Background The coronavirus disease 2019 (COVID-19) pandemic has caused significant morbidity and mortality worldwide. Knowledge about the pathophysiology of the disease and its effect on multiple systems is growing. Kidney injury has been a topic of focus, and rhabdomyolysis is suspected to be one of the contributing mechanisms. However, information on rhabdomyolysis in patients affected by COVID-19 is limited. We aim to describe the incidence, clinical characteristics, and outcomes of patients hospitalized with COVID-19 who developed rhabdomyolysis. Materials and methods A retrospective observational cohort consisted of patients who were admitted and had an outcome between March 16 to May 27, 2020, inclusive of those dates at a single center in the Bronx, New York City. All consecutive inpatients with lab-confirmed COVID-19 were identified. Patients with peak total creatine kinase (CK) over 1,000 U/L were reviewed; 140 patients were included in the study. The main outcomes during hospitalization were new-onset renal replacement therapy and in-hospital mortality. Results The median age was 68 years (range: 21-93); 64% were males. The most common comorbidities were hypertension (73%), diabetes mellitus (47%), and chronic kidney disease (24%). Median CK on admission was 1,323 U/L (interquartile range [IQR]: 775 - 2,848). Median CK on discharge among survivors was 852 (IQR: 170 - 1,788). Median creatinine on admission was 1.78 mg/dL (IQR: 1.23 - 3.06). During hospitalization, 49 patients (35%) received invasive mechanical ventilation, 24 patients (17.1%) were treated with renal replacement therapy (RRT), and 66 (47.1%) died. Conclusions Rhabdomyolysis was a common finding among hospitalized patients with COVID-19 in our hospital in the Bronx. The incidence of new-onset renal replacement therapy and in-hospital mortality is higher in patients who develop rhabdomyolysis. McMahon score, rather than isolated creatine kinase levels, was a statistically significant predictor of new-onset RRT. Clinicians should maintain a high level of suspicion for rhabdomyolysis in COVID-19 patients throughout their admission and use validated scores like McMahon score to devise their treatment plan accordingly.
BackgroundThe upper respiratory tract (URT) is the portal of entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and SARS-CoV-2 likely interacts with the URT microbiome. However, understanding of the associations between the URT microbiome and the severity of coronavirus disease 2019 (COVID-19) is still limited.ObjectiveOur primary objective was to identify URT microbiome signature/s that consistently changed over a spectrum of COVID-19 severity.MethodsUsing data from 103 adult participants from two cities in the United States, we compared the bacterial load and the URT microbiome between five groups: 20 asymptomatic SARS-CoV-2-negative participants, 27 participants with mild COVID-19, 28 participants with moderate COVID-19, 15 hospitalized patients with severe COVID-19, and 13 hospitalized patients in the ICU with very severe COVID-19.ResultsURT bacterial load, bacterial richness, and within-group microbiome composition dissimilarity consistently increased as COVID-19 severity increased, while the relative abundance of an amplicon sequence variant (ASV), Corynebacterium_unclassified.ASV0002, consistently decreased as COVID-19 severity increased.ConclusionsWe observed that the URT microbiome composition significantly changed as COVID-19 severity increased. The URT microbiome could potentially predict which patients may be more likely to progress to severe disease or be modified to decrease severity. However, further research in additional longitudinal cohorts is needed to better understand how the microbiome affects COVID-19 severity.
Vanishing White Matter (VWM) is a recessive neurodegenerative disease caused by mutations in translation initiation factor eIF2B and leading to progressive brain myelin deterioration, secondary axonal damage and death in early adolescence. Eif2b5R132H/R132H mice exhibit delayed developmental myelination, mild early neurodegeneration and a robust remyelination defect in response to cuprizone-induced demyelination. In the current study we used Eif2b5R132H/R132H mice for mass-spectrometry analyses, to follow the changes in brain protein abundance in normal diet- versus cuprizone-fed mice during the remyelination recovery phase. Analysis of proteome profiles suggested that dysregulation of mitochondrial functions, altered proteasomal activity and impaired balance between protein synthesis and degradation play a role in VWM pathology. Consistent with these findings, we detected elevated levels of reactive oxygen species (ROS) in mutant-derived primary fibroblasts and reduced 20S proteasome activity in mutant brain homogenates. These observations highlight the importance of tight translational control to precise coordination of processes involved in myelin formation and regeneration and point at cellular functions that may contribute to VWM pathology.
BackgroundMutations in any of the five subunits of eukaryotic translation initiation factor 2B (eIF2B) can lead to an inherited chronic-progressive fatal brain disease of unknown aetiology termed leucoencephalopathy with vanishing white matter (VWM). VWM is one of the most prevalent childhood white matter disorders, which markedly deteriorates after inflammation or exposure to other stressors. eIF2B is a major housekeeping complex that governs the rate of global protein synthesis under normal and stress conditions. A previous study demonstrated that Eif2b5R132H/R132H mice suffer delayed white matter development and fail to recover from cuprizone-induced demyelination, although eIF2B enzymatic activity in the mutant brain is reduced by merely 20%.Principal FindingsPoor astrogliosis was observed in Eif2b5R132H/R132H mice brain in response to systemic stress induced by peripheral injections of lipopolysaccharide (LPS). Even with normal rates of protein synthesis under normal conditions, primary astrocytes and microglia isolated from mutant brains fail to adequately synthesise and secrete cytokines in response to LPS treatment despite proper induction of cytokine mRNAs.ConclusionsThe mild reduction in eIF2B activity prevents the appropriate increase in translation rates upon exposure to the inflammatory stressor LPS. The data underscore the importance of fully-functional translation machinery for efficient cerebral inflammatory response upon insults. It highlights the magnitude of proficient translation rates in restoration of brain homeostasis via microglia-astrocyte crosstalk. This study is the first to suggest the involvement of microglia in the pathology of VWM disease. Importantly, it rationalises the deterioration of clinical symptoms upon exposure of VWM patients to physiological stressors and provides possible explanation for their high phenotypic variability.
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