Cardiopulmonary exercise testing in younger patients with persistent dyspnea following acute, outpatient COVID-19 infection.

Studies using cardiopulmonary exercise testing (CPET) to evaluate persistent dyspnea following infection with COVID-19 have focused on older patients with co-morbid diseases who are post-hospitalization. Less attention has been given to younger patients with post-COVID-19 dyspnea treated as outpatients for their acute infection. We sought to determine causes of persistent dyspnea in younger patients recovering from acute COVID-19 infection that did not require hospitalization. We collected data on all post-COVID-19 patients who underwent CPET in our clinic in the calendar year 2021. Data on cardiac function and respiratory response were abstracted, and diagnoses were assigned using established criteria. CPET data on 45 patients (238.3 ± 124 days post-test positivity) with a median age of 27.0 (22.0-40.0) were available for analysis. All but two (95.6%) were active-duty service members. The group showed substantial loss of aerobic capacity-average VO2 peak (L/min) was 84.2 ± 23% predicted and 25 (55.2%) were below the threshold for normal. Spirometry, diffusion capacity, high-resolution computed tomography, and echocardiogram were largely normal and were not correlated with VO2 peak. The two most common contributors to dyspnea and exercise limitation following comprehensive evaluation were deconditioning and dysfunctional breathing (DB). Younger active-duty military patients with persistent dyspnea following outpatient COVID-19 infection show a substantial reduction in aerobic capacity that is not driven by structural cardiopulmonary disease. Deconditioning and DB breathing are common contributors to their exercise limitation. The chronicity and severity of symptoms accompanied by DB could be consistent with an underlying myopathy in some patients, a disorder that cannot be differentiated from deconditioning using non-invasive CPET.

Intensive Care and Organ Support Related Mortality in Patients With COVID-19: A Systematic Review and Meta-Analysis.

To perform a systematic review and meta-analysis to generate estimates of mortality in patients with COVID-19 that required hospitalization, ICU admission, and organ support. DATA SOURCES: A systematic search of PubMed, Embase, and the Cochrane databases was conducted up to December 31, 2021. STUDY SELECTION: Previously peer-reviewed observational studies that reported ICU, mechanical ventilation (MV), renal replacement therapy (RRT) or extracorporeal membrane oxygenation (ECMO)-related mortality among greater than or equal to 100 individual patients. DATA EXTRACTION: Random-effects meta-analysis was used to generate pooled estimates of case fatality rates (CFRs) for in-hospital, ICU, MV, RRT, and ECMO-related mortality. ICU-related mortality was additionally analyzed by the study country of origin. Sensitivity analyses of CFR were assessed based on completeness of follow-up data, by year, and when only studies judged to be of high quality were included. DATA SYNTHESIS: One hundred fifty-seven studies evaluating 948,309 patients were included. The CFR for in-hospital mortality, ICU mortality, MV, RRT, and ECMO were 25.9% (95% CI: 24.0-27.8%), 37.3% (95% CI: 34.6-40.1%), 51.6% (95% CI: 46.1-57.0%), 66.1% (95% CI: 59.7-72.2%), and 58.0% (95% CI: 46.9-68.9%), respectively. MV (52.7%, 95% CI: 47.5-58.0% vs 31.3%, 95% CI: 16.1-48.9%; p = 0.023) and RRT-related mortality (66.7%, 95% CI: 60.1-73.0% vs 50.3%, 95% CI: 42.4-58.2%; p = 0.003) decreased from 2020 to 2021. CONCLUSIONS: We present updated estimates of CFR for patients hospitalized and requiring intensive care for the management of COVID-19. Although mortality remain high and varies considerably worldwide, we found the CFR in patients supported with MV significantly improved since 2020.

Poor Sleep Quality is Linked to Elevated Extracellular Vesicle-Associated Inflammatory Cytokines in Warfighters With Chronic Mild Traumatic Brain Injuries.

Background: Elevations of inflammatory cytokine levels occur immediately after mild traumatic brain injury (mTBI) and can persist for years. These elevations have been associated with neuropsychological outcomes, including depression and PTSD symptoms. Sleep disorders, another common sequelae of mTBI, are independently associated with inflammation in otherwise healthy individuals. However, whether sleep and inflammation are linked in chronic mTBI has not been reported. Methods: A retrospective cross-sectional cohort of warfighters was used to investigate the hypothesis that inflammation may be linked to sleep quality in chronic mTBI. Clinical history, peripheral blood samples, and sleep quality scores were collected from 182 warfighters (n = 138 mTBI; n = 44 controls) during enrollment in the Chronic Effects of Neurotrauma Consortium study. Biomarkers of inflammation (IL-6, IL-10, TNFα cytokines) from plasma and plasma-derived extracellular vesicles (EVs) were quantified using single molecule array. Relationships between sleep quality and cytokine levels were assessed, controlling for age, sex, and BMI. Using clinical cutoff scores for sleep quality, mTBI patients were then divided into "good" and "poor" sleepers and cytokine levels compared between groups. Results: In mTBI participants, sleep quality was significantly associated with EV levels of IL-10 [ß (SE) = 0.11 (0.04), p = 0.01] and TNFα [ß (SE) = 0.07 (0.03), p < 0.01]. When divided according to "good" versus "poor" sleepers, those reporting poor sleep had significantly elevated EV IL-10 compared to those reporting good sleep [ß (SE) = 0.12 (0.04), p < 0.01]. Plasma-derived associations were not significant. No associations were found between sleep quality and cytokine levels in controls. Conclusion: These results suggest a significant relationship between sleep quality and chronic inflammation in mTBI patients. Clinically, mTBI patients with a high likelihood of sleep disorders demonstrate elevated levels of inflammatory cytokines. Signal from EVs, though smaller in magnitude, may have stronger clinical associations than from plasma. Sleep-focused interventions may also serve to regulate chronic inflammatory processes in these patients. Larger prospective studies are needed to investigate the mechanisms and therapeutic implications of the likely bi-directional relationship between sleep and inflammation following mTBI.

Cryo-EM of full-length α-synuclein reveals fibril polymorphs with a common structural kernel.

α-Synuclein (aSyn) fibrillar polymorphs have distinct in vitro and in vivo seeding activities, contributing differently to synucleinopathies. Despite numerous prior attempts, how polymorphic aSyn fibrils differ in atomic structure remains elusive. Here, we present fibril polymorphs from the full-length recombinant human aSyn and their seeding capacity and cytotoxicity in vitro. By cryo-electron microscopy helical reconstruction, we determine the structures of the two predominant species, a rod and a twister, both at 3.7 Å resolution. Our atomic models reveal that both polymorphs share a kernel structure of a bent ß-arch, but differ in their inter-protofilament interfaces. Thus, different packing of the same kernel structure gives rise to distinct fibril polymorphs. Analyses of disease-related familial mutations suggest their potential contribution to the pathogenesis of synucleinopathies by altering population distribution of the fibril polymorphs. Drug design targeting amyloid fibrils in neurodegenerative diseases should consider the formation and distribution of concurrent fibril polymorphs.