Multiple Potential Molecular Contributors to Atrial Hypocontractility Caused by Atrial Tachycardia Remodeling in Dogs

Background-Atrial fibrillation impairs atrial contractility, inducing atrial stunning that promotes thromboembolic stroke. Action potential (AP)-prolonging drugs are reported to normalize atrial hypocontractility caused by atrial tachycardia remodeling (ATR). Here, we addressed the role of AP duration (APD) changes in ATR-induced hypocontractility. Methods and Results-ATR (7-day tachypacing) decreased APD (perforated patch recording) by approximate to 50%, atrial contractility (echocardiography, cardiomyocyte video edge detection), and [Ca2+](i) transients. ATR AP waveforms suppressed [Ca2+](i) transients and cell shortening of control cardiomyocytes; whereas control AP waveforms improved [Ca2+](i) transients and cell shortening in ATR cells. However, ATR cardiomyocytes clamped with the same control AP waveform had approximate to 60% smaller [Ca2+](i) transients and cell shortening than control cells. We therefore sought additional mechanisms of contractile impairment. Whole-cell voltage clamp revealed reduced I-CaL; I-CaL inhibition superimposed on ATR APs further suppressed [Ca2+](i) transients in control cells. Confocal microscopy indicated ATR-impaired propagation of the Ca2+ release signal to the cell center in association with loss of t-tubular structures. Myofilament function studies in skinned permeabilized cardiomyocytes showed altered Ca2+ sensitivity and force redevelopment in ATR, possibly due to hypophosphorylation of myosin-binding protein C and myosin light-chain protein 2a (immunoblot). Hypophosphorylation was related to multiple phosphorylation system abnormalities where protein kinase A regulatory subunits were downregulated, whereas autophosphorylation and expression of Ca2+-calmodulin-dependent protein kinase II delta and protein phosphatase 1 activity were enhanced. Recovery of [Ca2+](i) transients and cell shortening occurred in parallel after ATR cessation. Conclusions-Shortening of APD contributes to hypocontractility induced by 1-week ATR but accounts for it only partially. Additional contractility-suppressing mechanisms include I-CaL current reduction, impaired subcellular Ca2+ signal transmission, and altered myofilament function associated with abnormal myosin and myosin-associated protein phosphorylation. The complex mechanistic basis of the atrial hypocontractility associated with AF argues for upstream therapeutic targeting rather than interventions directed toward specific downstream pathophysiological derangements. (Circ Arrhythm Electrophysiol. 2010;3:530-541.

Psychotropic medication use pre and post-diagnosis of cluster B personality disorder: a Quebec’s health services register cohort

BackgroundCluster B personality disorders (PDs) are considered some of the most severe mental health conditions. Scarce evidence exists about the real-world utilization of psychotropics for cluster B PD individuals.ObjectiveWe aimed to uncover trends and patterns of psychotropic medication use among individuals diagnosed with cluster B PD in the year before and after their diagnosis and to identify factors associated with medication use in a large cohort of individuals newly diagnosed with cluster B PDs.MethodsWe conducted a population-based observational study using Quebec’s health services register. We identified Quebec residents aged ≥14 years and insured with the provincial drug plan with a first diagnosis of cluster B PD recorded between April 1, 2002, and March 31, 2019. Cluster B PD was defined with ICD-9/10 diagnostic codes. We retrieved all claims for the main psychotropic medication classes: antipsychotics, antidepressants, anxiolytics, mood stabilizers, and attention-deficit/hyperactivity disorder (ADHD) medications. We calculated the proportion of individuals exposed to these medication classes and analyzed trends over the years using robust Poisson regression models, adjusting for potential confounders. We used robust Poisson regression to identify factors associated with medication class use.ResultsWe identified 87,778 new cases of cluster B PD, with a mean age of 44.5 years; 57.5% were women. Most frequent psychiatric comorbidities in the five years before cluster B PD diagnosis were depression (50.9%), anxiety (49.7%), and psychotic disorders (37.5%). Most individuals (71.0%) received at least one psychotropic during the year before cluster B PD diagnosis, and 78.5% received at least one of these medications in the subsequent year. The proportion of users increased after the diagnosis for antidepressants (51.6–54.7%), antipsychotics (35.9–45.2%), mood stabilizers (14.8–17.0%), and ADHD medications (5.1–5.9%), and remained relatively stable for anxiolytics (41.4–41.7%). Trends over time showed statistically significant increased use of antipsychotics and ADHD medications, decreased use of anxiolytics and mood stabilizers, and a stable use of antidepressants.ConclusionPsychotropic medication use is highly prevalent among cluster B PD individuals. We observed an increase in medication use in the months following the diagnosis, particularly for antipsychotics, antidepressants, and mood stabilizers

The global burden of adolescent and young adult cancer in 2019 : a systematic analysis for the Global Burden of Disease Study 2019

Background In estimating the global burden of cancer, adolescents and young adults with cancer are often overlooked, despite being a distinct subgroup with unique epidemiology, clinical care needs, and societal impact. Comprehensive estimates of the global cancer burden in adolescents and young adults (aged 15-39 years) are lacking. To address this gap, we analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, with a focus on the outcome of disability-adjusted life-years (DALYs), to inform global cancer control measures in adolescents and young adults. Methods Using the GBD 2019 methodology, international mortality data were collected from vital registration systems, verbal autopsies, and population-based cancer registry inputs modelled with mortality-to-incidence ratios (MIRs). Incidence was computed with mortality estimates and corresponding MIRs. Prevalence estimates were calculated using modelled survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated as age-specific cancer deaths multiplied by the standard life expectancy at the age of death. The main outcome was DALYs (the sum of YLLs and YLDs). Estimates were presented globally and by Socio-demographic Index (SDI) quintiles (countries ranked and divided into five equal SDI groups), and all estimates were presented with corresponding 95% uncertainty intervals (UIs). For this analysis, we used the age range of 15-39 years to define adolescents and young adults. Findings There were 1.19 million (95% UI 1.11-1.28) incident cancer cases and 396 000 (370 000-425 000) deaths due to cancer among people aged 15-39 years worldwide in 2019. The highest age-standardised incidence rates occurred in high SDI (59.6 [54.5-65.7] per 100 000 person-years) and high-middle SDI countries (53.2 [48.8-57.9] per 100 000 person-years), while the highest age-standardised mortality rates were in low-middle SDI (14.2 [12.9-15.6] per 100 000 person-years) and middle SDI (13.6 [12.6-14.8] per 100 000 person-years) countries. In 2019, adolescent and young adult cancers contributed 23.5 million (21.9-25.2) DALYs to the global burden of disease, of which 2.7% (1.9-3.6) came from YLDs and 97.3% (96.4-98.1) from YLLs. Cancer was the fourth leading cause of death and tenth leading cause of DALYs in adolescents and young adults globally. Interpretation Adolescent and young adult cancers contributed substantially to the overall adolescent and young adult disease burden globally in 2019. These results provide new insights into the distribution and magnitude of the adolescent and young adult cancer burden around the world. With notable differences observed across SDI settings, these estimates can inform global and country-level cancer control efforts. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe

Chronic obstructive pulmonary disease in patients undergoing transcatheter aortic valve implantation: insights on clinical outcomes, prognostic markers, and functional status changes

OBJECTIVES: This study sought to determine the effects of chronic obstructive pulmonary disease (COPD) on clinical outcomes in patients undergoing transcatheter aortic valve implantation (TAVI) and to determine the factors associated with worse outcomes in COPD patients. BACKGROUND: No data exist on the factors determining poorer outcomes in COPD patients undergoing TAVI. METHODS: A total of 319 consecutive patients (29.5% with COPD) who underwent TAVI were studied. Functional status was evaluated by New York Heart Association (NYHA) functional class, Duke Activity Status Index, and the 6-min walk test (6MWT) at baseline and at 6 to 12 months. The TAVI treatment was considered futile if the patient either died or did not improve in NYHA functional class at 6-month follow-up. RESULTS: Survival rates at 1 year were 70.6% in COPD patients and 84.5% in patients without COPD (p = 0.008). COPD was an independent predictor of cumulative mortality after TAVI (hazard ratio: 1.84; 95% confidence interval: 1.08 to 3.13; p = 0.026). Improvement in functional status was observed after TAVI (p < 0.001 for NYHA functional class, Duke Activity Status Index, and 6MWT), but COPD patients exhibited less (p = 0.036) improvement in NYHA functional class. Among COPD patients, a shorter 6MWT distance predicted cumulative mortality (p = 0.013), whereas poorer baseline spirometry results (FEV1 [forced expiratory volume in the first second of expiration]) determined a higher rate of periprocedural pulmonary complications (p = 0.040). The TAVI treatment was futile in 40 COPD patients (42.5%) and a baseline 6MWT distance <170 m best determined the lack of benefit after TAVI (p = 0.002). CONCLUSIONS: COPD was associated with a higher rate of mortality at mid-term follow-up. Among COPD patients, a higher degree of airway obstruction and a lower exercise capacity determined a higher risk of pulmonary complications and mortality, respectively. TAVI was futile in more than one-third of the COPD patients, and a shorter distance walked at the 6MWT predicted the lack of benefit after TAVI. These results may help to improve the clinical decision-making process in this challenging group of patients