Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children

Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C

Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-alpha 2 in 10 patients: IFN-alpha 2 only in three, IFN-alpha 2 plus IFN-omega in five, and IFN-alpha 2, IFN-omega plus IFN-beta in two; IFN-omega only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-alpha 2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-omega in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-alpha 2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-. only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-omega and/or IFN-alpha 2

Psychosocial status of patients with epilepsy

27th International Epilepsy Congress -- JUL 08-12, 2007 -- Singapore, SINGAPOREWOS: 000253978700647…Int League Against Epilepsy, Int Bur Epileps

Spermatozoa selection by the swim-up procedure and two-layer percoll gradient centrifugation

PubMedID: 8899483The efficiency of the swim-up procedure and two-layer Percoll gradient centrifugation in procession of spermatozoa was assessed in ejaculates from 47 infertile men. A significantly higher total number of spermatozoa was harvested from Percoll gradients than from the swim-up procedure, the loss rates in concentration being -13.6±6.4% and -70.8±5.8%, respectively (p<0.0001). Recovery in per cent motility was significantly higher after the Percoll gradient than after the swim-up procedure (34.8±10.2% versus -10.4±17.2%, p<0.05). No significant difference was noted between the mean motility grades of the final solutions obtained by the two methods (2.7±0.2 and 2.0±0.4, respectively, p>0.05). When evaluation was conducted within three initial fresh sample concentration categories such as severe oligospermia (lower than 5×10 6/ml), moderate oligospermia (5 to 10×10 6/ml) and mild oligospermia (higher than 10×10 6/ml), the Percoll technique recovered, significantly higher number of spermatozoa than the swim-up procedure through all concentration categories (p<0.05 for each range). Despite being statistically insignificant, Percoll gradients produced final spermatozoa pools with higher per cent motility and motility quality within all concentration ranges. The results suggest that the Percoll gradient centrifugation should be the preferred selection method regardless of the initial fresh sample concentration. © 1996 Akadémiai Kiadó

Medicine use behaviors of people in the city of Adana, Turkey [Adana İlindeki İnsanlarI{dotless}n İlaç kullanI{dotless}m alI{dotless}şkanlI{dotless}klarI{dotless}]

AIM: The purpose of our study is to examine the medicine use behaviors of people in Adana. METHOD: The planned sample size was 1,222. The "Rational Use of Drugs Questionnaire" prepared by us was applied to 1,111 voluntary subjects over 18 years old telephone survey. RESULTS: 57.2% of these participants said that they used drugs without consulting a doctor. 98.4% of these participants told that they used analgesics without consulting a doctor. 30.5% said that they used antibiotics without asking a doctor in cases of common cold; 47.9% told that they discontinue the antibiotics the doctor prescribed for them before completely finishing; 85.8% said that they checked the expiry date of the medicines. CONCLUSION: The average Rational Use of Drug Score of all the participants is found to be 68.3±13.5 on the scale of 100. This score shows that the knowledge of the people in Adana about rational use of drug is not sufficient and that education and awareness levels of the people should be raised

Which is the best anthropometric technique to identify obesity: Body mass index, waist circumference or waist-hip ratio?

PubMedID: 17847914This study was designed to define the most suitable anthropometric technique among body mass index (BMI), waist circumference (WC) and waist-hip ratio (WHR) as indices of obesity in adult people living in Adana, a Southern province of Turkey. A random sample design was used. A total of 900 individuals (men and non-pregnant women aged 25-65 years) were enrolled in the study. Of subjects, 50.9% were females. Anthropometric measurements were performed. Data were analysed using statistical package program. The prevalence of obesity among adults living in Adana was 20.8% 28.4% when defined using BMI, 30.5% by WC and 15.8% 42.0% by WHR. Truncal obesity and gynoid obesity showed similar prevalence with 26.6%, in the same age group. Waist circumference, BMI and WHR identified different proportions of the population, as measured for obesity prevalence. The most common methods for diagnosing overweight and obesity are based on BMI (kg/m2). However, BMI is suboptimal marker for total body fat percentage and even less suitable to assess body fat distribution. WHR is the most useful measure of obesity and the best simple anthropometric index in predicting a wide range of risk factors and related health conditions

EPIDEMIOLOGY OF MENINGOCOCCAL INFECTIONS IN CHILDREN IN MIDSOUTHERN PART OF TURKEY

WOS: A1995RT82700005PubMed ID: 854970559 patients were treated for meningococcal infections in Cukurova University Faculty of Medicine, Division of Pediatric Infectious Diseases. 50.8% of patients were male, 33.9% were under two years of age and 61% were under five. 78% of patients were admitted to hospital in winter and spring time. Meningococcal meningitis (MM) was present in 39% of patients on admission, however, meningococcemia in 27.1% and meningococcemia and meningococcic meningitis (Meningococcemia + MM) in 33.9%. Fatality rate was 18.6% and no association was found between mortality and clinical type of disease (p > 0.05), but mortality ratio decreased with an increasing age (p < 0.01). No deaths occurred among the 12 patients who received IV penicillin treatment shortly before admitting to hospital, on the other hand 11 of 47 patients (23.4%) without such a previous treatment died