SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Effect of multi-walled carbon nanotubes on kidney of male albino rats with the potential ameliorative effect of alpha lipoic acid

 Multi-walled carbon nanotubes (MWCNTs) have been widely used in various industrial and medical applications. Alpha lipoic acid (ALA) plays a great role in the antioxidant defense system. This research was conducted to investigate the potential therapeutic effect of ALA on MWCNTs induced nephrotoxicity in rat. Forty albino rats were assigned into four equal groups: Group Ⅰ (Control) was treated with 1% tween-80 (0.25 mL/rat/IP) for 5 days, followed by distilled water (2 mL/kg/PO) for 10 days, group Ⅱ (ALA) was orally administered ALA suspension (200 mg/kg) for 10 days, group Ш (MWCNTs) was intraperitoneally injected with MWCNTs suspension at the concentration of 0.5 mg/kg daily for 5 days followed by (2 mL/kg per day) distilled water for 10 days, and group Ⅳ (MWCNTs+ALA) was treated with MWCNTs (0.5 mg/kg, once, IP) for 5 days followed by ALA (200 mg/kg, PO) for 10 days. At the end of experiment, the rats were euthanized. Blood and kidney samples were collected from all rats for biochemical, kidney for histopathological, and immunohistochemical analyses. MWCNTs substantially increased blood urea nitrogen, creatinine, and malondialdehyde. Meanwhile, they markedly reduced glutathione levels. Additionally, MWCNTs induced several histopathological alterations, including dilatation and congestion of most glomeruli, degenerative changes of renal tubules and prominent interstitial hemorrhage. A significant increase in area percentage of caspase 3 and COX 2 in MWCNTs exposed rats. On the other hand, ALA administration alleviated the adverse toxic effects induced by MWCNTs. Conclusion, ALA significantly ameliorate MWCNTs-induced nephrotoxicity through antioxidant, anti-inflammatory, and antiapoptotic mechanisms

Experimental study of the diffusion-controlled corrosion of copper in the bottom of a jet stirred reactor

<div><p>Abstract Jet stirred tank reactors are usually preferred to mechanically stirred tank reactors in the case of high pressure stirred tank reactors in order to avoid the mechanical problems inherent with mechanically agitated reactors. Owing to the impact force exercised by the fluid jet on the tank bottom, the tank bottom is subjected to severe corrosion. The aim of the present work is to address this problem using an accelerated system which simulates natural diffusion-controlled corrosion of metals. Diffusion-controlled corrosion of a fixed copper disc, at the bottom of a cylindrical tank, under a single phase forced jet flow of acidified dichromate solution was investigated. Variables studied were: physical properties of the solution, solution velocity through different diameters of jet nozzle, distance between the jet outlet nozzle and the copper disc surface; and the effect of using a drag reducing polymer. An overall correlation was obtained: Sh = 0.579 Sc 0.33 Re 0.975 (h/d) 0.049 valid for 850 < Sc < 1322, 1852 < Re < 5000 and 0.3 < h/d < 1.2. Addition of polyethylene oxide as a drag reducing polymer was found to diminish the rate of corrosion under single phase forced jet flow by an amount depending on the operation conditions.</p></div

Vasorelaxant Effects of Syzygium samarangense (Blume) Merr. and L.M.Perry Extract Are Mediated by NO/cGMP Pathway in Isolated Rat Thoracic Aorta

Syzygium samarangense (Blume) Merr. and L.M.Perry is utilized widely in traditional medicine. We have reported previously a wide array of pharmacological properties of its leaf extract, among them anti-inflammatory, antioxidant, hepatoprotective, antidiabetic, antiulcer, and antitrypanosomal activities. We also annotated its chemical composition using LC-MS/MS. Here, we continue our investigations and evaluate the vasorelaxant effects of the leaf extract on aortic rings isolated from rats and explore the possible underlying mechanisms. S. samarangense extract induced a concentration dependent relaxation of the phenylephrine-precontracted aorta in the rat model. However, this effect disappeared upon removing the functional endothelium. Pretreating the aortic tissues either with propranolol or NG-nitro-L-arginine methyl ester inhibited the relaxation induced by the extract; however, atropine did not affect the extract-induced vasodilation. Meanwhile, adenylate cyclase inhibitor, MDL; specific guanylate cyclase inhibitor, ODQ; high extracellular KCl; and indomethacin as cyclooxygenase inhibitor inhibited the extract-induced vasodilation. On the other hand, incubation of S. samarangense extract with aortae sections having their intact endothelium pre-constricted using phenylephrine or KCl in media free of Ca2+ showed no effect on the constriction of the aortae vessels induced by Ca2+. Taken together, the present study suggests that S. samarangense extract dilates isolated aortic rings via endothelium-dependent nitric oxide (NO)/cGMP signaling. The observed biological effects could be attributed to its rich secondary metabolites. The specific mechanisms of the active ingredients of S. samarangense extract await further investigations

Effect of silica nanoparticles on kidney of albino rats with the potential ameliorative efficacy of liposomal curcumin

Silica nanoparticles (SiO2-NPs) are widely used commercially in various biomedical and industrial applications. However, their potential toxicity on human and animal health hasattracted particular attention. Liposomal curcumin (LP-Cur) has effective antioxidant and anti-inflammatory defense mechanism.So, this study was achieved toassess the potential ameliorative effect of (LP-Cur) on (SiO2-NPs) induced nephrotoxicity in rats. Twenty four adult male albino  rats of the same weight  were divided into four groups: (Gp I) negative control group (received single intraperitoneal injection of 0.9% saline, standard diet and distilled water), (Gp II) SiO2-NPs  exposed group  (received 200 mg/kg body weight intraperitoneally), (Gp III) SiO2-NPs and LP-Cur co-treated  group  (received 200 mg/kg body weight SiO2-NPsintraperitoneally + 80 mg/kg body weight LP-Cur orally), and (Gp IV) LP-Cur treated group (received 80 mg/kg body weight orally) for 30 days. At the end of experiment, the rats were euthanized by inhalation of 2% isoflurane (0.10 ml) in internal volume of chamber. Blood and kidney samples were collected from all rats for biochemical, histopathological and immunohistochemical analyses. SiO2-NPssignificantly increased blood urea nitrogen (BUN), serum creatinine levels and malondialdehyde. Whereas they substantially reduced the glutathione levels. SiO2-NPs also caused dilatation, congestion ofmost glomeruli in addition to, some atrophied ones. Also, most renal tubulesshowed degenerative changes and marked interstitial hemorrhage. A significant increase in the immunoreactions of caspase-3 of SiO2-NPs exposed rats. Conversely, the administration of LP-Cur ameliorated the detrimental toxic effects caused by SiO2-NPs.In conclusion, antiapoptotic and antioxidant actions of LP-Cur ameliorate the nephrotoxic effect induced by SiO2-NP