Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Effects of antagonistic fungi, wastes materials and urea on the populations of Meloidogyne incognita and growth of tomato

Effects of three antagonistic fungi ( Paecilomyces lilacinus, Pochonia chlamydosporia , and Trichoderma harzianum ) alone and together with wastes materials (saw dust and neem leaf litter) and urea were studied on the growth of tomato and on the reproduction of Meloidogyne incognita in glass house experiments. Individually neem leaf litter was better in improving growth of plants without nematodes compared with any other single treatment. However, use of P. lilacinus against plants with M. incognita caused higher increase in plant growth than caused by P. chlamydosporia / T. harzianum or urea but similar to that caused by neem leaf litter or saw dust. Maximum increase in the growth of nematode inoculated plants was observed when P. lilacinus was used with neem leaf litter. P. lilacinus caused higher reduction in galling and nematode multiplication followed by P. chlamydosporia , neem leaf litter, urea, T. harzianum and saw dust. Maximum reduction in galling and nematode multiplication was observed when P. lilacinus was used with neem leaf litter

Effects of interaction of Meloidogyne incognita, Alternaria dauci and Rhizoctonia solani on the growth, chlorophyll, carotenoid and proline contents of carrot in three types of soil

Disease complex of carrot (Daucus carota L.) involving root knot nematode Meloidogyne incognita and two fungi Alternaria dauci and Rhizoctonia solani were studied in three soil types. More plant growth, chlorophyll, carotenoid and proline contents were found in carrot grown in fly ash mix soil than plants grown in sand mix soil and loamy soil. Inoculation of M. incognita, R. solani, and A. dauci reduced plant growth, chlorophyll and carotenoid but increased proline contents. Inoculation of M. incognita 20 days prior to a fungal pathogen caused a greater reduction in plant growth, chlorophyll and carotenoid than fungal pathogen was inoculated prior. Inoculation of A. dauci prior to R. solani or vice versa had a similar effect on plant growth, chlorophyll, and carotenoid. Nematode multiplication and galling was higher in plants grown in sand mix soil followed by loamy soil and fly ash mix soil. Both fungi had adverse effects on galling and nematode multiplication. Blight disease index caused by A. dauci was 3 and crown rot index by R. solani was also recorded 3. These disease indices were 5 when pathogens were inoculated in combinations

Greenhouse evaluation of rhizobia as biocontrol agent of root-infecting fungi in okra

Nine rhizobial strains isolated from the root nodules of Cicer arietinum, Vigna radiata, V. mungo, Samania saman, Sesbania sesban, Leucinia sp., Prosopis cineraria and Medicago sativa were used to study their effects on root-infecting fungi viz., Macrophomina phaseolina, Fusarium solani and Rhizoctonia solani. In dual culture plate assay, strains of Bradyrhizobium sp., and R. meliloti were found to inhibit radial growth of M. phaseolina, F. solani and R. solani producing zones of inhibition. Bradyrhizobium sp., and R. meliloti either used as seed dressing or as soil drench significantly suppressed root-rot infection caused by M. phaseolina, F. solani and R. solani in okra, a non-1eguminous crop under greenhouse conditions. Biomass of plants was also higher in the presence of rhizobia

Prevalence and Correlates of Vitamin D Deficiency in Children Aged Less than Two Years: A Cross-Sectional Study from Aseer Region, Southwestern Saudi Arabia

Background: Vitamin D is an essential nutrient for bone growth, mineralization, and other metabolic processes in the human body. Hence, insufficiency or deficiency of this vitamin can have long-term effects, particularly for children. Objectives: The aims of this study were to determine the prevalence of vitamin D deficiency in children up to 2 years of age and investigate the independent predictors of vitamin D deficiency. Methodology: This cross-sectional study was conducted among 484 children aged up to two years who were admitted to the hospital for the treatment of any acute condition from January to November 2021. Serum 25(OH)D was used to determine the level of vitamin D. The serum 25(OH)D was categorized into 3 groups: Sufficiency (>30 ng/mL), insufficiency (20–30 ng/mL), and the deficiency (<20 ng/mL). Results: Overall, vitamin D deficiency was observed in 70.5% of the children, of whom 45.9% had insufficient levels, and one-fourth (24.6%) showed deficiency. The children aged 2–12 months (infants) were more likely to be vitamin deficient compared to children aged 12 months and above. The children who lived in urban areas had a threefold increased risk of vitamin D deficiency (aOR = 3.0, 95% CI 1.78–5.08). The children who were exposed to sunlight for less than 3 days per week experienced a higher risk of developing vitamin D deficiency (aOR = 4.17, 95% CI 2.04–10.88). Children who had received only breast milk were more than two times more likely to experience vitamin D deficiency (aOR = 2.42, 95% CI 1.12–5.23) compared to their counterparts. Conclusion: Our study reveals a high prevalence of vitamin D deficiency among children aged up to two years. Infants, urban dwellers, only breastfed, and exposure to sunlight for less than three days per week were identified to be the independent risk factors for vitamin D deficiency. The results of this work call for enhancing awareness to ensure adequate levels of vitamin D for better health of the children in this region of Saudi Arabia