Covid-19: Is the placenta a safe space

Problem: Several large studies have demonstrated that COVID-19 pregnant individuals are at a significant risk for severe disease and adverse pregnancy outcomes. The mechanisms underlying these phenomena remain to be elucidated and are the focus of our project. Although fetal and placental infection is rare, placental abnormalities and adverse pregnancy outcomes associated with placental dysfunction in COVID-19 cases have been widely reported. In particular, placental thrombosis and lesions consistent with maternal vascular malperfusion (MVM) of the placenta are common in individuals with COVID-19. Since thrombotic complications have been associated with COVID-19, it is not surprising that pregnant individuals with COVID- 19 are at risk for placental thrombosis. Method of Study: Placentas were evaluated histologically. Extracellular vesicles were isolated by serial centrifugation. Result(s): Adverse pregnancy outcomes associated with these placental lesions, including hypertensive disorders of pregnancy (gestational hypertension and preeclampsia), small for gestational age (SGA, birthweight < 10th percentile for gestational age), and preterm birth (PTB, < 37 weeks) are significantly increased among pregnant individuals with COVID-19. Placental infection with SARSCoV- 2 is uncommon, but multiple inflammatory and metabolic factors are likely to affect the placenta, including circulating extracellular vesicles (EVs) derived from various organs that have been associated with COVID-19 pathology and disease severity.We have analyzed over 500 placentas from COVID-19 pregnancies and found marked changes in placental morphology, characterized by abnormal maternal and fetal vessels, intervillous thrombi, and fibrin deposition, even in the face of mild or asymptomatic disease. We detected increased levels of small EVs in maternal serum from COVID-19 cases compared to controls and increased levels of mitochondrial DNA in EVs from COVID-19 cases. In in vitro experiments, we found increased oxidative stress in uterine endothelial cells and primary trophoblasts. Syncytialization of trophoblast cells following exposure to EVs from pregnant COVID-19 patients was markedly reduced. RNAseq of trophoblast cells exposed to EVs from pregnant COVID-19 patients revealed disruption of multiple pathways related to mitochondria function, oxidative stress, coagulation defects, and inflammation. Timing of infection during pregnancy (first, second, and third trimester) altered EV size distribution, cargo content, and functional consequences of trophoblast EV exposure. Conclusion(s): Our studies show that COVID-19 infection during pregnancy has profound effects on placenta morphology and function. It remains to be determined what the long-term consequences are on the offspring.

Outcome of COVID-19 on Indian patients with cancer: A multicenter, retrospective study

Background: Managing patients with cancer during the coronavirus disease 2019 (COVID-19) pandemic has been challenging. Disruptions in cancer management have been observed due to cancellation of treatment, issues related to commuting, and dearth of health-care workers. Objective(s): This study was conducted during the first wave of the COVID-19 pandemic and was aimed at evaluating the 30-day all-cause mortality among patients with cancer and COVID-19 infection and the factors affecting it. Material(s) and Method(s): In this retrospective study, we collected secondary data from nine tertiary care centers in South India over a period of 10 months from March to Dec 2020. Patients across all age groups with histopathologically confirmed diagnosis of cancer who were affected by COVID-19 during their evaluation or treatment were included in the study. The primary outcome variables of the present study were 30-day all-cause mortality, cancer outcomes, and COVID-19 outcomes. Result(s): A total of 206 patients were included. Median age of the cohort was 55.5 years, and the male-To-female ratio was 1:1.03. The 30-day mortality rate was 12.6%. Twenty-Two patients (10.7%) had severe COVID-19 infection at the initial presentation. Predictors for severe pneumonia at the initial presentation were incomplete remission at the time of COVID-19 diagnosis and palliative intent of treatment. Severe pneumonia at the initial presentation, diagnosis of COVID-19 on or before August 2020, and need for ventilator support were associated with increased mortality. Conclusion(s): Severity of infection at the initial presentation, cancer status, and the intent of cancer treatment impact COVID-19 outcomes in patients with cancer.Copyright © 2022 Iranian Society of Ophthalmology. All rights reserved.

Determination of the Effects of Prenatal Remdesivir Exposure on Placenta Morphology, Placental IgG Transfer, and Fetal Growth in a Humanized Mouse Model

Remdesivir (RDV) is an antiviral medication used most recently for the treatment of COVID-19. Although no adverse effects were observed on perinatal parameters in reproductive and development toxicology studies at doses up to four-fold clinical area under the curve (AUC) exposures, some researchers have reported that therapeutic levels of RDV may impair early embryogenesis, as observed by in vitro studies. In addition, the influence of prenatal RDV exposure on maternal IgG transfer in the placenta is still unknown. Administration of RDV in pregnant humanized mouse model (Tg32), which expresses the human Fc gamma receptor and transporter (FCGRT) gene, was used to further evaluate potential effects on IgG transfer and concurrent perinatal endpoints. Animals were dosed daily from gestational days (GDs) 10- 14 with 25 mg/kg RDV (GS-5734) via intravenous injection (n=3-5 per group). Concurrent vehicle control animals were dosed intravenously with 12% sulfobutyl ether- beta-cyclodextrin in water (pH3.5;NaOH/HCl). All animals were administered 2 mg/kg human IgG via intravenous injection on GD 14. Placentae and fetuses were collected from dams on GD 14, 15, 16, and 18 and evaluated using histopathology and qPCR for inflammation markers. No abnormal morphologies (necrosis/apoptosis) of placentae were observed between the concurrent control and RDVdosed groups. Additionally, no differences in maternal body weights were observed. There were no statistically significant differences in placenta weights. There were no statistically significant changes in pregnancy parameters (implantation sites and dead fetuses/litter) and fetal weights between the RDV-dosed group and concurrent controls at GD 14, 15, 16, and 18. No changes were observed in transcript levels of inflammation markers in the RDV-dosed group when compared to the concurrent control group. There was a slightly lower ratio of fetal IgG level to maternal IgG levels in the RDV-dosed group;however, no statistically significant differences were observed between the RDV-dosed group and concurrent controls on GD 14, 15, 16, and 18. Our results suggest that a daily dose of 25 mg/kg RDV on GDs 10-14 in humanized mice did not cause adverse effects on placenta and fetal development. (Funded by the Perinatal Health Center of Excellence: E0300201.).

Correlation of Diagnostic Yield with Laboratory Parameters and Histopathological Examination in Clinically Suspected Cases of Mucormycosis in Post-COVID-19 Patients: A SingleCenter Study in Ahmedabad, India

Background and objectives: Mucormycosis is a complication in post-coronavirus disease 2019 (COVID-19) patients in India. This study was done to evaluate the prognostic value of clinical, histopathologic findings, microbiological features, and biochemical parameters such as D-dimer, lactate dehydrogenase, and serum ferritin in post- COVID-19-patients with rhino-orbital mucormycosis. Methods: This retrospective observational study was carried out on biopsies taken from 50 post-COVID-19 patients suspected of mucormycosis. The biopsy specimens were processed and stained with hematoxylin and eosin, periodic acid– schiff, and Wright-Giemsa. In addition, 10–20% potassium hydroxide wet mount and culture on sabouraud dextrose agar were performed to detect Mucor. The biochemical parameters were measured using ARCHITECT ci8200 chemistry analyzer. Results: Overall, 30 cases (60%) were positive for fungal elements, and growth of Mucor spp. was found in 28 cases (56%). In histopathology, 70% of cases (n=35) showed broad, aseptate, ribbon-like hyphae with wide-angled branching diagnostic of mucormycosis. There seemed to be a site-wise overlap between the nasal/maxillary sinus and rhinoorbital/rhino-cerebral variety. There was no difference between the patients in terms of gender. The most common risk factor was diabetes mellitus (observed in 80% of cases). In patients with invasive mucormycosis, inflammatory biomarkers such as serum ferritin, serum lactate dehydrogenase, C-reactive protein, and Ddimer were greater than the normal range, whereas procalcitonin was within the reference range. Conclusion: It can be concluded that raised metabolic markers, direct 10% KOH examination and histological features including angioinvasion as well as rhino-orbital and cerebral extension might assist doctors in diagnosis, progression, and survival rate. [ FROM AUTHOR] Copyright of Medical Laboratory Journal is the property of Golestan University of Medical Sciences, Deputy of Research & Technology and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

A retrospective observational study of CAR T-cell therapy outcomes-Experience from MSE Foundation Trust

The most common non-Hodgkin's lymphoma (NHL) is diffuse large B-cell lymphoma (DLBCL), an aggressive lymphoma that can be cured with standard frontline chemo-immunotherapy in 60%-70% of patients but with historically poor outcomes for relapsed/refractory disease. Patients with relapsed DLBCL after autologous stem cell transplant (ASCT) or with chemotherapy-refractory disease have a particularly dismal prognosis, with a median overall survival (OS) of only 6 months. Chimeric antigen receptor (CAR) T-cell therapy has significantly improved outcomes for patients with relapsed/refractory large B-cell lymphoma, mantle cell lymphoma and follicular lymphoma, with multiple FDA approved CAR T products now commercially available in many developed world including European countries. Ongoing studies seek to move CAR T cells to earlier lines of therapy and to characterise the efficacy and safety of CAR T-cell approaches in additional lymphoma histologies including relapsed/refractory follicular lymphoma and chronic lymphocytic leukaemias. Other areas of active research address CAR T in combination with other lymphoma-directed therapies, and mechanisms of CAR T resistance. We conducted a retrospective observational study assessing the outcomes of patients referred to our tertiary centre, University College London hospital NHS foundation Trust (UCLH) from January 2018 to December 2022, over a 48-month period. We collected data including patients' demographics, types of lymphomas, prior lines of therapies including stem cell transplantation, bridging therapies as appropriate, complications and overall response rate. We also analysed the communication between teams during the challenging period of the COVID-19 pandemic.

The Magnitude of Covid-19 Effect on Melanoma Diagnosis, Histopathologic Features and Stage of the Disease in University Hospital of Split

Introduction: Due to the COVID-19 pandemic, some planned medical activities have been postponed, for both national directives and out of concern of the patients who were afraid to go to hospitals. Skin cancers, especially melanomas, diagnosed during lockdown also differed from pre-lockdown tumors in several notable ways, such as number of newly diagnosed patients and histopathologic features. The primary tumor thickness (mm), ulceration (%), anatomic localization, and regional lymph node involvements are important elements for determining the melanoma staging and prognosis. Aim(s): The aim of this report was to investigate the difference in number of newly diagnosed melanoma patients, histopathological features and melanoma TNM-staging between comparable pre-pandemic (March 2019 until March 2020) and pandemic periods (March 2020 until March 2021). Method(s): We collected the data from hospital clinical and pathohistological databases on the total number of newly diagnosed patients with melanoma in University Hospital of Split. Comparative analyses were performed in a pre-pandemic and a pandemic cohort. Result(s): Comparing the first year of the pandemic (N=57) with the same period one year before (N=69), 17,4% decrease of melanoma cases was observed. Cohort analysis showed no differences in the distribution of age and sex. The median age of the melanoma patients in a pre-pandemic cohort was 66 years (29-86), and in pandemic cohort 68 years (31-88). The male gender predominated among melanoma patients. In a pre-pandemic cohort, 63,8% of melanoma patients were man, and in pandemic cohort 68,4%. Cohort analysis showed differences in the primary localization of skin melanoma. In pre-pandemic cohort, primary localization of melanoma were head and neck in 17 patients (25%), trunk in 26 patients (38%), upper extremities in 13 patients (19,1%), lower extremities in 10 patients (14.7%) and unknown primary site in 2 patients (2,9%). In pandemic cohort, primary localization of melanoma were head and neck in 10 patients (17,5%), trunk in 32 patients (56,1%), upper extremities in 8 patients (14%), lower extremities in 5 patients (8,8%) and unknown primary site in 2 patients (3,5%). Cohort analysis showed no differences in the pathohistological subtypes. The most common pathohistological subtypes in both cohorts were superficial spreading subtype (21,7% vs 25,8%), unclassified (21,7% vs 17,5%) and nodular subtype (14,5% vs 17,5%). In pandemic cohort we diagnosed patients with increased tumor thickness and positive lymph nodes. In pre-pandemic cohorts we had more patients with thickness less than 1 mm (40,6% vs 31,6%). We found more patients with tumor thickness between 1 to 2 mm (17,5% vs 4,3%) and more than 4 mm (25% vs 20%) in pandemic. Accordingly, in pandemic cohort we found more patients with positive lymph nodes then in pre-pandemic (22,9% vs 5,9%), and more patients with initially metastatic disease (22,8% vs 15,9%). We did not observed any differences in presence of ulceration among the studied cohorts (26% vs 28%). Conclusion(s): In the analysis conducted in University Hospital of Split, we observed a marked decrease of newly diagnosed melanoma patients in the first year of the pandemic compared to the same period before the pandemic. We observed increased tumor thickness, more patients with lymph nodes involvements and initially metastatic disease in post-lockdown period. These findings may be the result of delays in diagnosis due to the disruptions in routine dermatologic and oncologic care during Covid-19 pandemic. The further analyses are needed to fully understand the impact of the Covid-19 pandemic on melanoma outcomes.

Association of state-level COVID-19 mortality rates with real-world progression and real-world overall survival among patients with advanced non-small cell lung cancer, 2020-2022

Background: The COVID-19 pandemic impacted the delivery of cancer care and outcomes in the United States (US). We examined the association between time-varying state-level weekly COVID19 mortality and progression-free survival (rwPFS), time to progression (rwTTP), and survival (rwOS) among pts with advanced non-small cell lung cancer (advNSCLC). Method(s): This retrospective study used the nationwide Flatiron Health electronic health recordderived de-identified database. The cohort included community oncology pts diagnosed with advNSCLC between March 1, 2020 and December 31, 2021 (follow-up through March 30, 2022). We extracted US data on COVID-19 deaths from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University. We calculated state-level weekly COVID-19 death rates as weekly COVID-19 deaths per state population size from the 2019 American Community Survey. We categorized rates into quintiles based on all weekly rates during the observation period. Analyses were restricted to treated pts and indexed to start of first-line therapy. For rwPFS analyses, first occurrence of progression or death was considered an event, and pts were censored at last clinic note date. For rwTTP, only progression (not death) was considered an event, and pts with no event were censored at last clinic note date. For rwOS analyses, pts who did not die were censored at last structured activity. We used Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between weekly time-varying state-level COVID-19 mortality rates and outcomes of rwPFS, rwTTP, and rwOS, adjusted for age at diagnosis, race/ethnicity, and state. Result(s): Among 7,813 advNSCLC pts, the median age at diagnosis was 70 years, the majority of the cohort was non-Hispanic White (59%), had non-squamous cell histology (68%) and a history of smoking (87%). Compared to pts living in states with the lowest quintile of COVID-19 mortality rates (Q1), pts living in states with the highest COVID-19 mortality (Q5) had worse rwOS (Q5 vs. Q1: HR 1.46, 95% CI 1.26-1.69) and rwPFS (Q5 vs. Q1: HR 1.18, 95% CI 1.05-1.33). No association was observed with rwTTP (Q5 vs. Q1: HR 1.05, 95% CI 0.90-1.22). Conclusion(s): In this study of real-world oncology data, we demonstrated the use of publicly-available COVID-19 mortality data to measure the time-varying impact of COVID-19 severity on outcomes in pts with advNSCLC. Higher state-level COVID-19 mortality rates were associated with worse rwOS and rwPFS among advNSCLC pts. The association with increased mortality among pts with advNSCLC may be related to COVID-19-related mortality or other factors such as pre-existing comorbidities which were not explored in this study.

Pericytes may facilitate SARS-CoV-2 entry into the nervous system

Objective: Although the neurological and olfactory symptoms of coronavirus disease 2019 have been identified, the neurotropic properties of the causative virus, severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2), remain unknown. We sought to identify the susceptible cell types and potential routes of SARS-CoV-2 entry into the central nervous system, olfactory system, and respiratory system. Method(s): We collected single-cell RNA data from normal brain and nasal epithelium specimens, along with bronchial, tracheal, and lung specimens in public datasets. The susceptible cell types that express SARS-CoV-2 entry genes were identified using single-cell RNA sequencing and the expression of the key genes at protein levels was verified by immunohistochemistry. We compared the coexpression patterns of the entry receptor angiotensin-converting enzyme 2 (ACE2) and the spike protein priming enzyme transmembrane serine protease (TMPRSS)/cathepsin L among the specimens. Result(s): The SARS-CoV-2 entry receptor ACE2 and the spike protein priming enzyme TMPRSS/cathepsin L were coexpressed by pericytes in brain tissue;this coexpression was confirmed by immunohistochemistry. In the nasal epithelium, ciliated cells and sustentacular cells exhibited strong coexpression of ACE2 and TMPRSS. Neurons and glia in the brain and nasal epithelium did not exhibit coexpression of ACE2 and TMPRSS. However, coexpression was present in ciliated cells, vascular smooth muscle cells, and fibroblasts in tracheal tissue;ciliated cells and goblet cells in bronchial tissue;and alveolar epithelium type 1 cells, AT2 cells, and ciliated cells in lung tissue. Conclusion(s): Neurological symptoms in patients with coronavirus disease 2019 could be associated with SARS-CoV-2 invasion across the blood-brain barrier via pericytes. Additionally, SARS-CoV-2-induced olfactory disorders could be the result of localized cell damage in the nasal epithelium.Copyright © Wolters Kluwer Health, Inc. All rights reserved.

Chilblain lupus erythematosus associated with systemic lupus erythematosus: A classic diagnosis in a current epidemiological context

Objectives: Chilblain lupus erythematosus (LE) is a rare chronic cutaneous lupus erythematosus (CCLE) characterized by the appearance of violaceous plaques in acral regions most exposed to cold. The isolated form affects middle-aged women, while the familial form manifests in early childhood and is associated with mutations in the TREX1 gene. Result(s): A 13-year-old adolescent, with no relevant family history, was referred in March 2021 for suspected chilblain-like lesions associated with COVID-19 infection. The patient presented with multiple violaceous papules on hands and feet. The lesions were slightly painful. Small hyperkeratotic papules were also observed on finger pads. Physical examination also revealed some aphthae affecting the lips. No other systemic symptoms were reported. A skin biopsy and blood tests were performed due to presumed chilblain LE with probable systemic involvement. Histology revealed basal vacuolar damage and intense perivascular and periadnexal lymphocytic inflammatory dermal infiltrate. Remarkably, mucin was noted among the collagen bundles. Leukopenia and positive ANA antibodies (titre 1:320) were detected. Complement levels were normal. SARS-CoV2 infection was ruled out. Skin lesions disappeared within 1 month under topical corticosteroids. Hydroxychloroquine was afterwards started by Rheumatology without recurrence of skin symptoms until last follow-up. Discussion(s): We present an uncommon case of an adolescent with systemic LE presenting as chilblain LE. Chilblain LE can be accompanied by other discoid CCLE. It can progress to systemic LE in up to 20% of patients, especially when concomitant CCLE is present. This rare presentation of CCLE should be differentiated from typical chilblain and other resembling lesions, such as SARS-CoV2-associated chilblain and acral purpuric lesions (COVID toes). The Mayo Clinic diagnostic criteria can be helpful, particularly in this last SARS-CoV2 outbreak scenario, when the reporting of similar skin lesions has been significant.

Animal Pre-Clinical Study of an Inactivated SARS-CoV-2 Vaccine candidate (Osvid-19 ): Immunogenicity, Protective, and Safety Aspects

Background: This study aimed to evaluate the outcomes of preclinical studies on the safety and immunogenicity of an inactivated COVID-19 vaccine candidate to warrant further clinical evaluation. Method(s): SARS-CoV-2 positive nasopharyngeal swab specimens were confirmed by real-time polymerase chain reaction and next-generation sequencing. The safety and immunogenicity tests of the COVID-19 vaccine were carried out in rats and Rhesus monkeys, and Balb/C mice and Rhesus monkeys, respectively. Result(s): The candidate vaccine was well tolerated and induced promising levels of SARS-CoV-2- specific IgG1, IgG2a, and Granzyme B in Balb/C mice, and anti-SARS-CoV-2 spike IgG and neutralizing antibodies in Rhesus monkeys. Based on cVNT results, the inactivated vaccine in 0.5 and 1 microg/100 microL doses was able to induce a neutralizing effect against the SARS-CoV-2 virus up to a dilution of 1:512 and 1:1000. The protective efficacy of the vaccine candidate was challenged with 2 x108 PFU of live viruses and confirmed by lung CT scan and histopathological evaluations compared to the control group. Repeated intramuscular injection of the candidate vaccine was generally well-tolerated in Rats and Rhesuses. No significant side effects were observed in rats injected with ten full human doses and in the Rhesus monkeys with three full human doses. Conclusion(s): Based on the findings presented in this study, it is recommended that this vaccine be moved into human testing commencing with a phase I clinical trial.Copyright © 2021 Muslim OT et al.

Sonographer led one-stop neck lump clinic - 3 year review

A sonographer led one-stop neck lump clinic was introduced three years ago to support patient flow, improve two week wait times and provide quicker access to fine needle aspiration (FNA). The clinic was designed with a biomedical scientist support to provide immediate results regarding FNA adequacy. The objective of the audit was to provide an overview of the service and to identify any further areas of development. A retrospective audit was performed of all patients who attended the one-stop neck lump clinic within the 3-year period. CRIS records were used to obtain details of the scan type, any pathology identified, who performed the scan and whether FNA was performed. Histology of all FNAs was reviewed to form part of the final diagnosis and provide results on adequacy. Each 12-month period was reviewed and compared;special consideration was made to see if the service had been affected by COVID-19. Numbers attending the clinic over the 3-year period have remained similar with no impact due to COVID-19 other than the initial reduction in the first two weeks of the first 'lockdown'. The number of patients attending who had significant/malignant pathology also remained stable over the three years (approx. 20% of all attendees) although there seems to have been a shift with more thyroid pathology in year 3. The clinic was not significantly impacted by COVID-19 and is continuing to provide a good level of service to support the ENT team with quick access to FNA also enabling discharge of patients with benign findings at the same appointment.

Pandemic stress induces systemic immune changes and placental inflammation independently of SARS-CoV-2 infection in pregnancies

Problem: Environmental stress during pregnancy has known impacts on both maternal and fetal health. In terms of theCOVID-19 pandemic, the majority of published work has focused on the impact of the infection itself, without considering the potential immune impact of pandemic related-stress.We, therefore, assessed the impact of pandemic stress, independently of SARS-CoV-2 infection, on the circulating and placental immune profiles of pregnant individuals. Method(s): Placentas from 239 patients were collected at the Sainte- Justine Hospital, Montreal, Canada. Of these, 199 patients delivered during the pandemic and were exposed to pandemic stress with (+: 79) or without (-: 120) SARS-CoV-2 infection, the latter exposed to pandemic stress only. Pre-pandemic historic controls (uncomplicated pregnancies, Ctrl: 40), were also included. Placental biopsies were collected to assess cytokine levels by ELISAs and histopathological lesions. A sub-study with 35 pre-pandemic pregnancies (unexposed) and 20 who delivered during the pandemic (exposed) was also conducted. The latter (exposed/unexposed) were all uncomplicated pregnancies. We collected maternal blood prior to delivery for immunophenotyping, and plasma/peripheral blood mononuclear cells (PBMCs) were isolated. Inflammatory mediators in the plasma were quantified by ELISAs. Co-culture assays with PBMCs and human umbilical vein endothelial cells (HUVECs) were performed to assess endothelial activation. Demographical/obstetrical data were obtained through chart review. Result(s): SARS-CoV-2+ patients were multiethnic (63.4%), had higher pre-pregnancyBMI (28.9 vs. 24.8 inCtrl, P<.05), and elevated preterm birth rate (16.5% vs. 5.8% in SARS-CoV-2-, P < .05 and 0.0% in Ctrl, P < .01). In the placentas, we observed an increase in the levels of IL- 1Ra (P < .05) and CRP (P < .05) in both SARS-CoV-2 groups, while IL-6 (P = .0790) and MCP-1 (P < .001) were elevated solely in SARS-CoV- 2-. These changes were predominant in placentas with inflammatory lesions on histopathological analysis. Moreover, we observed elevated CD45+ cells (P < .001) in the placentas from both SARS-CoV-2 groups versus Ctrl. Considering that the differences we observed were important in the SARS-CoV-2- group, we performed a study solely on uncomplicated pregnancies, either exposed or unexposed to pandemic stress. At the systemic level, we observed a decrease in the percentage of Th2 cells (P < .001), leading to a pro-inflammatory Th1/Th2 imbalance in exposed individuals. Decreased Treg (P < .05) and Th17 (P < .05) versus unexposed was also observed. Surprisingly, decreased levels of circulating IL-6 (P < .05), MCP-1 (P < .01), and CRP (P<.05) were seen in exposed versus unexposed individuals. Finally,we observed increased secretion of ICAM, a marker of endothelial activation, solely in endothelial cells co-cultured with PBMCs from exposed individuals. Conclusion(s): Overall, placental inflammatory profiles differed between pregnant individuals exposed to pandemic stress with or without SARS-CoV-2 infection. Moreover, we observed that the pandemic stress exposed group presented a systemic pro-inflammatory bias. This highlights the need to understand the differences between the effects of pandemic-related stress and the added burden of SARS-CoV-2 infection itself on maternal and fetal health. Our work also supports an association between an increased risk of hypertension/ preeclampsia and SARS-CoV-2 infection that might be driven in part by pandemic-related stress.

COVID-associated pernio: Mechanistic insights to an abortive, seronegative SARS-CoV-2 infection

Introduction: SARS-CoV-2 replicates primarily in the airways but generates a systemic immune response mediated by Type I interferons (IFN-I). Pernio is a rare skin manifestation of disorders characterized by excessive IFN-I signalling. Although pernio increased in incidence during the pandemic, the relationship to SARS-CoV-2 remains controversial. Because of the pivotal nature of interferons in COVID-19 outcomes, pernio offers a window to investigate the biology underlying host resiliency to SARS-CoV-2 infection. Method(s): To further assess COVID-associated pernio, we characterized clinical samples from affected patients across 4 waves of the pandemic and investigated mechanistic feasibility in a rodent model. Patients were followed longitudinally with banking of blood and tissue. Golden hamsters were mock-treated or intra-nasally infected with SARS-CoV-2 and harvested at 3-and 30-days post-infection. Result(s): In affected tissue, immunophenotyping utilizing multiplex immunohistochemistry profiled a robust IFN-1 signature characterized by plasmacytoid dendritic cell activation. Viral RNA was detectable in a subset of cases using in situ hybridization for the SARS-CoV-2 S gene transcript. Profiling of the systemic immune response did not reveal a durable type 1 interferon signature. Consistent with previous literature, antibody and T-cell specific responses to SARS-CoV-2 were not detected. Nasopharyngeal SARS-CoV-2 inoculation in hamsters resulted in rapid dissemination of viral RNA and the generation of an IFN-I response that were both detectable in the paws of infected animals. Conclusion(s): Our data support a durable local IFN signature, with direct evidence of viral SARS-CoV-2 RNA in acral skin and suggest that COVID-associated pernio results from an abortive, seronegative SARS-CoV-2 infection.

Histopathological findings in renal biopsy of patients with COVID-19 and renal involvement / Hallazgos histopatológicos en biopsia renal de pacientes con COVID-19 y compromiso renal

Introducción. La lesión renal aguda (LRA) en el paciente con COVID-19 ocurre más frecuentemente en presencia de enfermedades crónicas como diabetes, obesidad, hipertensión arterial y enfermedad renal crónica previa, considerándose un fuerte predictor de resultados desfavorables y mortalidad. El propósito de este estudio fue describir las características histopatológicas en biopsias renales de pacientes hospitalizados por COVID-19, que experimentaron algún grado de daño renal durante su hospitalización. Metodología. Se incluyeron 30 pacientes mayores de 18 años, hospitalizados en diferentes centros de atención en Medellín, Colombia, con diagnóstico confirmado de COVID-19, sin antecedente de terapia de reemplazo renal, que durante la infección desarrollaron algún grado de daño renal, y que tuvieran estudio histopatológico de biopsia renal. Se analizaron las características demográficas, formas clínicas de presentación y hallazgos histopatológicos a nivel renal. Resultados. La mayoría de los pacientes eran de sexo masculino (70%). Los antecedentes patológicos más frecuentes fueron la enfermedad renal crónica previa (16,7%), diabetes mellitus (16,7%), trasplante renal (13,3%) y VIH (10%). El 35,7% de los pacientes no tenían ninguna comorbilidad subyacente. La manifestación clínica inicial más frecuente fue la LRA (56,7%). Algunos pacientes tuvieron más de una manifestación clínica inicial. El 100% de los pacientes evaluados tuvieron hallazgos histopatológicos renales, siendo la nefritis tubulointersticial aguda (40%) el más frecuente. Conclusión. Nuestro estudio no descarta una posible asociación del sexo masculino con peores desenlaces en la enfermedad COVID-19. La LRA fue el hallazgo clínico inicial más frecuente. Es posible que los hallazgos histopatológicos del presente estudio puedan ser consecuencia del daño directo a nivel tubulointersticial renal y la mala perfusión renal, dado el estado de choque por la tormenta inflamatoria, el empeoramiento de enfermedades preexistentes, o la superposición clínica con otras entidades. Sin embargo, son necesarios más estudios para dilucidar los mecanismos por los cuales se generan estas lesiones

Acute kidney injury (AKI) in patients with COVID-19 occurs more frequently in the presence of chronic diseases such as diabetes, obesity, hypertension, and previous chronic kidney disease, and is considered a strong predictor of unfavorable outcomes and mortality. The purpose of this study was to describe the histopathological characteristics in kidney biopsies from patients hospitalized for COVID-19, who experienced some degree of kidney damage during their hospitalization. Methodology. We included 30 patients over 18 years of age, hospitalized in different care centers in Medellín, Colombia, with a confirmed diagnosis of COVID-19, without a history of renal replacement therapy, who developed some degree of kidney disease during the infection, and had histopathological study of renal biopsy. Demographic characteristics, clinical manifestations and histopathological findings were analyzed. Results. Most of the patients were male (70%). The most frequent previous pathological findings were chronic kidney disease (16.7%), diabetes mellitus (16.7%), kidney transplant (13.3%) and HIV (10%). 35.7% of the patients did not have any underlying comorbidity. The most frequent initial clinical manifestation was AKI (56.7%). Some patients had more than one initial clinical manifestation. 100% of the patients had renal histopathological findings, with acute tubulointerstitial nephritis (40%) being the most frequent. Conclusion. Our study does not rule out a possible association of the male gender with worse outcomes in COVID-19 disease. AKI was the most common initial clinical finding. It is possible that the histopathological findings of this study may be a consequence of direct damage at the renal tubulointerstitial level and poor renal perfusion due to the inflammatory storm, worsening of pre-existing diseases, or clinical overlap with other entities. However, more studies are needed to elucidate the mechanisms by which these lesions are generated

CORRELATION OF SARS-COV-2 EXPRESSION IN THE PLACENTA AND THE INCIDENCE OF PREECLAMPSIA.

Background: The pandemic caused by SARS-CoV-2 also caused infection in some pregnant women. Some reports say this viral infection can show symptoms of preeclampsia. Material and Methods: We analyzed 25 pregnant women with SARS-CoV-2 infection with 4 patients presenting with symptoms of preeclampsia. we performed routine blood analysis, renal function, liver function, and IHC examination to see the expression of viral proteins in the placenta. Results: we obtained 4 patients with confirmed SARS-CoV-2 infection by RT-PCR. In these 4 cases, none of the cases showed expression of the SARS-CoV-2 viral protein in the placenta, and all 4 mothers were declared dead after treatment, and 2 babies delivered out of these 4 cases died. In one case we had fetal death in pregnancy while in one case prematurity. 2 babies born to mothers with SARS-CoV-2 infection with preeclampsia were born in good condition. There were no babies infected with SARS-CoV-2. Conclusion: We conclude that SAR-CoV-2 infection in pregnant women with comorbidities can lead to a poor prognosis for both mother and baby. We cannot yet conclude whether SARS-CoV-2 infection can cause preeclampsia, but SARS-CoV-2 infection can exacerbate preeclampsia symptoms.

Failing categorization of severe COVID-19 ARDS into ventilatory subphenotypes studied via the clinical-histopathologic relationship.

BACKGROUND: Categorization of severe COVID-19 related acute respiratory distress syndrome (CARDS) into subphenotypes does not consider the trajectories of respiratory mechanoelastic features and histopathologic patterns. This study aimed to assess the correlation between mechanoelastic ventilatory features and lung histopathologic findings in critically ill patients who died because of CARDS. METHODS: Mechanically ventilated patients with severe CARDS who had daily ventilatory data were considered. The histopathologic assessment was performed through full autopsy of deceased patients. Patients were categorized into two groups according to the median worst respiratory system compliance during ICU stay (CrsICU). RESULTS: Eighty-seven patients admitted to ICU had daily ventilatory data. Fifty-one (58.6%) died in ICU, 41 (80.4%) underwent full autopsy and were considered for the clinical-histopathological correlation analysis. Respiratory system compliance at ICU admission and its trajectory were not different in survivors and non-survivors. Median CrsICU in the deceased patients was 22.9 ml/cmH2O. An inverse correlation was found between the CrsICU and late-proliferative diffuse alveolar damage (DAD) (r = -0.381, p = 0.026). Late proliferative DAD was more extensive (p = 0.042), and the probability of stay in ICU was higher (p = 0.004) in the "low" compared to the "high" CrsICU group. Cluster analysis further endorsed these findings. CONCLUSIONS: In critically ill mechanically ventilated patients, worsening of the respiratory system compliance correlated pathologically with the transition from early damage to late fibroproliferative patterns in non-survivors of CARDS. Categorization of CARDS into ventilatory subphenotypes by mechanoelastic properties at ICU admission does not account for the complexity of the histopathologic features.

SARS-CoV-2 Infection Increases the Gene Expression Profile for Alzheimer's Disease Risk

The COVID-19 pandemic is a global outbreak of coronavirus, an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). One in five adults who have had COVID-19 in the past was still experiencing any one of the symptoms of long COVID like headache, brain fog, fatigue, and shortness of breath. Up to 30% of individuals with mild to severe infection show diverse neurological symptoms, including dementias. Hence, it is very much important to characterize the neurotropism and neurovirulence of the SARS-CoV-2 virus. This helps us understand the mechanisms involved in initiating inflammation in the brain, further leading to the development of earlyonset Alzheimer's disease and related dementias (ADRDs). In our brain gene expression analysis, we found that severe COVID-19 patients showed increased expression of innate immune response genes and genes that are implicated in AD pathogenesis. To study the infection-induced ADRDs, we used a mouse-adapted strain of the SARS-CoV-2 (MA10) virus to infect mice of different age groups (3, 6, and 20 Months). In this study, we found that aged mice showed evidence of viral neurotropism, prolonged viral infection, increased expression of tau aggregator FKBP51, interferoninducible gene Ifi204, and complement genes like C4 and C5AR1. Brain histopathology also showed the AD signature including tau-phosphorylation, tau-oligomerization, and alpha-synuclein expression in aged MA10-infected mice. The results from gene expression profiling of SARS-CoV-2 infected and AD brains and studies with MA10 aged mice show that COVID-19 infection increases the risk of AD in the aged population. Furthermore, this study helps us to understand the crucial molecular markers that are regulated during COVID infection that could act as major players in developing ADRDs. Future studies will be involved in understanding the molecular mechanisms of ADRD in response to COVID infection and developing novel therapies targeting AD.

Lung Aspergillus niger infection after SARS-CoV2

A 64-year-old never-smoker man, with professional exposure, presented to Marius Nasta Pneumophtisiology Institute for fatigability to effort, in the context of severe SARS-COV2 infection one month previously. His medical history includes pulmonary tuberculosis (55 years ago) and newly diagnosed type II diabetes (261 mg/dL glycemia). The thoracic tomography computer in the immediate post-COVID period (Fig. 1A) revealed the presence of glass ground lesions and a 3 cm nodule with cystic degeneration in the upper left lobe. A gross examination of the specimen identified a condensation area of 2.5 cm diameter, brown-grey colored, with necrosis and central ulceration. Microscopic examination showed the presence of bronchiectasis with squamous metaplasia of the epithelium, which appears ulcerated;numerous calcium oxalate crystals with adjacent foreign body granulomatous reaction;endobronchial are present fibrinous and inflammatory debris, brown-black pigment, and septate, dichotomous branching hyphae, suggestive of Aspergillus spp. A periodic acid-Schiff stain was performed, identifying the fungal hyphae. The histopathological diagnosis was bronchiectasis supra-infected and colonized with fungal filaments (Aspergillus niger).