Uncovering a neurological protein signature for severe COVID-19

Coronavirus disease of 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has sparked a global pandemic with severe complications and high morbidity rate. Neurological symptoms in COVID-19 patients, and neurological sequelae post COVID-19 recovery have been extensively reported. Yet, neurological molecular signature and signaling pathways that are affected in the central nervous system (CNS) of COVID-19 severe patients remain still unknown and need to be identified. Plasma samples from 49 severe COVID-19 patients, 50 mild COVID-19 patients, and 40 healthy controls were subjected to Olink proteomics analysis of 184 CNS-enriched proteins. By using a multi-approach bioinformatics analysis, we identified a 34-neurological protein signature for COVID-19 severity and unveiled dysregulated neurological pathways in severe cases. Here, we identified a new neurological protein signature for severe COVID-19 that was validated in different independent cohorts using blood and postmortem brain samples and shown to correlate with neurological diseases and pharmacological drugs. This protein signature could potentially aid the development of prognostic and diagnostic tools for neurological complications in post-COVID-19 convalescent patients with long term neurological sequelae

Age, Disease Severity and Ethnicity Influence Humoral Responses in a Multi-Ethnic COVID-19 Cohort

The COVID-19 pandemic has affected all individuals across the globe in some way. Despite large numbers of reported seroprevalence studies, there remains a limited understanding of how the magnitude and epitope utilization of the humoral immune response to SARS-CoV-2 viral anti-gens varies within populations following natural infection. Here, we designed a quantitative, multi-epitope protein microarray comprising various nucleocapsid protein structural motifs, including two structural domains and three intrinsically disordered regions. Quantitative data from the microarray provided complete differentiation between cases and pre-pandemic controls (100% sensitivity and specificity) in a case-control cohort (n = 100). We then assessed the influence of disease severity, age, and ethnicity on the strength and breadth of the humoral response in a multi-ethnic cohort (n = 138). As expected, patients with severe disease showed significantly higher antibody titers and interestingly also had significantly broader epitope coverage. A significant increase in antibody titer and epitope coverage was observed with increasing age, in both mild and severe disease, which is promising for vaccine efficacy in older individuals. Additionally, we observed significant differences in the breadth and strength of the humoral immune response in relation to ethnicity, which may reflect differences in genetic and lifestyle factors. Furthermore, our data enabled localization of the immuno-dominant epitope to the C-terminal structural domain of the viral nucleocapsid protein in two independent cohorts. Overall, we have designed, validated, and tested an advanced serological assay that enables accurate quantitation of the humoral response post natural infection and that has revealed unexpected differences in the magnitude and epitope utilization within a population

Prognostic tools and candidate drugs based on plasma proteomics of patients with severe COVID-19 complications

COVID-19 complications still present a huge burden on healthcare systems and warrant predictive risk models to triage patients and inform early intervention. Here, we profile 893 plasma proteins from 50 severe and 50 mild-moderate COVID-19 patients, and 50 healthy controls, and show that 375 proteins are differentially expressed in the plasma of severe COVID-19 patients. These differentially expressed plasma proteins are implicated in the pathogenesis of COVID-19 and present targets for candidate drugs to prevent or treat severe complications. Based on the plasma proteomics and clinical lab tests, we also report a 12-plasma protein signature and a model of seven routine clinical tests that validate in an independent cohort as early risk predictors of COVID-19 severity and patient survival. The risk predictors and candidate drugs described in our study can be used and developed for personalized management of SARS-CoV-2 infected patients. 2022, The Author(s).The authors would like to thank all the patients, volunteers, and the healthcare co-workers from Allergy and Immunology Section-HMC, and Dr. Mohamed G.H. Mohamedali, Mr. Hassen Maatoug, and Mr. Ahmed Soliman from Hezm Mebairek General Hospital-HMC for developing disposable racks for samples transportation, tubes labeling, blood collection, and handling. We thank the support provided by Qatar University Biomedical Research Centre, Biosafety Level 3, and Associate Professor Hadi M. Yassine (M.Sc., Ph.D.). We also acknowledge the help of the Anti-Doping Lab-Qatar (ADLQ) and Qatar Red Crescent (QRC) for recruiting control samples. This work was supported by a grant fund from Hamad Medical Corporation (fund number MRC-05-003) and core funding from Qatar Biomedical Research Institute (QBRI).Scopu

Age, Disease Severity and Ethnicity Influence Humoral Responses in a Multi-Ethnic COVID-19 Cohort

The COVID-19 pandemic has affected all individuals across the globe in some way. Despite large numbers of reported seroprevalence studies, there remains a limited understanding of how the magnitude and epitope utilization of the humoral immune response to SARS-CoV-2 viral anti-gens varies within populations following natural infection. Here, we designed a quantitative, multi-epitope protein microarray comprising various nucleocapsid protein structural motifs, including two structural domains and three intrinsically disordered regions. Quantitative data from the microarray provided complete differentiation between cases and pre-pandemic controls (100% sensitivity and specificity) in a case-control cohort (n = 100). We then assessed the influence of disease severity, age, and ethnicity on the strength and breadth of the humoral response in a multi-ethnic cohort (n = 138). As expected, patients with severe disease showed significantly higher antibody titers and interestingly also had significantly broader epitope coverage. A significant increase in antibody titer and epitope coverage was observed with increasing age, in both mild and severe disease, which is promising for vaccine efficacy in older individuals. Additionally, we observed significant differences in the breadth and strength of the humoral immune response in relation to ethnicity, which may reflect differences in genetic and lifestyle factors. Furthermore, our data enabled localization of the immuno-dominant epitope to the C-terminal structural domain of the viral nucleocapsid protein in two independent cohorts. Overall, we have designed, validated, and tested an advanced serological assay that enables accurate quantitation of the humoral response post natural infection and that has revealed unexpected differences in the magnitude and epitope utilization within a population

Effect of hyperhydration on the pharmacokinetics and detection of orally administered budesonide in doping control analysis

The aim of the present study was to investigate if hyperhydration could influence the excretion and subsequent detection of budesonide (BDS) and its main metabolites (6β-hydroxy-budesonide and 16α-hydroxy-prednisolone) during doping control analysis by leading to concentrations below the WADA reporting level (30 ng/mL). The influence of hyperhydration on the plasma and urinary pharmacokinetic (PK) profiles of BDS and metabolites was also examined. Seven healthy physically active non-smoking Caucasian males participated in a 15-day clinical study. BDS was administered orally at a single dose of 9 mg on Days 1, 7, and 13. Hyperhydration was applied in the morning on two consecutive days, that is, 0 and 24 hours after first fluid ingestion. Water and a commercial sports drink were used as hyperhydration agents (20 mL/kg body weight). Results showed no significant difference (P > 0.05, 95% CI) on plasma or urinary PK parameters under hyperhydration conditions for all the analytes. However, significant differences (P < 0.05, 95% CI) due to hyperhydration were observed on the urinary concentrations of BDS and metabolites. To compensate the dilution effect due to hyperhydration, different adjustment methods were applied based on specific gravity, urinary flow rate, and creatinine. All the applied methods were able to adjust the concentration values close to the baseline ones for each analyte; however, specific gravity was the optimum method in terms of effectiveness and practicability. Furthermore, no masking of the detection sensitivity of BDS or its metabolites was observed due to hyperhydration either in plasma or urine samples. © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Lt

Clinical Characteristics and Long-term Follow-up of Patients with Diabetes Due To PTF1A Enhancer Mutations

Context: Biallelic mutations in the PTF1A enhancer are the commonest cause of isolated pancreatic agenesis. These patients do not have severe neurological features associated with loss-of-function PTF1A mutations. Their clinical phenotype and disease progression have not been well characterized. Objective: To evaluate phenotype and genotype characteristics and long-term follow-up of patients with PTF1A enhancer mutations. Setting: Twelve tertiary pediatric endocrine referral centers. Patients: Thirty patients with diabetes caused by PTF1A enhancer mutations. Median follow-up duration was 4 years. Main outcome measures: Presenting and follow-up clinical (birthweight, gestational age, symptoms, auxology) and biochemical (pancreatic endocrine and exocrine functions, liver function, glycated hemoglobin) characteristics, pancreas imaging, and genetic analysis. Results: Five different homozygous mutations affecting conserved nucleotides in the PTF1A distal enhancer were identified. The commonest was the Chr10:g.23508437A>G mutation (n = 18). Two patients were homozygous for the novel Chr10:g.23508336A>G mutation. Birthweight was often low (median SDS = -3.4). The majority of patients presented with diabetes soon after birth (median age of diagnosis: 5 days). Only 2/30 presented after 6 months of age. All patients had exocrine pancreatic insufficiency. Five had developmental delay (4 mild) on long-term follow-up. Previously undescribed common features in our cohort were transiently elevated ferritin level (n = 12/12 tested), anemia (19/25), and cholestasis (14/24). Postnatal growth was impaired (median height SDS: -2.35, median BMI SDS: -0.52 SDS) with 20/29 (69%) cases having growth retardation. Conclusion: We report the largest series of patients with diabetes caused by PTF1A enhancer mutations. Our results expand the disease phenotype, identifying recurrent extrapancreatic features which likely reflect long-term intestinal malabsorption.This article is available to RD&E staff via NHS OpenAthens (subject to any publisher embargo). Click on the Publisher URL, and log in with NHS OpenAthens if prompted.Genetic testing for neonatal diabetes was funded through a Wellcome Trust Senior Investigator award (grant number: 098395/Z/12/Z). EDF is a Diabetes UK RD Law rence Fellow (19/005971), and SEF has a Sir Henry Dale Fellow ship jointly funded by the Wellcome Trust and the Royal Society (105636/Z/14/Z).published version, accepted version (12 month embargo), submitted versio

Prognostic tools and candidate drugs based on plasma proteomics of patients with severe COVID-19 complications

COVID-19 complications still present a huge burden on healthcare systems and warrant predictive risk models to triage patients and inform early intervention. Here, we profile 893 plasma proteins from 50 severe and 50 mild-moderate COVID-19 patients, and 50 healthy controls, and show that 375 proteins are differentially expressed in the plasma of severe COVID-19 patients. These differentially expressed plasma proteins are implicated in the pathogenesis of COVID-19 and present targets for candidate drugs to prevent or treat severe complications. Based on the plasma proteomics and clinical lab tests, we also report a 12-plasma protein signature and a model of seven routine clinical tests that validate in an independent cohort as early risk predictors of COVID-19 severity and patient survival. The risk predictors and candidate drugs described in our study can be used and developed for personalized management of SARS-CoV-2 infected patients.</div

Cosmic kidney disease: an integrated pan-omic, physiological and morphological study into spaceflight-induced renal dysfunction.

Missions into Deep Space are planned this decade. Yet the health consequences of exposure to microgravity and galactic cosmic radiation (GCR) over years-long missions on indispensable visceral organs such as the kidney are largely unexplored. We performed biomolecular (epigenomic, transcriptomic, proteomic, epiproteomic, metabolomic, metagenomic), clinical chemistry (electrolytes, endocrinology, biochemistry) and morphometry (histology, 3D imaging, miRNA-ISH, tissue weights) analyses using samples and datasets available from 11 spaceflight-exposed mouse and 5 human, 1 simulated microgravity rat and 4 simulated GCR-exposed mouse missions. We found that spaceflight induces: 1) renal transporter dephosphorylation which may indicate astronauts' increased risk of nephrolithiasis is in part a primary renal phenomenon rather than solely a secondary consequence of bone loss; 2) remodelling of the nephron that results in expansion of distal convoluted tubule size but loss of overall tubule density; 3) renal damage and dysfunction when exposed to a Mars roundtrip dose-equivalent of simulated GCR