COVID-19 is a complex disease caused by SARS-CoV-2. The molecular and cellular mechanisms of the disease are unclear and their study is one of the greatest challenges for the modern science. Since the lung is the biggest target for SARS-CoV-2, the studies on cellular and molecular changes in this organ are essential to establish the pathogenesis of the disease. To date there is increasing number of reports on the lung pathology of fatal COVID-19 and the results are mainly obtained by autopsies of elderly patients, since this age group shows highest mortality. Little is known about the progression of the disease in children and especially newborn and infants and, to our knowledge, there are no reports on the lung features of fatal COVID-19 in this age group.

In the present case study, we have investigated the lung morphological features in 11-months old infant who has died as a result of complications from COVID-19. Immunohistochemistry for immune cell markers and transmission electron microscopy for alveolocytes type II (ATII) are made.

Immediate cause of the death was acute respiratory failure resulting from bilateral interstitial pneumonia and subsequent acute cardiovascular failure. The histopathology shows lung edema, hyaline membranes, airway mucus plugging and interstitial inflammation. On cellular level we have observed a substantial increase in the number of ATII cells. ATII cells were marked with cytokeratin 19, TTF1 and napsin A. Transmission elec-tron microscopy reveals ongoing apoptosis in these cells with a typical chromatin clustering and condensation towards the inner nuclear membrane. Immunohisto-chemistry shows significant increase of CD68+ macro-phages in the alveoli, increase of IL-6 in immune and stromal cells, moderate elevation of FOXP3+ and IL-17+ cells and expression of CD4+ and CD8+ cells in alveolar walls. Immune cell interactions are discussed in the sense of ongoing cytokine storm.

Our findings highlight the complexity of COVID-19 lung affection, involving ATII cell hyperplasia, interstitial mononuclear cell infiltration and macrophages increase. The findings provide an additional knowledge on the pathophysiology of COVID-19 in the lung and can serve as a basis for investigation of molecular mechanisms of this disease.

The Global pandemic of coronavirus disease 2019 was initiated by the emergence of severe acute respiratory syndrome coronavirus 2. In addition to conventional pulmonary lesions, a range of neurological injury symptoms have been identified in clinical practice, but the aetiology of neurological disorders linked to SARS-CoV-2 infection remains poorly understood. Syrian hamsters, which are highly susceptible to SARS-CoV-2 infection, exhibit a disease phenotype similar to that observed in human COVID-19 patients. In this study, a hamster model of COVID-19 infection was used to analyze molecular changes in different tissues at various time points post infection with distinct strains using proteomic and phosphoproteomic approaches. Multi-omics analysis showed that SARS-COV-2 infection triggers sustained downregulation of the abundance and phosphorylation levels of neuronal and synapse-associated proteins in the brain, suggesting that neuronal damage persists even during the recovery period. Additionally, infections with SARS-CoV-2 may contribute to the onset of long-term symptoms of COVID-19 by impacting energy metabolism, neurotransmitter release, and synaptic transmission pathways. This study provides a comprehensive molecular profile of hamsters infected with different SARS-CoV-2 strains in different tissues, offering foundational insights into the pathogenic mechanisms of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a substantial global threat. SARS-CoV-2 nonstructural proteins (NSPs) are essential for impeding the host replication mechanism while also assisting in the production and organization of new viral components. However, NSPs are not incorporated into viral particles, and their subsequent fate within host cells remains poorly understood. Additionally, their role in viral pathogenesis requires further investigation.

This study aimed to discover the ultimate fate of NSP6 in host cells and to elucidate its role in viral pathogenesis.

We investigated the effects of NSP6 on cell death and explored the underlying mechanism; moreover, we examined the degradation mechanism of NSP6 in human cells, along with analysing its correlation with coronavirus disease 2019 (COVID-19) severity in patient peripheral blood mononuclear cells (PBMCs).

NSP6 was demonstrated to induce cell death. Specifically, NSP6 interacted with EI24 autophagy-associated transmembrane protein (EI24) to increase intracellular Ca2+ levels, thereby enhancing the interactions between unc-51-like autophagy activating kinase 1 (ULK1) and RB1 inducible coiled-coil 1 (RB1CC1/FIP200), as well as beclin 1 (BECN1) and phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3). This cascade ultimately triggers autophagy, thus resulting in cell death. Additionally, we discovered that the homeostasis of the NSP6 protein was regulated by K48-linked ubiquitination. We identified kelch-like protein 22 (KLHL22) as the E3 ligase that was responsible for ubiquitinating and degrading NSP6, restoring intracellular calcium homeostasis and reversing NSP6-induced autophagic cell death. Moreover, NSP6 expression levels were observed to be positively associated with the severity of SARS-CoV-2-induced disease.

This study reveals that KLHL22-mediated ubiquitination controls NSP6 stability and that NSP6 induces autophagic cell death via calcium overload, highlighting its cytotoxic role and suggesting therapeutic strategies that target calcium signaling or promote NSP6 degradation as potential interventions against COVID-19.

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has led to a significant burden on global healthcare systems. COVID-19-induced acute kidney injury (AKI) is among one of the complications, that has emerged as a critical and frequent condition in COVID-19 patients. This AKI among COVID-19 patients is associated with poor outcomes, and high mortality rates, especially in those with severe AKI or requiring renal replacement therapy. COVID-19-induced AKI represents a significant complication with complex pathophysiology and multifactorial risk factors. Indeed, several pathophysiological mechanisms, including direct viral invasion of renal cells, systemic inflammation, endothelial and thrombotic abnormalities as well as nephrotoxic drugs and rhabdomyolysis are believed to underlie this condition. Moreover, histopathological and immunohistopathological findings commonly observed in postmortem studies include acute tubular necrosis, glomerular injury, and the presence of viral particles within renal tissue and urine. Identified risk factors for developing AKI vary among studies, depending on regions, underlying conditions, and the severity of the disease. Moreover, histopathological and immunohistopathological findings commonly observed in postmortem studies include show acute tubular necrosis, glomerular injury, and viral particles within renal tissue and urine. While, identified risk factors for developing AKI vary among studies, according to regions, underlying conditions, and the gravity of the disease. This narrative review aims to synthesize current knowledge on the incidence, pathophysiology, risk factors, histopathology, and outcomes of AKI induced by COVID-19.

Patients surviving coronavirus disease of 2019 (COVID-19) often complain of skeletal muscle weakness that may be very limiting and long-lasting. There are almost no studies on the skeletal muscle of these patients, and electron microscopic data are scarce. We assessed the ultrastructural changes in the quadriceps of eight patients with COVID-19 and found a combination of features different from those reported in corticosteroid myopathy and acute relaxant-steroid myopathy. The most remarkable and constant changes involved the endothelial cells and consisted of massive amounts of pinocytotic vesicles, degenerative changes, platelet aggregates and, most characteristic of all, an increase in the external lamina thickness that seems to stem from reduplication due to successive bouts of endothelial cell damage and subsequent regeneration. Viral particles were not found in any of the cases. This distinct and quite common set of alterations defines the myopathy associated with infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This association seems to be the result of an inflammatory process that would arise in infected cells but could damage non-infected endomysial blood vessels, thus resulting in persistent changes of the microvasculature that would be related to long-standing myopathic clinical features.

The COVID-19 pandemic has caused at least 780 million cases globally. While available treatments and vaccines have reduced the mortality rate, spread and evolution of the virus are ongoing processes. Despite extensive research, the long-term impact of SARS-CoV-2 infection is still poorly understood and requires further investigation. Routine analysis provides limited access to the tissues of patients, necessitating alternative approaches to investigate viral dissemination in the organism. We address this issue by implementing a whole-body in vivo imaging strategy to longitudinally assess the biodistribution of SARS-CoV-2. We demonstrate in a COVID-19 non-human primate model that a single injection of radiolabeled [89Zr]COVA1-27-DFO human monoclonal antibody targeting a preserved epitope of the SARS-CoV-2 spike protein allows longitudinal tracking of the virus by positron emission tomography with computed tomography (PET/CT). Convalescent animals exhibit a persistent [89Zr]COVA1-27-DFO PET signal in the lungs, as well as in the brain, three months following infection. This imaging approach also allows viral detection in various organs, including the airways and kidneys, of exposed animals during the acute infection phase. Overall, the technology we developed offers a comprehensive assessment of SARS-CoV-2 distribution in vivo and provides a promising approach for the non-invasive study of long-COVID pathophysiology.

The biological effects of SARS-CoV-2 infection in transplanted kidneys are uncertain with little pathological information.

This single-center, prospective observational study evaluated kidney transplant biopsies from recipients of deceased donors with COVID-19, current recipients contracting SARS-CoV-2 Omicron variant in 2022, against prior BK virus (BKV) infection and uninfected (without SARS-CoV-2 or BKV) samples, as respective positive and negative comparators (n = 503 samples).

We demonstrated nonvirus tubular injury in implanted tissue from infected donors and prevalent recipients with mild acute COVID-19 and acute kidney injury, excluding direct viral infection as a cause of kidney damage. COVID particles were absent in 4116 ultrastructural images of 295 renal tubules from 4 patients with acute COVID-19. No viral cytopathic effect, viral allograft nephropathy, or SARS-CoV-2 RNA was detected in acute tissues, nor in 128 sequential samples from infected donors or recipients with COVID-19. Following recipient COVID-19 (mean 16.8 ± 12.0 wk post-infection), the biopsy-prevalence of rejection was 33.0% (n = 100 biopsies) versus 13.4% for contemporaneous uninfected controls (n = 337; P  < 0.001). Prior COVID-19 was an independent risk factor for incident rejection using multivariable generalized estimating equation adjusted for competing risks (odds ratio, 2.195; 95% confidence interval, 1.189-4.052; P  = 0.012). Landmark and matched-pair analyses confirmed an association of SARS-CoV-2 with subsequent transplant rejection, with a similar pattern following BKV infection.

Transplantation from COVID-19+ deceased donors yielded good recipient outcomes without evidence of viral tissue transmission. Acute kidney injury during COVID-19 was mediated by archetypical tubular injury and infection correlated with an increased risk of subsequent rejection.

Abnormal coagulation and thrombotic complications prompted many guidelines to recommend thromboprophylaxis for patients hospitalised with COVID-19, but the dose required for prophylaxis remains unclear. This systematic review (SR) analyses the safety and efficacy of therapeutic dose anticoagulation (TDA) versus non-therapeutic dose anticoagulation (NDA) in COVID-19 patients.

According to the Cochrane Handbook of Systematic Review of Interventions, we performed an SR. The protocol is registered in Prospero (CRD42021269197, date 12 August 2021).

In this SR of 18 studies, TDA was shown to reduce all-cause mortality (risk ratio [RR] 0.83; 95% confidence interval [95% CI] 0.70, 0.99) in COVID-19 infection. TDA also reduced thrombosis (RR 0.55; 95% CI 0.48, 0.72) but increased major bleeding (RR 1.87; 95% CI 1.29, 2.69). A stratified analysis according to severity revealed that, in non-critical patients, TDA resulted in mortality benefit (RR 0.79; 95% CI 0.67, 0.94). In critical patients, TDA did not affect all-cause mortality (RR 1.03; 95% CI 0.89, 1.18) but reduced thrombosis (RR 0.65; 95% CI 0.48, 0.86) and increased major bleeding (RR 1.85; 95% CI 1.06, 3.23).

TDA significantly reduced all-cause mortality and thrombosis in non-critical COVID-19 patients at the expense of increased major bleeding. In critical COVID-19, this mortality benefit was not observed.

There are increasing reports of glomerular disease (GD) following COVID-19 infection and vaccination. Current evidence on the possible link between COVID-19 infection or vaccination and GD is conflicting.

The present study undertakes a scoping review of research to describe the relationship between COVID-19 infection and vaccination with GD and the common management strategies and overall outcomes of the disease to identify knowledge gaps and guide further research.

All original research studies published in English until 5th September 2022 were considered for inclusion in the review. Exclusion criteria were animal studies, autopsy studies, and data involving patients who were paediatric patients (< 16 years), were transplant recipients, had a recurrence of glomerular disease, had concomitant cancer or non-COVID-19 infection which may cause glomerular disease, or did not receive a renal biopsy.

The five electronic databases searched were MEDLINE, PubMed, Scopus, EMBASE, and Cochrane.

Two separate search strings related to COVID-19, and glomerular disease were combined using the Boolean operator 'AND'. Filters were used to limit publications to original research studies published in English. Search results from each database were imported into Covidence software ( www.covidence.org ) and used for de-duplication, article screening, and data extraction. Descriptive analyses were used to summarise demographics, diagnoses, and treatment outcomes.

After removing duplicates, 6853 titles and abstracts were screened. Of the 188 studies included, 106 studies described 341 patients with GD following COVID-19 infection and 82 described 146 patients with GD following a COVID-19 vaccination. IgA nephropathy was the most common GD pathology reported following COVID-19 vaccination with GD most common following mRNA vaccines. Collapsing focal segmental glomerulosclerosis was the most common GD following COVID-19 infection. Immunosuppressive treatment of GD was more common in the vaccine cohort than in the infection cohort.

Despite the significant number of COVID-19 infections and vaccinations around the world, our understanding of GD associated with COVID-19 infection and vaccination remains poor, and more research is needed to understand the possible relationship better.

This multicentric study aims to characterize and assess the occurrence of neuroradiological findings among patients with SARS-CoV-2 infection during the first Italian wave of the pandemic outbreak.

Patients' data were collected between May 2020 and June 2020. Clinical and laboratory data, chest imaging, brain CT, and MRI imaging were included. Acquired data were centralized and analyzed in two hospitals: ASST Spedali Civili, Brescia, and IRRCS San Raffaele Research Hospital, Milan, Italy. COVID-19 patients were classified into two different subgroups, vascular and nonvascular. The vascular pattern was further divided into ischemic and hemorrhagic stroke groups.

Four hundred and fifteen patients from 20 different Italian Centers were enrolled in the study. The most frequent symptom was focal neurological deficit, found in 143 patients (34.5%). The most frequent neuroradiological finding was ischemic stroke in 122 (29.4%) patients. Forty-four (10.6%) patients presented a cerebral hemorrhage. Forty-seven patients had non-stroke neuroimaging lesions (11.3%). The most common was PRES-like syndrome (28%), SWI hypointensities (22%), and encephalitis (19%). The stroke group had higher CAD risk (37.5% vs 20%, p = .016) and higher D-dimer levels (1875 ng/mL vs 451 ng/mL, p < .001) compared to the negative group.

Our study describes the biggest cohort study in Italy on brain imaging of COVID-19 patients and confirms that COVID-19 patients are at risk of strokes, possibly due to a pro-thrombotic microenvironment. Moreover, apart from stroke, the other neuroradiological patterns described align with the ones reported worldwide.

SARS-CoV-2 infection is marked by an excessive inflammatory response, leading to elevated production of pro-inflammatory cytokines through activation of intracellular pathways like mitogen-activated protein kinase (MAPK). Viruses can use the MAPK signaling pathway to their advantage, but the relationship of this pathway to the severe SARS-CoV-2 period has not been fully elucidated. MAP2K4 is involved in the MAPK signaling pathway and affects cellular processes such as cell-cell junction, cell proliferation, differentiation and apoptosis.

In this study, we sought to determine the associated biomarkers that are involved in the MAP2K4 pathway and elucidate its possible roles in terms of some clinical features associated with COVID-19. We evaluated the expressions of MAP2K4, SNAI1, SLUG, ZEB1 and E-Cadherin. For this purpose, we prospectively recruited 66 individuals, 39 of whom were women and had a mean age of 65 years. The results revealed that MAP2K4 upregulation increased SNAI1 gene expression level whereas E- Cadherin level was decreased in SARS-CoV-2 positive participants. In addition, negative correlations were determined with PLT, Lymphocyte and CKMB and E- Cadherin levels in positive participants. We also observed a negative correlation between the MAP2K4 and AST, and a positive correlation between SLUG and BUN, ZEB1 and CK.

We conclude that SARS-CoV-2 infection triggers fibrosis by increasing MAP2K4 regulation. Additionally, this is the first study to demonstrate the possible contribution of MAP2K4 in influencing COVID-19 clinical features, which may be relevant for identifying COVID-19 positive participants with severe complications.

Post-acute sequelae of COVID-19 (PASC) are a diverse set of symptoms and syndromes driven by dysfunction of multiple organ systems that can persist for years and negatively impact the quality of life for millions of individuals. We currently lack specific therapeutics for patients with PASC, due in part to an incomplete understanding of its pathogenesis, especially for non-pulmonary sequelae. Here, we discuss three animal models that have been utilized to investigate PASC: non-human primates (NHPs), hamsters, and mice. We focus on neurological, gastrointestinal, and cardiovascular PASC and highlight advances in mechanistic insight that have been made using these animal models, as well as discussing the sequelae that warrant continued and intensive research.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been associated with systemic inflammation and vascular injury, which contribute to the development of acute respiratory syndrome (ARDS) and the mortality of COVID-19 infection. Moreover, multiorgan complications due to persistent endothelial dysfunction have been suspected as the cause of post-acute sequelae of SARS-CoV-2 infection. Therefore, elucidation of the vascular inflammatory effect of SARS-CoV-2 will increase our understanding of how endothelial cells (ECs) contribute to the short- and long-term consequences of SARS-CoV-2 infection. Here, we investigated the interaction of SARS-CoV-2 spike protein with human ECs from aortic (HAoEC) and pulmonary microvascular (HPMC) origins, cultured under physiological flow conditions. We showed that the SARS-CoV-2 spike protein triggers prolonged expression of cell adhesion markers in both ECs, similar to the effect of TNF-α. SARS-CoV-2 spike treatment also led to the release of various cytokines and chemokines observed in severe COVID-19 patients. Moreover, increased binding of leucocytes to the endothelial surface and a procoagulant state of the endothelium were observed. Transcriptomic profiles of SARS-CoV-2 spike-activated HPMC and HAoEC showed prolonged upregulation of genes and pathways associated with responses to virus, cytokine-mediated signaling, pattern recognition, as well as complement and coagulation pathways. Our findings support experimental and clinical observations of the vascular consequences of SARS-CoV-2 infection and highlight the importance of EC protection as one of the strategies to mitigate the severe effects as well as the possible post-acute complications of COVID-19 disease.

Extrapulmonary complications (EPCs) are common in patients hospitalized for coronavirus disease 2019 (COVID-19), but data on their clinical consequences and association with viral replication and systemic viral dissemination are lacking.

Patients hospitalized for COVID-19 and enrolled in the Therapeutics for Inpatients with COVID-19 (TICO) platform trial at 114 international sites between August 2020 and November 2021 were included in a prospective cohort study. We categorized EPCs into 39 event types within 9 categories and estimated their frequency through day 28 and their association with clinical outcomes through day 90. We analyzed the association between baseline viral burden (plasma nucleocapsid antigen [N-Ag] level and upper airway viral load) and EPCs, adjusting for other baseline factors.

A total of 2625 trial participants were included in the study. Their median age was 57 years (interquartile range, 46-68 years), 57.7% were male, and 537 (20.5%) had ≥1 EPC. EPCs were associated with higher day-90 all-cause mortality rate (hazard ratio, 9.6 [95% confidence interval, 7.3-12.7]) after adjustment for other risk factors. The risk of EPCs increased with increasing baseline plasma N-Ag level (hazard ratio, 1.21 per log10 ng/L increase [95% confidence interval, 1.09-1.34]), and upper airway viral load (1.12 per log10 copies/mL increase [1.04-1.19), after adjustment for comorbid conditions, disease severity, inflammatory markers, and other baseline factors. Trial treatment allocation had no effect on EPC risk.

Systemic viral dissemination as evidenced by high plasma N-Ag level and high respiratory viral burden are associated with development of EPCs in COVID-19, which in turn are associated with higher 90-day mortality rates.

The aim of this study was to compare the histopathological findings in the resected tracheal ring of tracheotomized critically ill patients with or without severe SARS-CoV-2 infection.

This is a prospective case-control study. The data collection period was between May 2020 and 2022. Eighty tracheostomies were performed on patients with long intubation, and the resected tracheal ring was examined by standard microscopy. Forty consecutive tracheotomies were carried out in COVID-19-positive and -negative patients.

The mean age was 67.1 (6.9 SD) years in the COVID-19 group and 67.8 (9.6 SD) in the control group (p = 0.3). The number of men in each group was 30 (75.0%) versus 27 (67.5%), respectively (p = 0.5). No relevant histological alterations were found in 82.5% of samples. Chronic subepithelial inflammation was found in 13.8% of cases. Two cases presented with vasculitis (2.5%), and one case presented with thrombotic microangiopathy (1.2%), all of them in the COVID-19 group. We found no statistically significant dependence between relevant histologic findings versus no alterations (X2 = 0.779, p= 0.377) and no significant risk indices (RR = 1.8, OR = 2.032, PAR = 44%).

There is no evidence of increased risk of histopathological findings in the resected tracheal ring of patients with long intubation and COVID-19 disease.

A life-threatening complication of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is acute respiratory distress syndrome. Our understanding of the pathologic changes in coronavirus disease 2019 (COVID-19) is based almost exclusively on post-mortem analyses of adults. These studies established several hallmarks of SARS-CoV-2 lung infection, including diffuse alveolar damage, microvascular thrombi, and acute bronchopneumonia. We describe a fatal example of COVID pneumonia in a 9-year-old girl who presented with fever 10 months following the diagnosis of ALK-positive anaplastic large cell lymphoma (ALCL). A chest computed tomography scan revealed left upper lobe lung consolidation and nodular airspace disease, and an initial SARS-CoV-2 nasopharyngeal swab (RT-PCR) was negative. A subsequent lung biopsy performed due to concern for relapsed ALCL demonstrated sheets of intra-alveolar and interstitial macrophages, and macrophage-rich fibrinous exudates. Immunohistochemical and in-situ hybridization stains confirmed these macrophages as the predominant SARS-CoV-2-infected cell type. Subsequent RT-PCR testing of upper and lower respiratory tract samples was positive for SARS-CoV-2 infection. Whole genome sequencing confirmed the presence of the B.1.617.2 (Delta) variant. This biopsy illustrates the histopathologic features of early COVID pneumonia in antemortem lung tissue from a pediatric patient, and establishes macrophages as a potential source of SARS-CoV-2 amplification.

SARS-CoV-2 penetrates human cells via its spike protein, which mainly interacts with ACE2 receptors, triggering viral replication and an exacerbated immune response characterized by a cytokine storm. Vimentin III, an intermediate filament protein predominantly found in mesenchymal cells, has garnered considerable attention in recent research due to its multifaceted biological roles and significance in the endothelial-mesenchymal transition (EndMT) during various fibrotic processes. However, the pathophysiological mechanisms linking vimentin to SARS-CoV-2 remain incompletely elucidated. In this study, we determined the expression profiles of vimentin in three cohorts: patients admitted to the intensive care unit with SARS-CoV-2 infection, individuals in the 6-12 month convalescent phase post-infection and COVID-19 negative controls. Our objective was to assess the association between peripheral blood biomarkers implicated in endothelial dysfunction and genes related to fibrosis. Serum levels of vimentin and N-cadherin were determined by ELISA, while vimentin gene expression was determined by qRT-PCR. In addition, we examined the correlation between clinical parameters and serum levels of vimentin and N-cadherin in severe COVID-19 patients and healthy counterparts. Our findings revealed elevated serum vimentin levels and increased gene expression in severe COVID-19 patients compared to healthy controls. Conversely, serum N-cadherin levels were diminished in both acute and convalescent stages of severe COVID-19 relative to healthy individuals. Notably, associations were observed between C-reactive protein, lactate dehydrogenase, lymphocyte count and vimentin levels in severe COVID-19 patients, indicative of endothelial dysfunction. Furthermore, our study identified vimentin and N-cadherin as potential diagnostic markers via ROC analysis. Overall, delineating the dysregulation of vimentin and N-cadherin due to SARS-CoV-2 infection in disease pathogenesis and tissue homeostasis offers novel insights for clinical management and targeted therapeutic interventions.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) preferentially infects the respiratory tract; however, several studies have implicated a multi-organ involvement. Hepatic dysfunctions caused by SARS-CoV-2 infection have been increasingly recognized and described to correlate with disease severity. To elucidate molecular factors that could contribute towards hepatic infection, we concentrated on microRNAs (miRNAs), a class of small non-coding RNAs that modulate various cellular processes and which are reported to be differentially regulated during liver injury. We aimed to study the infection of primary human hepatocytes (PHH) with SARS-CoV-2 and to evaluate the potential of miRNAs for modulating viral infection.

We analysed liver autopsies from a coronavirus disease 19 (COVID-19)-positive cohort for the presence of viral RNA using Nanopore sequencing. PHH were used for the infection with SARS-CoV-2. The candidate miRNAs targeting angiotensin converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) were identified using in silico approaches. To discover the potential regulatory mechanism, transfection experiments, qRT-PCRs, western blots and luciferase reporter assays were performed.

We could detect SARS-CoV-2 RNA in COVID-19-positive liver autopsies. We show that PHH express ACE2 and TMPRSS2 and can be readily infected with SARS-CoV-2, resulting in robust replication. Transfection of selected miRNA mimics reduced SARS-CoV-2 receptor expression and SARS-CoV-2 burden in PHH. In silico and biochemical analyses supported a potential direct binding of miR-141-3p to the SARS-CoV-2 genome.

We confirm that PHH are susceptible to SARS-CoV-2 infection and demonstrate selected miRNAs targeting SARS-CoV-2 entry factors and/or the viral genome reduce viral loads. These data provide novel insights into hepatic susceptibility to SARS-CoV-2 and associated dysfunctions in COVID-19.

The large number of patients with COVID-19 subjected to prolonged invasive mechanical ventilation has been expected to result in a significant increase in tracheal stenosis in the next years. The aim of this study was to evaluate and compare postoperative outcomes of patients who survived COVID-19 critical illness and underwent tracheal resection for postintubation/posttracheostomy tracheal stenosis with those of non-COVID-19 patients.

It was single-center, retrospective study. All consecutive patients with post-intubation/posttracheostomy tracheal stenosis who underwent tracheal resection from February 2020 to March 2022 were enrolled. A total of 147 tracheal resections were performed: 24 were in post-COVID-19 patients and 123 were in non-COVID-19 patients. A 1:1 propensity score matching analysis was performed, considering age, gender, body mass index, and length of stenosis. After matching, 2 groups of 24 patients each were identified: a post-COVID-19 group and a non-COVID group.

No mortality after surgery was registered. Posttracheostomy etiology of stenosis resulted more frequently in post-COVID-19 patients (n = 20 in the post-COVID-19 group vs n = 11 in the non-COVID-19 group; P = .03), as well as intensive care unit admissions during the postoperative period (16 vs 9 patients; P = .04). Need for postoperative reintubation for glottic edema and respiratory failure was higher in the post-COVID-19 group (7 vs 2 postoperative reintubation procedures; P = .04). Postoperative dysphonia was observed in 11 (46%) patients in the post-COVID-19 group versus 4 (16%) patients in the non-COVID-19 group (P = .03).

Tracheal resection continues to be safe and effective in COVID-19-related tracheal stenosis scenarios. Intensive care unit admission rates and postoperative complications seem to be higher in post-COVID-19 patients who underwent tracheal resection compared with non-COVID-19 patients.

To characterize the preoperative and intraoperative findings of symptomatic tracheal stenosis associated with COVID-19 related respiratory failure requiring tracheal resection.

We performed a retrospective review identifying all patients with a history of tracheal stenosis secondary to COVID-19 related respiratory failure who subsequently received a tracheal resection at our institution between January 2020 and June 2023. Clinical, radiological, pathological, and surgical characteristics were recorded to describe and characterize pre-operative and intraoperative findings associated with tracheal stenosis in the setting of a previous COVID-19 infection.

We retrospectively reviewed 11 patients with COVID-19 related tracheal stenosis that required open tracheal or cricotracheal resection. The mean age was 54.1. Patients were hospitalized for a mean of 49.5 days related to COVID-19 complications. Tracheotomy was completed in 10 patients (90.9%) during their initial hospitalization with COVID-19 related respiratory failure. Patients were intubated a mean of 18.6 days prior to tracheotomy completion. Ten patients (90.9%) underwent endoscopic operative interventions for their tracheal stenosis prior to open resection. Intraoperatively, the mean stenosis length was 3.33 cm. The mean tracheal resection length was 3.96 cm. Patients were hospitalized for a mean of 8.27 days post operatively with no significant post operative complications.

Symptomatic tracheal stenosis in the setting of prolonged intubation due to COVID-19 is an under-described etiology. This is one of the largest single institution retrospective reviews that identifies 11 patients with prolonged intubation who developed symptomatic tracheal stenosis refractory to conservative management and ultimately requiring tracheal resection.

Coronaviruses are highly transmissible respiratory viruses that cause symptoms ranging from mild congestion to severe respiratory distress. The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored the need for new antivirals with broad-acting mechanisms to combat increasing emergence of new variants. Currently, there are only a few antivirals approved for treatment of SARS-CoV-2. Previously, the rocaglate natural product silvestrol and synthetic rocaglates such as CR-1-31b were shown to have antiviral effects by inhibiting eukaryotic translation initiation factor 4A1 (eIF4A) function and virus protein synthesis. In this study, we evaluated amidino-rocaglates (ADRs), a class of synthetic rocaglates with the most potent eIF4A-inhibitory activity to-date, for inhibition of SARS-CoV-2 infection. This class of compounds showed low nanomolar potency against multiple SARS-CoV-2 variants and in multiple cell types, including human lung-derived cells, with strong inhibition of virus over host protein synthesis and low cytotoxicity. The most potent ADRs were also shown to be active against two highly pathogenic and distantly related coronaviruses, SARS-CoV and MERS-CoV. Mechanistically, cells with mutations of eIF4A1, which are known to reduce rocaglate interaction displayed reduced ADR-associated loss of cellular function, consistent with targeting of protein synthesis. Overall, ADRs and derivatives may offer new potential treatments for SARS-CoV-2 with the goal of developing a broad-acting anti-coronavirus agent.

Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is a severe disease in older adults and in individuals with associated comorbidities such as diabetes mellitus. Patients with diabetes infected with SARS-CoV-2 are more likely to develop severe pneumonia, hospitalization, and mortality compared with infected non-diabetic patients. During diabetes, hyperglycemia contributes to the maintenance of a low-grade inflammatory state which has been implicated in the microvascular and macrovascular complications associated with this pathology. The receptor for advanced glycation end products (RAGE) is a multi-ligand pattern recognition receptor, expressed on a wide variety of cells, which participates as an important mediator of inflammatory responses in many diseases, including lung diseases. This review highlights the role of RAGE in the pathophysiology of COVID-19 with special emphasis on diabetic patients. These data could explain the severity of the disease, positioning it as a key therapeutic target in the clinical management of this infection.

The extensive spread of Coronavirus disease 2019 (COVID-19) worldwide has caused a dramatic negative impact on many individuals' health. This study aims to systematically and comprehensively analyze the current status and possible future directions of diabetes mellitus (DM) and COVID-19 research.

We obtained publications about COVID-19 and DM from the Web of Science Core Collection (WoSCC) using the search terms "COVID-19″ and similar terms combined with "DM" and similar terms, with a date range of January 2020 to May 2024. And we used CiteSpace V 6.3.R2 to perform the bibliometric visualization analysis.

The search enrolled 6266 publications. The USA is a country with the most publications; Harvard University was the most productive institution in this field. The highest-ranked journal was the PLOS ONE, and the most cited journal was Lancet. The 20 most cited journals have all been cited 28754 times, accounting for 28 % of the total cites; the range of those journals was 790-3197. Publications on COVID-19 and DM research exhibited a distinct trajectory, shifting from an initial emphasis on understanding the impact of diabetes on COVID-19 infection and its associated pathophysiological mechanisms to a focus on analyzing the differential responses of diverse patient populations. Subsequently, research has progressed to examine the effects of medications and vaccines, as well as the long-term consequences of COVID-19 in diabetic individuals. Throughout this research endeavor, the exploration of diverse therapeutic interventions, their efficacy, and ultimate outcomes have consistently remained a paramount focus. And " metabolic syndrome," " long COVID," and " gestational diabetes" are still likely to be the hotspots and frontiers of research in the future.

This bibliometric analysis related to DM in COVID-19 illuminates the current research situation and developmental trends, supporting researchers in the exploration of prospective directions for research.

This comprehensive review articulates critical insights into the nexus of environmental stressors and their health impacts across diverse species, underscoring significant findings that reveal profound effects on both wildlife and human health systems. Central to our examination is the role of pollutants, climate variables, and pathogens in contributing to complex disease dynamics and physiological disruptions, with particular emphasis on immune and endocrine functions. This research brings to light emerging evidence on the severe implications of environmental pressures on a variety of taxa, including predatory mammals, raptorial birds, seabirds, fish, and humans, which are pivotal as indicators of broader ecosystem health and stability. We delve into the nuanced interplay between environmental degradation and zoonotic diseases, highlighting novel intersections that pose significant risks to biodiversity and human populations. The review critically evaluates current methodologies and advances in understanding the morphological, histopathological, and biochemical responses of these organisms to environmental stressors. We discuss the implications of our findings for conservation strategies, advocating for a more integrated approach that incorporates the dynamics of zoonoses and pollution control. This synthesis not only contributes to the academic discourse but also aims to influence policy by aligning with the Global Goals for Sustainable Development. It underscores the urgent need for sustainable interactions between humans and their environments, which are critical for preserving biodiversity and ensuring global health security. By presenting a detailed analysis of the interdependencies between environmental stressors and biological health, this review highlights significant gaps in current research and provides a foundation for future studies aimed at mitigating these pressing issues. Our study is significant as it proposes integrative and actionable strategies to address the challenges at the intersection of environmental change and public health, marking a crucial step forward in planetary health science.

Since the onset of the COVID-19 pandemic, the SARS-CoV-2 virus has caused over 600 million confirmed infections and more than 6.8 million deaths worldwide, with ongoing implications for human health. COVID-19 has been extensively documented to have extrapulmonary manifestations due to the widespread expression of necessary ACE2 receptors in the human body. Nevertheless, the association between COVID-19 and cancer risk remains inadequately explored. This study employs Mendelian randomization (MR) methods to examine the causal relationship between genetic variations associated with COVID-19 and the risk of developing cancer. The findings indicate that COVID-19 has negligible impact on most cancer risks. Interestingly, a higher COVID-19 impact is associated with a decreased risk of thyroid cancer. In summary, our findings demonstrate a genetic correlation between COVID-19 and thyroid cancer, contributing to our understanding of the interplay between COVID-19 and cancer risk.

To systematically evaluate potential risk factors for tracheal stenosis and to provide a reference for the prevention and management of patients with this condition.

Databases were searched to identify studies of the risk factors for tracheal stenosis, from their inception to October 2023, then a meta-analysis was performed. The study was registered with PROSPERO under the registration number CRD42023428906.

Ten studies of a total of 2525 patients were included. The meta-analysis showed that tracheotomy, diabetes, the duration of intubation, the duration of mechanical ventilation, respiratory tract infection, a high incision, and a ratio of intratracheal tube cuff diameter (C)/transverse diameter at the level of the clavicle (T) >150% were risk factors for the development of tracheal stenosis.

Measures such as shortening the duration of mechanical ventilation and intubation, reducing and avoiding tracheotomy after prolonged intubation, early tracheotomy in patients with obesity who require prolonged mechanical ventilation, appropriate choices of incision location and catheter, the maintenance of appropriate C/T, the prevention of respiratory infection, and the control of diabetes mellitus should limit the risk of tracheal stenosis.

Post-Covid-19 syndrome is defined as non-self-sustaining signs and/or symptoms lasting more than 12 weeks, occurring during or after a Covid-19 infection. The primary outcome was the analysis of the respiratory muscle training (RMT) result in respiratory muscle strength, (maximum inspiratory pressure (MIP) e maximum expiratory pressure (MEP)); and the secondary results were the analysis of lung function, dyspnea, quality of life (QoL), fatigue and functional performance.

The PICO description for this research was: P: patients diagnosed with post-Covid-19; I: RMT; C: Sham or simulated inspiratory or expiratory muscle training and usual care; O: MIP, MEP, Lung Function, level of dyspnea, QoL and functional performance. On January 15, 2024, the following databases were consulted: PubMed, Lilacs, Cochrane Library, PEDro and EMBASE. Randomized clinical trials were included without restrictions on year of publication or language. The data selection and extraction steps were carried out by two independent reviewers.

The search in the databases resulted in a total of 14,216 studies, and after the eligibility process, 7 studies were included with a sample of 527 patients. The MIP results suffered a statistically significant increase, that is, the RMT was favorable to improve the MIP (MD = 29.55cmH2O IC 95%: 7.56cmH2O to 51.54cmH2O, p = 0,00001). For the MEP outcome, the results were statistically significant in favor of RMT (MD = 10.93cmH2O CI 95%: 3.65cmH2O to 18.21cmH2O, p = 0.00001). We also noticed a significant improvement for the group that received the RMT in the distance covered in the 6-Minute Walk Test (6MWT) MD = 40.70 m CI 95%: 18.23 m to 65.17 m%, p = 0.01).

We noticed that RMT is being used in patients with respiratory diseases, including post-Covid-19. Our systematic review observed that this training provides an increase in inspiratory and expiratory muscle strength, a reduction in dyspnea levels, and an increase in the distance covered in the 6MWT and improved QoL in post-covid patients after intervention.

The adult mammalian heart contains a large population of pericytes that play important roles in homeostasis and disease. In the normal heart, pericytes regulate microvascular permeability and flow. Myocardial diseases are associated with marked alterations in pericyte phenotype and function. This review manuscript discusses the role of pericytes in cardiac homeostasis and disease. Following myocardial infarction (MI), cardiac pericytes participate in all phases of cardiac repair. During the inflammatory phase, pericytes may secrete cytokines and chemokines and may regulate leukocyte trafficking, through formation of intercellular gaps that serve as exit points for inflammatory cells. Moreover, pericyte contraction induces microvascular constriction, contributing to the pathogenesis of 'no-reflow' in ischemia and reperfusion. During the proliferative phase, pericytes are activated by growth factors, such as transforming growth factor (TGF)-β and contribute to fibrosis, predominantly through secretion of fibrogenic mediators. A fraction of pericytes acquires fibroblast identity but contributes only to a small percentage of infarct fibroblasts and myofibroblasts. As the scar matures, pericytes form a coat around infarct neovessels, promoting stabilization of the vasculature. Pericytes may also be involved in the pathogenesis of chronic heart failure, by regulating inflammation, fibrosis, angiogenesis and myocardial perfusion. Pericytes are also important targets of viral infections (such as SARS-CoV2) and may be implicated in the pathogenesis of cardiac complications of COVID19. Considering their role in myocardial inflammation, fibrosis and angiogenesis, pericytes may be promising therapeutic targets in myocardial disease.

Coronavirus disease 2019 (COVID-19) has claimed millions of lives since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and lung disease appears the primary cause of death in COVID-19 patients. However, the underlying mechanisms of COVID-19 pathogenesis remain elusive, and there is no existing model where human disease can be faithfully recapitulated and conditions for the infection process can be experimentally controlled. Herein we report the establishment of an ex vivo human precision-cut lung slice (hPCLS) platform for studying SARS-CoV-2 pathogenicity and innate immune responses, and for evaluating the efficacy of antiviral drugs against SARS-CoV-2. We show that while SARS-CoV-2 continued to replicate during the course of infection of hPCLS, infectious virus production peaked within 2 days, and rapidly declined thereafter. Although most proinflammatory cytokines examined were induced by SARS-CoV-2 infection, the degree of induction and types of cytokines varied significantly among hPCLS from individual donors. Two cytokines in particular, IP-10 and IL-8, were highly and consistently induced, suggesting a role in the pathogenesis of COVID-19. Histopathological examination revealed focal cytopathic effects late in the infection. Transcriptomic and proteomic analyses identified molecular signatures and cellular pathways that are largely consistent with the progression of COVID-19 in patients. Furthermore, we show that homoharringtonine, a natural plant alkaloid derived from Cephalotoxus fortunei, not only inhibited virus replication but also production of pro-inflammatory cytokines, and thus ameliorated the histopathological changes caused by SARS-CoV-2 infection, demonstrating the usefulness of the hPCLS platform for evaluating antiviral drugs.

Here, established an ex vivo human precision-cut lung slice platform for assessing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, viral replication kinetics, innate immune response, disease progression, and antiviral drugs. Using this platform, we identified early induction of specific cytokines, especially IP-10 and IL-8, as potential predictors for severe coronavirus disease 2019 (COVID-19), and uncovered a hitherto unrecognized phenomenon that while infectious virus disappears at late times of infection, viral RNA persists and lung histopathology commences. This finding may have important clinical implications for both acute and post-acute sequelae of COVID-19. This platform recapitulates some of the characteristics of lung disease observed in severe COVID-19 patients and is therefore a useful platform for understanding mechanisms of SARS-CoV-2 pathogenesis and for evaluating the efficacy of antiviral drugs.

To evaluate the influence of previous physical activity (PA) during childhood, adolescence, and current PA practice on the production of antibodies and inflammatory response between the first and second doses of the COVID-19 vaccine.

Fifty-nine men and 56 women were evaluated before the first vaccine, and 12 weeks later, blood samples were taken to quantify production of anti-severe acute respiratory syndrome coronavirus-2 immunoglobulin G antibodies and cytokines. Previous PA during childhood and adolescence was self-referred, and current PA was assessed using the International Physical Activity Questionnaire.

A positive and significant association was observed only between PA practice during adolescence and an increase in antibody production in adulthood (β = 2012.077, 95% confidence interval, 257.7953-3766.358, P = .025). Individuals who practiced PA during adolescence showed higher production of antibodies between the first and second vaccine dose compared to nonpractitioners (P = .025) and those that accumulated ≥150 minutes per week of current moderate-vigorous PA (MVPA), and presented higher antibody production in relation to who did <150 minutes per week of MVPA (P = .046). Individuals that were practitioners during childhood produced higher G-CSF (P = .047), and those that accumulated ≥150 minutes per week of current MVPA demonstrated lower IP-10 levels (P = .033). However, PA practitioners during adolescence presented higher G-CSF (P = .025), IL-17 (P = .038), IL-1RA (P = .005), IL-1β (P = .020), and IL-2 (P = .026) levels.

Our results suggest that adults that accumulated at least 150 minutes of MVPA per week or practiced PA during adolescence developed an improved immune and inflammatory response against COVID-19 vaccination.

Coronavirus disease 2019 (COVID-19), caused by the highly pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), primarily impacts the respiratory tract and can lead to severe outcomes such as acute respiratory distress syndrome, multiple organ failure, and death. Despite extensive studies on the pathogenicity of SARS-CoV-2, its impact on the hepatobiliary system remains unclear. While liver injury is commonly indicated by reduced albumin and elevated bilirubin and transaminase levels, the exact source of this damage is not fully understood. Proposed mechanisms for injury include direct cytotoxicity, collateral damage from inflammation, drug-induced liver injury, and ischemia/hypoxia. However, evidence often relies on blood tests with liver enzyme abnormalities. In this comprehensive review, we focused solely on the different histopathological manifestations of liver injury in COVID-19 patients, drawing from liver biopsies, complete autopsies, and in vitro liver analyses. We present evidence of the direct impact of SARS-CoV-2 on the liver, substantiated by in vitro observations of viral entry mechanisms and the actual presence of viral particles in liver samples resulting in a variety of cellular changes, including mitochondrial swelling, endoplasmic reticulum dilatation, and hepatocyte apoptosis. Additionally, we describe the diverse liver pathology observed during COVID-19 infection, encompassing necrosis, steatosis, cholestasis, and lobular inflammation. We also discuss the emergence of long-term complications, notably COVID-19-related secondary sclerosing cholangitis. Recognizing the histopathological liver changes occurring during COVID-19 infection is pivotal for improving patient recovery and guiding decision-making.

Early stages of deadly respiratory diseases including COVID-19 are challenging to elucidate in humans. Here, we define cellular tropism and transcriptomic effects of SARS-CoV-2 virus by productively infecting healthy human lung tissue and using scRNA-seq to reconstruct the transcriptional program in "infection pseudotime" for individual lung cell types. SARS-CoV-2 predominantly infected activated interstitial macrophages (IMs), which can accumulate thousands of viral RNA molecules, taking over 60% of the cell transcriptome and forming dense viral RNA bodies while inducing host profibrotic (TGFB1, SPP1) and inflammatory (early interferon response, CCL2/7/8/13, CXCL10, and IL6/10) programs and destroying host cell architecture. Infected alveolar macrophages (AMs) showed none of these extreme responses. Spike-dependent viral entry into AMs used ACE2 and Sialoadhesin/CD169, whereas IM entry used DC-SIGN/CD209. These results identify activated IMs as a prominent site of viral takeover, the focus of inflammation and fibrosis, and suggest targeting CD209 to prevent early pathology in COVID-19 pneumonia. This approach can be generalized to any human lung infection and to evaluate therapeutics.