Association of specific ACE2 and TMPRSS2 variants with circulatory cytokines of COVID-19 Emirati patients.

Introduction: The COVID-19 pandemic represented one of the most significant challenges to researchers and healthcare providers. Several factors determine the disease severity, whereas none alone can explain the tremendous variability. The Single nucleotide variants (SNVs) in angiotensin-converting enzyme-2 (ACE2) and transmembrane serine protease type-2 (TMPRSS2) genes affect the virus entry and are considered possible risk factors for COVID-19. Methods: We compiled a panel of gene variants from both genes and used in-silico analysis to predict their significance. We performed biological validation to assess their capacity to alter the ACE2 interaction with the virus spike protein. Subsequently, we conducted a retrospective comparative genome analysis on those variants in the Emirati patients with different disease severity (total of 96) along with 69 healthy control subjects. Results: Our results showed that the Emirati population lacks the variants that were previously reported as associated with disease severity, whereas a new variant in ACE2 "Chr X:g.15584534" was associated with disease severity specifically among female patients. In-silico analysis revealed that the new variant can determine the ACE2 gene transcription. Several cytokines (GM-CSF and IL-6) and chemokines (MCP-1/CCL2, IL-8/CXCL8, and IP-10/CXCL10) were markedly increased in COVID-19 patients with a significant correlation with disease severity. The newly reported genetic variant of ACE2 showed a positive correlation with CD40L, IL-1ß, IL-2, IL-15, and IL-17A in COVID-19 patients. Conclusion: Whereas COVID-19 represents now a past pandemic, our study underscores the importance of genetic factors specific to a population, which can influence both the susceptibility to viral infections and the level of severity; subsequently expected required preparedness in different areas of the world.

Temporal dynamics and genomic programming of plasma cell fates.

Affinity-matured plasma cells (PCs) of varying lifespans are generated through a germinal center (GC) response. The developmental dynamics and genomic programs of antigen-specific PC precursors remain to be elucidated. Here, using a model antigen in mice, we demonstrate biphasic generation of PC precursors, with those generating long-lived bone marrow PCs preferentially produced in the late phase of GC response. Clonal tracing using single-cell RNA sequencing and B cell antigen receptor sequencing in spleen and bone marrow compartments, coupled with adoptive transfer experiments, reveals a new PC transition state that gives rise to functionally competent PC precursors. The latter undergo clonal expansion, dependent on inducible expression of TIGIT. We propose a model for the proliferation and programming of precursors of long-lived PCs, based on extended antigen encounters in the GC.

Dermatomyositis Flare-Up Following the SARS-CoV-2 Vaccine: A Case Report and Literature Review.

Dermatomyositis is a rare auto-immune inflammatory myopathy of unknown etiology. Several environmental factors, including vaccines, have been identified as potential triggers in genetically susceptible individuals. Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, the development of vaccines (mRNA and vector-based) has been the most effective tool in reducing the incidence, hospitalization rates, and mortality of COVID-19. However, among individuals with immune dysregulation and auto-immune conditions, unique challenges may arise with immune stimulation. We present a case of a dermatomyositis flare-up following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. A 40-year-old Hispanic female presented to the emergency department with shortness of breath, muscle pain and weakness, and skin rash for two days. She had been recently diagnosed with dermatomyositis six months prior based on clinical presentation, laboratory investigations, and characteristic muscle biopsy findings. She had been on treatment with mycophenolate mofetil, prednisone, and hydroxychloroquine since. She reported receiving the second dose of the BNT162b2 COVID-19 vaccine one day prior to the onset of symptoms. Physical examination revealed erythematous plaques over her cheeks, upper chest, and arms, in addition to Gottron papules on her hands. She had reduced proximal muscle strength and scattered dry crackles bilaterally on lung auscultation. Her laboratory investigations were remarkable for elevated erythrocyte sedimentation rate, C-reactive peptide, creatinine kinase, and troponin T. The SARS- CoV-2 PCR test was negative. CT scan of the chest showed evidence of pneumonitis. A diagnosis of the dermatomyositis flare-up potentially secondary to the SARS-CoV-2 BNT162b2 vaccine was established. The patient was admitted and treated with pulse steroids and intravenous immunoglobulin. She responded well to therapy and was discharged home four days later. There have been several reports of a new onset of dermatomyositis following the SARS-CoV-2 vaccine which highlights the need for further large-scale studies to estimate the prevalence of such adverse effects. The benefits of the SARS-CoV-2 vaccine outweigh the risks even among patients with auto-immune and rheumatologic conditions; however, it is important for clinicians to recognize the possibility of occurrence of such events in order to manage patients appropriately.

Agenesis of the Intrahepatic Inferior Vena Cava: A Case Report and Literature Review.

Anomalies of the inferior vena cava (IVC) are an uncommon finding in the general population. A wide range of IVC anomalies has been described in the literature, the majority of which lack clinical significance. Agenesis of the IVC (AIVC) is a rare anomaly of the IVC in the general population. This anomaly may involve either complete agenesis of the IVC or agenesis of a segment of the IVC. Agenesis of the suprarenal segment is the most commonly occurring variant, while agenesis of the infrarenal and hepatic segments is less common. Here we report a case of agenesis of the intrahepatic segment of the IVC.

March of the Eosinophils: A Case of Eosinophilic Gastroenteritis, Immune Thrombocytopenia, and Iron Deficiency Anemia.

Eosinophilic gastrointestinal disorders (EGIDs) refer to eosinophilic infiltration of various sections of the gastrointestinal tract in the absence of secondary causes. Diagnosis of EGID requires histological evidence of eosinophilic infiltration of the GI tract. Here, we present a case of a young male with biopsy-proven eosinophilic gastroenteritis with a concomitant established diagnosis of immune thrombocytopenic purpura (ITP).  Presently, EGIDs remain an underexplored clinical entity. While its pathophysiology is not fully understood at this time, TH2 mediated activation of B-cells and subsequent stimulation of eosinophils locally appears to be at play. This is in contrast to the TH1 predominant cytokine profile underlying ITP, which this patient also has. Treatment typically involves dietary modifications and glucocorticoids.

Boerhaave Syndrome: A Report of Two Cases and Literature Review.

Boerhaave's syndrome is a rare yet serious condition associated with high mortality and morbidity. Diagnosis of this syndrome is usually done with the aid of imaging and prompt management should be initiated to improve the outcomes. Treatment for this syndrome has been mainly surgical since its discovery by Herman Boerhaave; however, multiple endoscopic approaches have been successfully used recently with the advancement of this field. Here, we describe two cases of Boerhaave's syndrome that were endoscopically managed along with a brief literature review of the different endoscopic methods used to manage this syndrome.

Autonomous spheroid formation by culture plate compartmentation.

Scaffold-free 3D cell cultures (e.g. pellet cultures) are widely used in medical science, including cartilage regeneration. Their drawbacks are high time/reagent consumption and lack of early readout parameters. While optimisation was achieved by automation or simplified spheroid generation, most culture systems remain expensive or require tedious procedures. The aim of this study was to establish a system for resource efficient spheroid generation with additional early readout parameters. This was achieved by a new approach for spheroid generation via self-assembly from monolayer via compartmentation of cell culture surfaces utilising laser engraving (grid plates). The compartmentation triggered contraction and rolling up of the cell monolayer, finishing in condensation into a spheroid in human adipose-derived stem cell (ASC/TERT1) and human articular chondrocytes (hACs)-ASC/TERT1 co-cultures, when cultivated on grid plates under chondrogenic conditions. Plates with 1 and 3 mm grid size yielded stable diameters (about 140µm and 300µm, respectively). ASC/TERT1 spheroids fully formed within 3 weeks while co-cultures took 1-2 weeks, forming significantly faster with increasing hAC ratio (p< 0.05 and 0.01 for 1:1 and 1:4 ASC/TERT1:hAC ratio, respectively). Co-cultures showed slightly lower spheroid diameters, due to earlier spheroid formation and incomplete monolayer formation. However, this was associated with a more homogeneous matrix distribution in the co-culture. Both showed differentiation capacity comparable to standard pellet culture in (immune-)histochemistry and RT-qPCR. To assess usability for cartilage repair, spheroids were embedded into a hydrogel (fibrin), yielding cellular outgrowth and matrix deposition, which was especially pronounced in co-cultures. The herein presented novel cell culture system is not only a promising tool for autonomous spheroid generation with the potential of experimental and clinical application in tissue engineering, but also for the generation of 'building blocks' for subsequential biofabrication strategies such as bioprinting.

Synergic Interactions Between Hepatic Stellate Cells and Uveal Melanoma in Metastatic Growth.

Uveal melanoma (UM) is a malignant intraocular tumor that spreads to the liver in half of the cases. Since hepatic cells could play a role in the therapeutic resistance of metastatic UM, the purpose of our study was to investigate the pro-invasive role of hepatic stellate cells (HSteCs) in metastatic UM at the micro- and macro-metastatic stages. We first performed an immunostaining with the alpha-smooth muscle actin (αSMA) to localize activated HSteCs in UM liver macro-metastases from four patients. Their accumulation of collagen was assessed with Masson's Trichrome stain. Next, we inoculated metastatic UM cells alone or with human HSteCs in triple-immunodeficient mice, in order to determine if HSteCs are recruited as early as the micro-metastatic stage. The growth of metastatic foci was imaged in the liver by ex vivo fluorescence imaging. Histological analyses were performed with Masson's Trichrome and Picrosirius Red stains, and antibodies against Melan-A and αSMA. The collagen content was measured in xenografts by quantitative polarization microscopy. In patient hepatectomy samples, activated HSteCs and their pathological matrix were localized surrounding the malignant lesions. In the mouse xenograft model, the number of hepatic metastases was increased when human HSteCs were co-inoculated. Histological analyses revealed a significant recruitment of HSteCs near the micro/macrolesions, and an increase in fibrillar collagen production. Our results show that HSteCs can provide a permissive microenvironment and might increase the therapeutic resistance of metastatic UM.

Intensity of care and withdrawal of life-sustaining therapies in severe traumatic brain injury patients: a post-hoc analysis of a multicentre retrospective cohort study.

PURPOSE: The intensity of care provided to critically ill patients has been shown to be associated with mortality. In patients with traumatic brain injury (TBI), specialized neurocritical care is often required, but whether it affects clinically significant outcomes is unknown. We aimed to determine the association of the intensity of care on mortality and the incidence of withdrawal of life-sustaining therapies in critically ill patients with severe TBI. METHODS: We conducted a post hoc analysis of a multicentre retrospective cohort study of critically ill adult patients with severe TBI. We defined the intensity of care as a daily cumulative sum of interventions during the intensive care unit stay. Our outcome measures were all-cause hospital mortality and the incidence of withdrawal of life-sustaining therapies. RESULTS: Seven hundred sixteen severe TBI patients were included in our study. Most were male (77%) with a mean (standard deviation) age of 42 (20.5) yr and a median [interquartile range] Glasgow Coma Scale score of 3 [3-6]. Our results showed an association between the intensity of care and mortality (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.63 to 0.74) and the incidence of withdrawal of life-sustaining therapy (HR, 0.73; 95% CI, 0.67 to 0.79). CONCLUSION: In general, more intense care was associated with fewer deaths and a lower incidence of withdrawal of life-sustaining therapies in critically ill patients with severe TBI.