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Muscle fatigue represents the most prevalent symptom of long-term COVID, with elusive pathogenic mechanisms. We performed a longitudinal study to characterize histopathological and transcriptional changes in skeletal muscle in a hamster model of respiratory SARS-CoV-2 infection and compared them with influenza A virus (IAV) and mock infections. Histopathological and bulk RNA sequencing analyses of leg muscles derived from infected animals at days 3, 30, and 60 post-infection showed no direct viral invasion but myofiber atrophy in the SARS-CoV-2 group, which was accompanied by persistent downregulation of the genes related to myofibers, ribosomal proteins, fatty acid β-oxidation, tricarboxylic acid cycle, and mitochondrial oxidative phosphorylation complexes. While both SARS-CoV-2 and IAV infections induced acute and transient type I and II interferon responses in muscle, only the SARS-CoV-2 infection upregulated TNF-α/NF-κB but not IL-6 signaling in muscle. Treatment of C2C12 myotubes, a skeletal muscle cell line, with combined IFN-γ and TNF-α but not with IFN-γ or TNF-α alone markedly impaired mitochondrial function. We conclude that a respiratory SARS-CoV-2 infection can cause myofiber atrophy and persistent energy metabolism suppression without direct viral invasion. The effects may be induced by the combined systemic interferon and TNF-α responses at the acute phase and may contribute to post-COVID-19 persistent muscle fatigue.

Elevated pernio incidence was observed during the COVID-19 pandemic. This prospective study enrolled subjects with pandemic-associated pernio in Wisconsin and Switzerland. Because pernio is a cutaneous manifestation of the interferonopathies, and type I interferon (IFN-I) immunity is critical to COVID-19 recovery, we tested the hypothesis that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-mediated IFN-I signaling might underlie some pernio cases. Tissue-level IFN-I activity and plasmacytoid dendritic cell infiltrates were demonstrated in 100% of the Wisconsin cases. Across both cohorts, sparse SARS-CoV-2 RNA was captured in 25% (6/22) of biopsies, all with high inflammation. Affected patients lacked adaptive immunity to SARS-CoV-2. A hamster model of intranasal SARS-CoV-2 infection was used as a proof-of-principle experiment: RNA was detected in lungs and toes with IFN-I activity at both the sites, while replicating virus was found only in the lung. These data support a viral trigger for some pernio cases, where sustained local IFN-I activity can be triggered in the absence of seroconversion., Competing Interests: The authors declare no competing interests.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins bind to host mitochondrial proteins, likely inhibiting oxidative phosphorylation (OXPHOS) and stimulating glycolysis. We analyzed mitochondrial gene expression in nasopharyngeal and autopsy tissues from patients with coronavirus disease 2019 (COVID-19). In nasopharyngeal samples with declining viral titers, the virus blocked the transcription of a subset of nuclear DNA (nDNA)-encoded mitochondrial OXPHOS genes, induced the expression of microRNA 2392, activated HIF-1α to induce glycolysis, and activated host immune defenses including the integrated stress response. In autopsy tissues from patients with COVID-19, SARS-CoV-2 was no longer present, and mitochondrial gene transcription had recovered in the lungs. However, nDNA mitochondrial gene expression remained suppressed in autopsy tissue from the heart and, to a lesser extent, kidney, and liver, whereas mitochondrial DNA transcription was induced and host-immune defense pathways were activated. During early SARS-CoV-2 infection of hamsters with peak lung viral load, mitochondrial gene expression in the lung was minimally perturbed but was down-regulated in the cerebellum and up-regulated in the striatum even though no SARS-CoV-2 was detected in the brain. During the mid-phase SARS-CoV-2 infection of mice, mitochondrial gene expression was starting to recover in mouse lungs. These data suggest that when the viral titer first peaks, there is a systemic host response followed by viral suppression of mitochondrial gene transcription and induction of glycolysis leading to the deployment of antiviral immune defenses. Even when the virus was cleared and lung mitochondrial function had recovered, mitochondrial function in the heart, kidney, liver, and lymph nodes remained impaired, potentially leading to severe COVID-19 pathology.

Background: Safety-net clinics are an important source of low-cost or free mental healthcare to those with limited financial resources. Such clinics are often staffed by trainees in early stages of their career. Only limited data exist on best practices in treatment-implementation and on clinical outcomes attained in such clinics. The primary purpose of this article is to describe the design of an outpatient psychiatry student-run free clinic (SRFC) serving uninsured individuals in New York City's East Harlem neighborhood and to analyze the quality of services provided and the clinical outcomes attained., Methods: The authors conducted a retrospective chart review of n = 69 patients treated in the EHHOP Mental Health Clinic (E-MHC) to describe the demographic and clinical characteristics of the study population. Utilizing Health Effectiveness Data and Information Set metrics, they estimated the likelihoods of patients meeting metric quality criteria compared to those in other New York State (NYS) insurance groups. The authors derived linear mixed effect and logistic regression models to ascertain factors associated with clinical outcomes. Finally, the authors collected patient feedback on the clinical services received using a customized survey., Results: Almost all patients were of Hispanic ethnicity, and about half of patients had more than one psychiatric disorder. The clinical service performance of the E-MHC was non-inferior on most measures examined. Factors associated with symptom improvement were the number of treatment sessions and certain demographic and clinical variables. Patients provided highly positive feedback on the mental healthcare services they received., Conclusions: SRFCs can provide quality care to vulnerable patients that leads to clinically meaningful reductions in psychiatric symptoms and is well-received by patients., (© 2022. The Author(s).)

Morbidity and mortality in response to SARS-CoV-2 infection are significantly elevated in people of advanced age. To understand the underlying biology of this phenotype, we utilize the golden hamster model to compare how the innate and adaptive immune responses to SARS-CoV-2 infection differed between younger and older animals. We find that while both hamster cohorts showed similar virus kinetics in the lungs, the host response in older animals was dampened, with diminished tissue repair in the respiratory tract post-infection. Characterization of the adaptive immune response also revealed age-related differences, including fewer germinal center B cells in older hamsters, resulting in reduced potency of neutralizing antibodies. Moreover, older animals demonstrate elevated suppressor T cells and neutrophils in the respiratory tract, correlating with an increase in TGF-β and IL-17 induction. Together, these data support that diminished immunity is one of the underlying causes of age-related morbidity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

SARS-CoV-2 infects less than 1% of cells in the human body, yet it can cause severe damage in a variety of organs. Thus, deciphering the non-cell-autonomous effects of SARS-CoV-2 infection is imperative for understanding the cellular and molecular disruption it elicits. Neurological and cognitive defects are among the least understood symptoms of COVID-19 patients, with olfactory dysfunction being their most common sensory deficit. Here, we show that both in humans and hamsters, SARS-CoV-2 infection causes widespread downregulation of olfactory receptors (ORs) and of their signaling components. This non-cell-autonomous effect is preceded by a dramatic reorganization of the neuronal nuclear architecture, which results in dissipation of genomic compartments harboring OR genes. Our data provide a potential mechanism by which SARS-CoV-2 infection alters the cellular morphology and the transcriptome of cells it cannot infect, offering insight to its systemic effects in olfaction and beyond., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

SARS-CoV-2 has caused morbidity and mortality across the globe. As the virus spreads, new variants are arising that show enhanced capacity to bypass preexisting immunity. To understand the memory response to SARS-CoV-2, here, we monitored SARS-CoV-2–specific T and B cells in a longitudinal study of infected and recovered golden hamsters (Mesocricetus auratus). We demonstrated that engagement of the innate immune system after SARS-CoV-2 infection was delayed but was followed by a pronounced adaptive response. Moreover, T cell adoptive transfer conferred a reduction in virus levels and rapid induction of SARS-CoV-2–specific B cells, demonstrating that both lymphocyte populations contributed to the overall response. Reinfection of recovered animals with a SARS-CoV-2 variant of concern showed that SARS-CoV-2–specific T and B cells could effectively control the infection that associated with the rapid induction of neutralizing antibodies but failed to block transmission to both naïve and seroconverted animals. These data suggest that the adaptive immune response to SARS-CoV-2 is sufficient to provide protection to the host, independent of the emergence of variants.

Purpose: In this study, we describe the patterns of hepatocellular carcinoma (HCC) screening with imaging and factors associated with imaging modality selection in a tertiary care transplant center., Methods: This was a retrospective study where all adult patients with cirrhosis and/or chronic hepatitis B virus infection referred for HCC screening with ultrasound (US), CT or MRI were identified during 2017. The association between imaging methods, demographic/clinical data were analyzed by uni- and multivariate analysis., Results: A total of 1437 patients were included (median age 61y, 59% male, median BMI 27.5 kg/m 2 , median AFP 3.4 ng/mL, 37% with HCV and 87% with cirrhosis). Index screening imaging method utilization included MRI (51%), US (33%) and CT (16%). Use of US as the index imaging modality for screening was significantly associated with race/ethnicity [Odds Ratio (OR) 1.71-2.01, all p < 0.05] in multivariate analysis. Presence of cirrhosis (OR 0.29, p < 0.001) and referral by a hepatologist (OR 0.23, p < 0.001) were associated with screening with MRI in the multivariate analysis; while gender, age, BMI, etiology and income at ZIP code of residence were not significantly associated with imaging modality selection. HCC was observed in 62 patients (prevalence 4.3%). Rate of HCC detection was significantly higher with MRI vs US (5.9% vs. 1.5%, p = 0.001)., Conclusion: MRI was the most frequently used modality (> 50%) for HCC screening in our tertiary care center, in contrast with the current practice guidelines. Race/ethnicity, cirrhosis and referral by a hepatologist were associated with the imaging method used for HCC screening., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)