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1.
IJID Reg ; 5: 154-162, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2095486

ABSTRACT

Objective: The aim of this study was to identify clinical and laboratory phenotype distribution patterns and their usefulness as prognostic markers in COVID-19 patients admitted to the intensive care unit (ICU) at Tygerberg Hospital, Cape Town. Methods and results: A latent class analysis (LCA) model was applied in a prospective, observational cohort study. Data from 343 COVID-19 patients were analysed. Two distinct phenotypes (1 and 2) were identified, comprising 68.46% and 31.54% of patients, respectively. The phenotype 2 patients were characterized by increased coagulopathy markers (D-dimer, median value 1.73 ng/L vs 0.94 ng/L; p < 0.001), end-organ dysfunction (creatinine, median value 79 µmol/L vs 69.5 µmol/L; p < 0.003), under-perfusion markers (lactate, median value 1.60 mmol/L vs 1.20 mmol/L; p < 0.001), abnormal cardiac function markers (median N-terminal pro-brain natriuretic peptide (NT-proBNP) 314 pg/ml vs 63.5 pg/ml; p < 0.001 and median high-sensitivity cardiac troponin (Hs-TropT) 39 ng/L vs 12 ng/L; p < 0.001), and acute inflammatory syndrome (median neutrophil-to-lymphocyte ratio 15.08 vs 8.68; p < 0.001 and median monocyte value 0.68 × 109/L vs 0.45 × 109/L; p < 0.001). Conclusion: The identification of COVID-19 phenotypes and sub-phenotypes in ICU patients could help as a prognostic marker in the day-to-day management of COVID-19 patients admitted to the ICU.

2.
J Biomed Semantics ; 13(1): 25, 2022 10 21.
Article in English | MEDLINE | ID: covidwho-2089232

ABSTRACT

BACKGROUND: The current COVID-19 pandemic and the previous SARS/MERS outbreaks of 2003 and 2012 have resulted in a series of major global public health crises. We argue that in the interest of developing effective and safe vaccines and drugs and to better understand coronaviruses and associated disease mechenisms it is necessary to integrate the large and exponentially growing body of heterogeneous coronavirus data. Ontologies play an important role in standard-based knowledge and data representation, integration, sharing, and analysis. Accordingly, we initiated the development of the community-based Coronavirus Infectious Disease Ontology (CIDO) in early 2020. RESULTS: As an Open Biomedical Ontology (OBO) library ontology, CIDO is open source and interoperable with other existing OBO ontologies. CIDO is aligned with the Basic Formal Ontology and Viral Infectious Disease Ontology. CIDO has imported terms from over 30 OBO ontologies. For example, CIDO imports all SARS-CoV-2 protein terms from the Protein Ontology, COVID-19-related phenotype terms from the Human Phenotype Ontology, and over 100 COVID-19 terms for vaccines (both authorized and in clinical trial) from the Vaccine Ontology. CIDO systematically represents variants of SARS-CoV-2 viruses and over 300 amino acid substitutions therein, along with over 300 diagnostic kits and methods. CIDO also describes hundreds of host-coronavirus protein-protein interactions (PPIs) and the drugs that target proteins in these PPIs. CIDO has been used to model COVID-19 related phenomena in areas such as epidemiology. The scope of CIDO was evaluated by visual analysis supported by a summarization network method. CIDO has been used in various applications such as term standardization, inference, natural language processing (NLP) and clinical data integration. We have applied the amino acid variant knowledge present in CIDO to analyze differences between SARS-CoV-2 Delta and Omicron variants. CIDO's integrative host-coronavirus PPIs and drug-target knowledge has also been used to support drug repurposing for COVID-19 treatment. CONCLUSION: CIDO represents entities and relations in the domain of coronavirus diseases with a special focus on COVID-19. It supports shared knowledge representation, data and metadata standardization and integration, and has been used in a range of applications.


Subject(s)
COVID-19 , Communicable Diseases , Coronavirus , Vaccines , Humans , SARS-CoV-2 , Pandemics , Amino Acids
3.
Clinical and Experimental Rheumatology ; 40(10):83, 2022.
Article in English | EMBASE | ID: covidwho-2067780

ABSTRACT

Sjogren's syndrome (SS) is a chronic and systemic autoimmune disease characterized by lymphocytic infiltration and the development of dry eyes and dry mouth due to the secretory dysfunction of the lacrimal and salivary glands. In recent years, infectious pathogens have been proved to be associated with SS, including Cytomegalovirus, Coxsackie, EBV, and lymphotropic virus-1 (HTLV-1). Studies suggest that infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may trigger an autoimmune response, as evidenced by increased autoantibodies in patients diagnosed with Coronavirus disease 2019 (COVID-19). To investigate the relationship between SARS-CoV-2 and SS, the study was performed by infecting humanized ACE2 mice with SARS-CoV-2. Mice infected with the virus showed a decreased saliva flow rate, elevated antinuclear antibodies (ANAs) and anti-SSB/La, and lymphocyte infiltration in the lacrimal and salivary glands. We detected the viral nucleocapsid protein in mice exocrine glands with significant apoptotic bodies by the acinar cells. Confirmed with clinical data, we also observed the elevation of SS-specific autoantibodies (ANA, anti-SSB/Ro52, and anti-SSA/La) and specific ANA patterns in sera from COVID-19 patients. One unique aspect of SS is the high degree of sexual dimorphism, with women being affected 10-20 times more than men. To determine whether COVID-19 patients exhibited an element of sexual dimorphism in the autoantibody response, we grouped the sera by sex. We found the male patients showed elevated anti-SSA/Ro52 compared to female patients (p=0.0029), and female patients had more diverse ANA patterns. Lastly, monoclonal antibodies isolated from recovered patients using singlecell antibody nanowells technology were shown to recognize the nuclear antigens. Overall, by observing SS-like phenotypes in mouse models and patients, our study confirms a direct pathogenic role of SARS-CoV-2 in SS.

4.
Pulmonologiya ; 32(2):151-161, 2022.
Article in Russian | EMBASE | ID: covidwho-2067423

ABSTRACT

Bronchial asthma occurs in 0.9 - 17% of patients hospitalized with COVID-19. However, it is not clear whether asthma is a risk factor for the development and severity of COVID-19. Studies have shown that patients with asthma appear to be more susceptible to COVID-19 infection, but severe disease progression is not related to medication use, including asthma biologics, but rather to older age and comorbidities. Aim. To evaluate the clinical course of SARS-CoV-2 infection in elderly patients with asthma, to examine the effect of asthma and comorbidities on COVID-19-related outcomes, and to determine predictors of mortality. Methods. Elderly patients [WHO, 2020] (> 60 years, n = 131, median age 74 (67;80) years;59 men, 72 women) with asthma hospitalized for COVID-19 were included in the study. COVID-19 was confirmed by laboratory tests (PCR smear) and/or clinical and radiological examinations. All patients had a history of a documented diagnosis of asthma (GINA, 2020). Results. Out of 131 patients, 30 (22.9%) died in the hospital, and 15 (14.9%) died after discharge from the hospital (within 90 days). The group of patients with lethal outcome showed the following differences from those who recovered: values of Charlson index, respiration rate, degree of lung damage on CT scan, absolute number of leukocytes, neutrophils and neutrophils-to-lymphocytes ratio, C-reactive protein on the 5th day of hospitalization, and LDH were statistically significantly higher, while absolute number of eosinophils, total protein content, SpO2 and SpO2/FiO2 levels were lower;steroid intake during the year and non-atopic asthma were more common. Multivariate and ROC analysis revealed the most significant predictors of hospital mortality and their thresholds: Charlson comorbidity index ≥ 6 points, neutrophil/lymphocyte ratio ≥ 4.5, total protein ≤ 60 g/l, eosinophil level ≤ 100 cells/μL. Conclusion. The most significant predictors of hospital mortality in elderly patients with severe COVID-19 against asthma are Charlson comorbidity, neutrophil/lymphocyte ratio;lower eosinophil and total protein levels. Survival time of patients has an inverse correlation with the number of mortality risk factors present.

5.
Otolaryngology - Head and Neck Surgery ; 167(1 Supplement):P144-P145, 2022.
Article in English | EMBASE | ID: covidwho-2064489

ABSTRACT

Introduction: Olfactory dysfunction is a common symptom associated with COVID-19 infection. While often transient, nearly 1 in 8 patients experience persistent dysfunction after initial infection resolution. Given the known association between impaired olfaction and mild cognitive impairment (MCI), this persistent COVID-19 olfactory dysfunction may impede early detection of cognitive decline. Method(s): Patients with confirmed COVID-19-associated hyposmia (n=73), MCI (n=58), and normal controls (n=86) were prospectively enrolled. Demographic data were collected alongside formal olfactory testing via AROMA (Affordable Rapid Olfaction Measurement Assay) at time of initial enrollment. MCI was assessed via MoCA (Montreal Cognitive Assessment). Multivariate logistic regressions were utilized to evaluate for associations between variables and etiology of olfactory dysfunction. Result(s): After controlling for age and gender, when compared against normal controls, the inability to smell licorice, cinnamon, and lemon at the lowest 3 concentrations increased odds of COVID-19 hyposmia by 10.8 (95% CI, 4.6-25.6), 5.7 (95% CI, 2.7-11.7), and 5.3 (95% CI, 2.6-10.8), respectively. While the inability to smell coffee (9.9 odds ratio [OR];95% CI, 2.02-48.1), eucalyptus (6.7 OR;95% CI, 2.2-20.0), and rose (4.0 OR;95% CI, 1.7-9.7) were associated with MCI, decreased ability to smell licorice, cinnamon, and lemon were not. When combined into a composite score and compared against controls, decreased detection of licorice, cinnamon, and lemon was associated with a 16.5 OR (95% CI, 6.6-41.3) for COVID-19 hyposmia. This composite score was not significantly associated with MCI (1.2 OR;95% CI, 0.6-2.2) and, as such, performed well at discriminating between COVID-19 and MCI patients (receiver operating characteristic area under the curve=0.76). Conclusion(s): Distinct patterns of impaired olfaction were noted for COVID-19. We show that this etiology-specific phenotype has good discriminative performance when differentiating from MCI-associated hyposmia, which may allow for continued utilization of olfactory screening for MCI even among those with previous COVID-19 infection.

6.
Otolaryngology - Head and Neck Surgery ; 167(1 Supplement):P159, 2022.
Article in English | EMBASE | ID: covidwho-2064479

ABSTRACT

Introduction: Anatomic assessment of the upper airway remains important in directing and monitoring of care for patients with obstructive sleep apnea (OSA). Nasopharyngoscopy is routine in clinical practice, but it can be invasive and potentially less attractive in the post-COVID-19 care setting. It also only allows subjective assessment. Ultrasound imaging of the upper airway with backscattered imaging analyzed via machine learning algorithm is investigated as a potential alternative. Method(s): Sixty-three subjects (14 female) with a mean age of 39.4 (12.6) years, body mass index (BMI) of 26.4 (4.6) kg/m2, and apnea-hypopnea index (AHI) of 19.0 (16.1) were consented from Stanford sleep surgery (July 2020 to May 2021). A standardized ultrasound protocol was used to image the soft palate, oropharynx, tongue base, and epiglottis. Via ultrasound device cleared by US Food and Drug Administation, backscattered ultrasound imaging (BUI) of the upper airway was performed and analyzed with machinelearning algorithms. Combined with B-mode measurements of airway muscular cross-sections, a logistic regression model was built to correlate with OSA severity. Result(s): The BUI of subjects with mild OSA was different from moderate-severe (AHI>=15) OSA at the soft palate (P=.0007). The axial-to-lateral ratio of upper airway length was reduced in the lower soft palate of the moderate-severe group (P=.0207). The logistic regression model with BUI, axial-to-lateral ratio at the soft palate, and BMI showed an area under the receiver-operating characteristic curve of 0.84 (95% CI, 0.726-0.920) in moderate-severe OSA. Conclusion(s): A noninvasive yet replicable technique to visualize and phenotype the upper airway is critical in the management of patients with sleep-disordered breathing. Sonographic BUI combined with B-mode airway measurements analyzed by machine learning show promise in characterizing the upper airway in patients with moderate-severe OSA.

7.
Hypertension. Conference: American Heart Association's Hypertension ; 79(Supplement 1), 2022.
Article in English | EMBASE | ID: covidwho-2064367

ABSTRACT

The high transmissibility and the broad spectrum of clinical manifestations of COVID-19 are in part due to the high affinity of SARS-CoV-2 for its receptor, Angiotensin Converting Enzyme 2 (ACE2). The depletion of the biological functions of ACE2, due to the internalization of the receptor along with SARS-CoV-2, leads to impairment of Renin Angiotensin System (RAS), which can contribute to COVID-19 pathogenesis. In addition, genetic differences in RAS may be associated with more severe symptoms and complications observed in COVID-19 patients. This study aims to perform a comparative analysis between COVID-19 positive patients and uninfected individuals, to correlate such disease profiles with ACE I/D (Insertion/Deletion) and ACE2 G8790A polymorphisms, and their enzymatic activities. The anthropometric, demographic, clinical and cardiovascular parameters of 764 individuals from Ipaussu/SP (Brazil) were evaluated. ACE and ACE2 activities were measured by fluorometric assays, and assessment of both enzymes polymorphisms was performed by PCR. In this cohort, 35,2% (269 of 764) the volunteers were positive for COVID-19. The prevalence of COVID-19 was higher among women (67%) and individuals aged between 18 and 49 years. Also, comorbidities as obesity and arterial hypertension were more frequent in the positive group, when considered individuals under 60 years old. Higher ACE and ACE2 enzymatic activities were observed in positive group (46.4 vs 41.6 and 11.3 vs 8.5, respectively). Individuals with ID genotype in the positive group presented higher ACE activity compared to individuals with same genotype in control group (46.9 vs 41.7). In the positive group, ACE activity was increased in the DD (54.5) when compared to ID (46.9) and II (37.9) genotypes. No significant differences related to ACE2 activity and polymorphism were observed. ACE/ACE2 activity ratio was higher in the COVID-19 negative group (4.7 vs 3.7). The increased ACE activity for the DD genotype was in line with the literature data for hypertension and cardiovascular diseases. We can suggest a synergic effect between ACE DD genotype and COVID-19 infection enhancing ACE activity, what may contribute to pro-inflammatory phenotype and more severe symptoms of COVID-19.

8.
American Journal of Transplantation ; 22(Supplement 3):873, 2022.
Article in English | EMBASE | ID: covidwho-2063493

ABSTRACT

Purpose: Kidney transplant recipients (KTRs) are highly vulnerable to severe COVID-19, however are poorly protected by vaccination. Additional vaccine doses have achieved limited improvements in serological neutralisation or T cell response. A novel strategy to boost vaccine response is needed. Method(s): KTRs (n=80) and healthy cohabitants (HCs;n=80) were recruited from a transplant centre in South Australia to undergo a 2-dose vaccination schedule with BNT162b2 or ChAdOx1. KTRs were most commonly receiving the standard-of-care (SOC) triple therapy: tacrolimus, mycophenolate mofetil, prednisolone. Following 2 vaccine doses (median 21 days;IQR 21-24), spike-specific IgG and T cell responses (by IFNgamma ELISpot) were measured to assess vaccine immunogenicity, and live virus neutralisation and anti-receptor binding domain (RBD) IgG (Elecsys, Roche) were evaluated as correlates of protection from infection and disease. In an extended cohort comparing SOC (n=15) and sirolimus-inclusive (n=15) protocols, function and phenotype of antigen-specific T cells were further interrogated by flow cytometry. Result(s): Vaccine immunogenicity was profoundly reduced in KTRs, with a >1,000- fold lower median anti-spike IgG titre, and >10-fold lower median antiviral T cell response relative to HCs. Thresholds for protective anti-RBD IgG (100 U/mL) and serological neutralisation (50% neutralisation at a serum dilution of 1/40) were achieved by 6.7% and 10.9% of KTRs, respectively, and by 100% of cohabitants. In an extended cohort, patients on mTOR inhibitors (mTORi;sirolimus or everolimus) achieved 4-fold higher rates of serological neutralisation than those on SOC therapy (34.6% vs 7.9%). Remarkably, sirolimus use was associated with a median antiviral T cell response 55-fold greater than SOC therapy, and 5-fold greater than HCs. SARSCoV- 2-specific CD4+ and CD8+ T cells in these patients were highly polyfunctional and formed robust central memory out to 3 months post second vaccine dose. Conclusion(s): These data underscore priority vaccination of cohabitants as an effective strategy to protect KTRs, and support a randomised controlled trial of immunosuppression modification with sirolimus as a strategy to directly improve vaccine responses in KTRs.

9.
American Journal of Transplantation ; 22(Supplement 3):426-427, 2022.
Article in English | EMBASE | ID: covidwho-2063400

ABSTRACT

Purpose: Due to heterogeneity observed in the kidney transplant population, it has been extremely challenging for traditional methods such as histopathology to predict graft outcomes. In this real-world evidence(RWE) study, we applied machine learning (ML) models to a multi-analyte urinary biomarker assay to predict whether a kidney allograft would experience a rejection episode. Method(s): A cohort of 550 (37.5% biopsy matched) urine samples from patients across 3 renal transplant centers were used to develop a predictive ML model (scaled 0-100) to prognosticate allograft failure. Samples were collected between 1-1539 days post-transplant from allograft recipients with ages ranging from 7-77 years. Of the 206 biopsy matched samples, acute kidney allograft rejection (AR) and no-rejection (NR) phenotypes were confirmed in 136 and 70 respectively. We also evaluated the developed ML model on two additional cohorts of 15 COVID+ transplant recipients and 30 non-transplant healthy population. The ML model incorporates clinico-demographics with 6 urinary biomarkers: Clusterin, total protein, CXCL10, Creatinine, cfDNA and methylated cfDNA. Monte Carlo confidence intervals for the model incorporated biomarker assay and sample variances. Result(s): The novel rejection score was able to discriminate AR from NR efficiently. Score below 32 classified stable allograft, score range of 32 - 55 identified progression of AR, and Score > 55 identified AR with high sensitivity: 92%, and specificity: 89%;AUC: 96% and accuracy: 91%(figure). The associated NPV and PPV of 87% and 93% respectively. In the COVID cohort with 86% clinician assessed rejection, the median score was 51(IQR:30-87). In the non-transplants the median score was 19(IQR:13-26). It was established that presence of COVID was not a confounder in the model. Conclusion(s): The accuracy of the novel rejection score emphasizes the promise of applying ML algorithms as an aid to decision-making in evaluating graft outcomes with high sensitivity and specificity. Moreover, this RWE retrospective analysis demonstrates the efficacy of the urine multi-analyte approach to accurately predict acute rejection in kidney transplant recipients. (Figure Presented).

10.
American Journal of Transplantation ; 22(Supplement 3):457, 2022.
Article in English | EMBASE | ID: covidwho-2063392

ABSTRACT

Purpose: While SARS-CoV-2 vaccination has dramatically reduced COVID-19 severity in the general population, fully vaccinated solid organ transplant recipients (SOTRs) demonstrate reduced seroconversion and increased breakthrough infection rates. Furthermore, a third vaccine dose only increases antibody and T cell responses in a proportion of SOTRs. We sought to investigate the underlying mechanisms resulting in varied humoral responses in SOTRs. Method(s): Within a longitudinal prospective cohort of SOTRs, anti-spike IgG, total and spike-specific B cells were evaluated in 44 SOTR participants before and after a third vaccine dose using high dimensional flow cytometry to assess immunologic and metabolic phenotypes. B cell phenotypes were compared to those of 10 healthy controls who received a standard two-dose mRNA series. Result(s): Notably, even in the absence anti-spike antibody after two doses, spikespecific B cells were detectable in most SOTRs (76%). While 15% of participants were seropositive before the third dose, 72% were seropositive afterward. B cells, however, were differentially skewed towards non-class switched B cells in SOTRs as compared to healthy control B cells. Expansion of spike-specific class-switched B cells in SOTRs following a third vaccine dose correlated with increased classswitched (IgG) antibody titers. Antibody response to a third vaccine dose was associated with expanded populations of germinal center-like (CD10+CD27+) B cells, as well as CD11c+ alternative lineage B cells with specific upregulation of CPT1a, the rate limiting enzyme of fatty acid oxidation and a preferred energy source of germinal center B cells. Conclusion(s): This analysis defines a distinct B cell phenotype in SOTRs who respond to a third SARS-CoV-2 vaccine dose, specifically identifying fatty acid oxidation as pathway that could be targeted to improve vaccine response such as through targeted immunosuppressive modulation. (Figure Presented).

11.
Tissue Engineering - Part A ; 28:345-346, 2022.
Article in English | EMBASE | ID: covidwho-2062827

ABSTRACT

Purpose/Objectives: The delivery of nucleic acids to cells has revolutionized medicine and enabled new technologies such as mRNA vaccines and stem cell therapies. These recent advances rely on delivery vehicles to stabilize the genetic payload and increase cellular transfection. While engineered viruses are efficient vectors for ex vivo cellular reprogramming, they are not ideal for in vivo gene therapies as repeated dosing leads to anti-vector immunity. Lipid nanoparticles have thus emerged as the best alternative to viral vectors for in vivo nucleic acid delivery. However, all FDA-approved lipid nanoparticles have been linked to inflammatory responses, undesirable for regenerative medicine applications that require precise immunomodulation. Thus, non-immunogenic delivery materials must be developed to fulfill the immense potential of gene therapy in regenerative medicine. Lipid nanoparticles typically comprise 4 different lipids, with the ionizable amino lipid being the main driver of potency and immunogenicity. A way to reduce immunogenicity is to develop lipid nanoparticles that minimize the amount of lipids per gram of nucleic acids. To do so, we developed a novel class of ionizable amino lipids with high charge density. Our primary objective is to design a lipid nanoparticle that maximizes RNA delivery and minimizes immunogenicity. Methodology: We designed a library of proprietary ionizable lipids based on the structure of a poly(amido amine) dendron. The structure is modular, which allowed us to systematically vary molecular motifs to optimize important physiochemical parameters: Lipid-to-RNA ratio;apparent pKa;surface zeta potential;size distribution;and RNA encapsulation These structures are also designed to include a higher number of amines compared to current ionizable lipids. This improves ionization charge density of the lipid and lowers the amount of lipid required to encapsulate RNA. In this study, lipid nanoparticles contain an ionizable lipid selected from our library, cholesterol, a phospholipid, and a PEG-lipid. The lipids and formulation conditions were selected to mimic Moderna's COVID-19 vaccine (SpikeVax), albeit with different lipid-to-RNA ratios. C57BL/6 mice were injected intramuscularly with nanoparticles co-formulated with a firefly luciferase mRNA and ovalbumin mRNA to simultaneously study transfection efficiency and antigen-specific immune responses. Nanoparticles that comprise SM-102, the ionizable lipid used in SpikeVax, were used as a comparative control due to their high potency and immunogenicity. Luciferase activity was detected using an IVIS Spectrum, and key organs were harvested for immune phenotyping. Results: We have so far determined the effect of hydrophobic motifs on apparent pKa and RNA encapsulation. Our best lipids with optimized tails did not induce IFN-I responses in vitro and demonstrated comparable in vivo efficacy to SM-102. We are currently in the process of collecting immunogenicity data which we expect to complete prior to the conference. Conclusion/Significance: We have produced a novel set of lipid nanoparticles that efficiently transfect cells in vivo. These new particles deliver RNA with half of the lipid mass used in SpikeVax, which can reduce the amount of material-induced immunogenicity. This result opens the door to developing mRNA vaccines with fewer side effects and equitable gene therapies for untreatable diseases such as inflammatory and autoimmune disorders.

12.
Acta Cardiologica ; 77:17, 2022.
Article in English | EMBASE | ID: covidwho-2062409

ABSTRACT

Background/Introduction: Recovered COVID-19 patients often display cardiac dysfunction, even after a relatively mild infection. Purpose: We present an in-depth physiological and histological timeline of the cardiac consequences of SARS-CoV-2 infection using a hamster model. Methods: We used several methods, including transthoracic echocardiography, RNA sequencing on in vitro cultures, and in-situ hybridization techniques, complemented with histological analysis. Results: We analysed cardiac function by echocardiography over a period of 35 dpi. Already by 14 dpi and continuing at 35 dpi, infected hamsters presented with an increased E/E', decreased MV deceleration time, and an increased isovolumetric contraction time as compared to control, indicating the presence of diastolic dysfunction. Histologically, cardiomyocytes were enlarged already by 4 dpi and remained enlarged over 5 weeks. We observed the presence of fibrin-rich microthrombi at 4 dpi, which were resolved by 14 dpi. SARS-CoV-2 RNA was present in cardiac pericytes, accompanied by reduced pericyte coverage of capillaries at 4 dpi and 14 dpi, which mostly recovered by 35 dpi. At 14 dpi, the reduced pericyte coverage coincided with increased vascular permeability, suggesting that SARS-CoV-2 infection of pericytes affects microvascular integrity. SARS-CoV-2 infection of pericytes in vitro induced the expression of genes involved in viral defence, and affected genes involved in pericyte contractility and extracellular matrix proteins. Loss of cardiac pericytes was observed in cardiac biopsies from patients recovered from SARSCoV- 2 infection. Conclusion(s): Overall, our results demonstrate that SARS-CoV-2 infection causes a phenotype similar to ischemia-reperfusion, without overt ischemia. We propose that partial occlusion by microthrombi and microvascular dilation caused by pericyte loss induces regional variations in blood flow, and results in a stiffer ;swollen' heart that shows diastolic dysfunction.

13.
Cardiology in the Young ; 32(Supplement 2):S92-S93, 2022.
Article in English | EMBASE | ID: covidwho-2062132

ABSTRACT

Background and Aim: Multi-system inflammatory syndrome in chil-dren (MIS-C) causes widespread systemic inflammation including a pancarditis in the weeks following a COVID infection. Further coronavirus surges appear inevitable and with vaccination rates lower in young people an understanding of the medium-term car-diac impacts of this condition is important for planning further treatment and understanding the impacts on their health. Method(s): A retrospective single-center study of 67 consecutive patients with MIS-C was performed. Three time points were determined as the point of worst cardiac dysfunction during the acute admission, then at intervals of 6-8 weeks and 6-8 months. Echocardiographic findings were used to evaluate both 2D and 3D measures of cardiac function. Coronary artery measurements were recorded. Corresponding serial ECG findings were evaluated. Result(s): The worst cardiac function arose 6.8 +/- 2.4 days after the onset of fever. The mean M mode-derived FS was 30.9 +/- 8.1% during the acute phase. The mean 3D left ventricle (LV) ejection fraction (EF) was borderline at 50.5 +/- 9.8%. A pancarditis was typ-ically present: 46.3% showed cardiac impairment;31.3% had some pericardial effusion;26.8% had moderate (or worse) valvar regur-gitation and;26.8% had coronary dilatation. Cardiac function returned to normal in all patients by 6-8 weeks (mean 3D LV EF 61.3 +/- 4.4%, plt;0.001 compared to admission). Coronary dila-tation normalized in all but one patient who initially developed large aneurysms at presentation;these continued 6 months later. ECG findings mainly featured T-wave changes resolving at fol-low-up. There were a small number of adverse events: need for ECMO (2), death as an ECMO-related complication (1), suben-docardial infarction (1), LV thrombus formation (1). Conclusion(s): MIS-C causes a pancarditis with decreased cardiac function and almost a quarter of patients showing coronary changes. In most, discharge from long-term follow-up can be con-sidered as full cardiac recovery is expected by 8 weeks. The excep-tion includes patients with medium sized aneurysms or greater or those with more of a Kawasaki disease phenotype as these require on-going surveillance for persistence of coronary changes.

14.
Cardiology in the Young ; 32(Supplement 2):S247, 2022.
Article in English | EMBASE | ID: covidwho-2062100

ABSTRACT

Background and Aim: An infection with SARS-CoV-2 is associated with systemic inflammation, that also affects the endothelium. This may result in endothelitis, which can influence vascular regulation and morphology. Until now, the specific mechanism of vessel damage after a SARS-CoV-2 infection is still unclear, especially in children and adolescents. The LICO Study (Long term impact of COVID-19) aims to investigate the long-term effects of a SARS-CoV-2 infection on vascular structure and function in chil-dren and adolescents. Method(s): Children and adolescents with confirmed evidence of survived SARS-CoV-2 infection are screened 6 +/- 3 months post-infection. Vascular function is assessed by flow-mediated vas-odilation (FMD) and aortic pulse wave velocity (PWV). Carotid intima-media thickness (cIMT) and retinal diagnostics (arteriove-nous ratio-AVR) are used to examine vascular structure. The matched control group without prior SARS-CoV-2 infection undergoes the same examination procedure. Result(s): So far, we have been able to evaluate 24 (9 post-covid) subjects (13.5 +/- 1.9 years;9 girls). Compared to the mean refer-ence values of the control group, 5 post-covid subjects have higher cIMT (0.49 +/- 0.01 mm vs. reference value 0.46 +/- 0.03 mm). Of these, 3 post-covid subjects even deviate from the norm PWV (4.96 +/- 0.16 m/sec vs. reference value 4.63 +/- 0.29 m/sec). The same 3 post-covid subjects are also below the norm FMD (2.06 +/- 1.05 % vs. reference value 4.18 +/- 7.04 %). None of the post-covid subjects deviates from the norm AVR values (refer-ence value 0.85 +/- 0.07). Conclusion(s): It is shown that infection with SARS-CoV-2 has the potential to impair vascular regulation. These initial results provide trends for early vascular changes among children and adolescents after recovered SARS-CoV-2 infection. Due to that this is an ongoing study, the results are constantly being expanded and may still change. To determine lasting changes in morphology, the examination is repeated after 6 months and the further results of this longitudinal study must be awaited.

15.
The British Journal of Nutrition ; 128(8):1459-1469, 2022.
Article in English | ProQuest Central | ID: covidwho-2062085

ABSTRACT

Vitamin D is both a nutrient and a neurologic hormone that plays a critical role in modulating immune responses. While low levels of vitamin D are associated with increased susceptibility to infections and immune-related disorders, vitamin D supplementation has demonstrated immunomodulatory effects that can be protective against various diseases and infections. Vitamin D receptor is expressed in immune cells that have the ability to synthesise the active vitamin D metabolite. Thus, vitamin D acts in an autocrine manner in a local immunologic milieu in fighting against infections. Nutrigenetics and nutrigenomics are the new disciplines of nutritional science that explore the interaction between nutrients and genes using distinct approaches to decipher the mechanisms by which nutrients can influence disease development. Though molecular and observational studies have proved the immunomodulatory effects of vitamin D, only very few studies have documented the molecular insights of vitamin D supplementation. Until recently, researchers have investigated only a few selected genes involved in the vitamin D metabolic pathway that may influence the response to vitamin D supplementation and possibly disease risk. This review summarises the impact of vitamin D supplementation on immune markers from nutrigenetics and nutrigenomics perspective based on evidence collected through a structured search using PubMed, EMBASE, Science Direct and Web of Science. The research gaps and shortcomings from the existing data and future research direction of vitamin D supplementation on various immune-related disorders are discussed.

16.
American Journal of Transplantation ; 22(Supplement 3):441-442, 2022.
Article in English | EMBASE | ID: covidwho-2063342

ABSTRACT

Purpose: Correlates of protection for SARS-CoV-2 vaccines are not well-established in kidney transplant recipients(KTRs). Studies have highlighted the importance of neutralizing antibodies(Abs), however data suggests T cell responses may play a secondary role in preventing reinfection. We performed a longitudinal assessment of immunogenicity, T and B cell response in KTRs following SARS-CoV-2 vaccination. Method(s): KTRs eligible for SARS-CoV-2 vaccination from 3/12/21 were enrolled. Baseline and weekly blood samples were collected for routine lab, SARS-CoV-2 spike protein Ab titers and cellular phenotyping for 12 weeks. Ab response was defined as a 10-fold increase in total binding IgG titers. To determine if T cell responses were induced by vaccination, we considered the proportion of activated non-naive CD4+ and CD8+ T cells post-vaccination. Result(s): 49 KTRs were enrolled ( Demographics -Table 1). 10 patients (20.4%) mounted an Ab response following vaccination. A history of COVID-19 was associated with an increased likelihood of developing an Ab response (OR: 18.3, 95% CI 3.2, 105.0, p=0.0005). For non-naive CD8+ T cells, a subset co-expressing CD38+Ki67+ was induced 1 week after the 1st immunization in some SARS-CoV- 2-naiive patients (P=0.12 versus P=0.14 for SARS-CoV-2-experienced adults, Fig 1A/B). For non-naive CD4+ T cells, induction of a subset co-expressing CD38+Ki67+ was observed at 1 week after the 1st immunization for SARS-CoV-2-naive participants (P = 0.09 for SARS-CoV-2-naive, P=0.03 for SARS-CoV-2-experienced adults, Fig 1C/D). For CD8+ and CD4+ T cells, dose 2 stimulated weak induction of the CD38+Ki67+ subset in the SARS-CoV-2-naive patients only (Fig 1A-D). Conclusion(s): Quantitative Ab responses were strongly associated with prior SARS-CoV-2 infection. Activated CD4+ and CD8+ T cell responses were evident in most patients irrespective of history of COVID-19. Further studies are needed to determine whether these activated CD4+ and CD8+ T cell responses were antigenspecific or confer immunity. (Table Presented).

17.
Neuromodulation ; 25(7 Supplement):S247, 2022.
Article in English | EMBASE | ID: covidwho-2061713

ABSTRACT

Introduction: Mobile devices and smartphones have made technology in healthcare more accessible to patients, with COVID-19 further expediting the integration of technology into healthcare. Depression and anxiety are measured via self-report, personality assessments, or during a psychological evaluation with a mental health clinician. These methods of assessing symptomatology lack the benefits of today's technology. This study aims to explore the utility of passive and portable data collection in individuals with anxiety and depression. Materials / Methods: A systematic literature search was conducted through ScienceDirect, PubMed, NCBI, and JMIR electronic databases for studies that were published between 2015-2021 using the following keywords: depression, mobile health, digital phenotyping, mobile applications, mobiles phones, passive EMA, psychiatric assessment, and mhealth. Inclusion criteria;(1) peer-reviewed articles published between 2015 and 2021;(2) studies published in English;(3) studies that use data sensors to monitor and measure the symptomatology of anxiety, depression, and cardiovascular health. A total of 15 studies met criteria. Result(s): Of the 13 studies reviewed, all found at least some correlation between mobile phone usage and depressive symptomatology. 5 studies found a large correlation between GPS data and severity of depressive symptomatology. Contrastingly, one study found that, although people with depressive symptoms spend less time calling and texting others, they spend more time on their phones. Another study states that individuals with depression let their phones ring for longer and have more missed calls. Additionally, 6 studies found a correlation between usage and anxious symptomatology. Mobile phone utilization was found to be far less correlated with anxiety and is a weaker predictor of such symptomatology. The studies found that increased calls, speech presence, and social media usage were directly correlated with increased anxiety. Discussion(s): All research analyzed shows the significance of passive sensor data when screening individuals for emotional symptomatology. This is stated with the implication that EMA are used alongside the sensor data to give a comprehensive picture of the patient. GPS data plays a central role in the ability to screen for symptomatology related to depression and anxiety due to location variability or lack thereof. Conclusion(s): Future research should focus on longer-term studies, that collect more passive data, and have larger sample sizes to ensure that the full extent of interaction between these pathologies can be understood. It should also be noted that other sensors such as ambient light and audio sensors displayed significant results, however, data on their ability to correlate to symptomatology is limited. Learning Objectives: 1. Learn the new and emerging methods of screening for depression and anxiety. 2. Learn new ways to interpret passive sensor data. 3. Learn how a combined approach of passive data collection and active EMA can improve the identification of symptomatology. Keywords: mobile health, digital phenotyping, passive EMA, psychiatric assessment, mobile sensors, depression Copyright © 2022

18.
European Neuropsychopharmacology ; 63:e175, 2022.
Article in English | EMBASE | ID: covidwho-2061165

ABSTRACT

Background: Most neuropsychiatric disorders are moderately heritable but characterized by many genetic risk variants with weak effects. As such, it is difficult to point to direct causes or elucidate mechanisms of action. Despite the ease in gathering genetic data from humans, genetic data does not easily explain mechanistic effects. Gene expression on the other hand, which can more easily explain mechanistic effects, is harder to gather, especially in brain regions that are critical to the understanding of neuropsychiatric disease. To address this, we developed methods to impute genetically regulated gene expression (GReX) from genotypes and imputed GReX in over 440,000 European individuals in the Million Veteran Program (MVP) for a wide variety of tissues and cell types. Method(s): We use EpiXcan (based on PrediXcan) to develop machine learning models from training genotype, expression, and epigenetic data. We use custom scripts to impute individual GReX and perform a variety of downstream association analyses, including GReX Phenome Wide Association Studies (PheWAS) and Transcriptome Wide Association Studies (TWAS). Result(s): Results show an overlap in Schizophrenia genes identified by individual level TWAS and those identified by summary level TWAS informed by GWAS. TWASs for neuropsychiatric phenotypes identify genes established in the literature, but also novel targets. Inverse-variance meta-analyzed single gene imputation efforts across ancestries confirm clinical results obtained from COVID-19 positive individuals in both IL10RB and IFNAR2. GReX PheWAS for these particular genes using a novel negative binomial distribution for phecodes confirm COVID-19 related phenotypes. Finally, we describe various enriched pathways found in a COVID-19 TWAS, including immunological pathways. Discussion(s): GReX presents a unique solution to integrate effects across the genome and increase sample size in gene expression analyses. We are pursuing the creation of additional EpiXcan models, improved statistical methods for downstream association analyses, and replication efforts across biobanks. We plan to perform these analyses in all ancestries, available EpiXcan and PrediXcan models, and phenotypes. Disclosure: Nothing to disclose. Copyright © 2022

19.
European Neuropsychopharmacology ; 63:e2, 2022.
Article in English | EMBASE | ID: covidwho-2061164

ABSTRACT

: Background: Twin studies have consistently shown a high genetic overlap amongst anxiety disorders and depression. Some research has also identified modest genetic specificity to fear-based anxiety disorders not shared with general anxiety. Identifying the genetic variants shared amongst all anxiety disorders or specific to one or more requires large sample sizes. Measuring anxiety disorders in large cohorts typically involves in-depth symptom-based diagnoses or minimally phenotyped single-item self-report diagnoses. A trade-off exists between maximising sample size and the level of detail in the phenotyping. Aims: First, to explore genetic correlations between generalised anxiety disorder (GAD) and the fear disorders (panic disorder, agoraphobia, specific phobia and social phobia) using a combination of in-depth and minimal phenotyping. Second, to compare the results from using minimal phenotyping of the anxiety disorders to that of in-depth phenotyping. Methods: We will use two case-only samples for analyses: the Genetic Links to Anxiety and Depression (GLAD) Study (∼N = 18,000) and the Australian Genetics of Depression Study (AGDS) (∼18,000). In addition, we will use three studies that provide both cases and controls: the COVID-19 Psychiatric and Neurological Genetics (COPING) study (N = ∼10,000), the QSkin study (N = ∼18,000) and the UK Biobank (N = ∼157,366). We will conduct three independent sets of case-control anxiety disorder genome-wide association studies (GWAS) before meta-analysing all five samples together (expected N cases ∼53,000, N controls ∼160,000). Results from GWAS meta-analyses of lifetime anxiety disorder, GAD, and fear-based disorders will be used to explore genetic correlations across anxiety disorders and depression and a wide range of complex traits. As sensitivity analyses, we will explore genetic correlations between anxiety phenotypes assessed using minimally phenotyped single-item diagnoses versus in-depth symptom-based diagnoses. Results: We hypothesise that the anxiety disorders will have a SNP-based heritability of approximately 15%. We also hypothesise that GAD and fear-based disorders will be moderately to highly genetically correlated, with some genetic variants that are specific to the fear disorders [1]. Disclosure: Nothing to disclose.

20.
Chest ; 162(4):A1192, 2022.
Article in English | EMBASE | ID: covidwho-2060788

ABSTRACT

SESSION TITLE: Rare Genetic Mutations and Anatomical Variants SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 12:25 pm - 01:25 pm INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a fatal disease affecting older adults that results in progressive scarring of the lung parenchyma. Familial IPF (FPF), defined by disease in two or more first-degree relatives, is estimated to occur in 2–20% of all IPF cases and can present with varying phenotypes which may be difficult to diagnose. Inherited gene variation as well as environmental factors predispose a patient to disease development. Additionally, rare genetic variants in the genes encoding surfactant A (SFTPA1, and SFTPA2) that affect alveolar stability and endoplasmic reticulum stress have been reported in less than 1% of FPF cases. Understanding these genetic variants is essential in the diagnosis and management of patients with FPF. CASE PRESENTATION: A 47-year-old Hispanic male with a history of COVID-19 one year ago (not requiring hospitalization) presented to the hospital for a two-day history of subjective fever and shortness of breath. He was hypoxic requiring oxygen via high flow nasal cannula. He was admitted four months ago for shortness of breath and treated for pneumonia. Since then, he has had chronic dyspnea with exertion. Computed tomography of the chest showed extensive ground glass opacities, worse in the right lung, with basilar and upper lobe honeycombing, and air bronchograms in the bilateral lower lobes. Family history was significant for a mother, maternal aunt, maternal grandfather, and maternal cousin who all died from pulmonary fibrosis. His maternal cousin was treated at our facility, in which genetic sequencing revealed a mutation in SFTPA2, c.697T>C. Our patient was found to have the same genetic mutation. DISCUSSION: The genetic basis of IPF remains poorly understood. Prior studies suggest only 20-30% of FPF cases harbor an identifiable causative genetic variant. Rare variants in two biologic pathways contribute to the known heritability of FPF including pathologic variants in surfactant related genes which cause improper protein trafficking leading to endoplasmic reticulum stress, defects in autophagy, and type II alveolar cell toxicity. SFTPA1 and SFTPA2 variants have been associated with FPF and lung adenocarcinoma in a small number of families and there are few reported cases. While currently the SFTPA2, c.697T>C mutation, previously reported by our group in 2016, is considered a variant of unknown significance, its occurrence in two relatives with serious progressive interstitial lung diseases suggests that it is indeed pathogenic. CONCLUSIONS: Gene sequencing should be considered for all patients with a family history of pulmonary fibrosis as identification of a rare genetic variant may offer guidance to diagnosis, prognostication, and risk stratification when considering lung transplantation as well as identify additional relatives who may be affected by IPF. Reference #1: Kropski JA, Young LR, Cogan JD, et al. Genetic Evaluation and Testing of Patients and Families with Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2017;195(11):1423-1428. doi:10.1164/rccm.201609-1820PP Reference #2: Wang Y, Kuan PJ, Xing C, Cronkhite JT, Torres F, Rosenblatt RL, DiMaio JM, Kinch LN, Grishin NV, Garcia CK. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am J Hum Genet. 2009 Jan;84(1):52-9. doi: 10.1016/j.ajhg.2008.11.010. Epub 2008 Dec 18. PMID: 19100526;PMCID: PMC2668050. Reference #3: Pulmonary Fibrosis Due to a Novel Surfactant Protein Mutation R.A. Arciniegas Flores, I.A. Vital, K. Medepalli, D. DeMarzo, M.K. Glassberg Csete, R.A. Alvarez. https://doi.org/10.1164/ajrccm-conference.2019.199.1_Meetings.A5437 DISCLOSURES: No relevant relationships by Roger Alvarez No relevant relationships by Eduardo Lopez Gonzalez No relevant relationships by Anita Singh

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