reports a low occurrence of new‐onset SAIDs following COVID‐19 vaccination, primarily IIMs, PMR, and inflammatory arthritis. Identified risk factors included pre‐existing AID multimorbidity, mental health diseases, and mixed race. Revaccination was well tolerated by most patients; therefore, we recommend continuing COVID‐19 vaccination in the general population. However, long‐term studies are needed to understand the autoimmune phenomena arising post‐vaccination.