Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative

Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p=5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights. Author SummaryCOVID-19 clinical outcomes vary immensely, but a patients genetic make-up is an important determinant of how they will fare against the virus. While many genetic variants commonly found in the populations were previously found to be contributing to more severe disease by the COVID-19 Host Genetics Initiative, it isnt clear if more rare variants found in less individuals could also play a role. This is important because genetic variants with the largest impact on COVID-19 severity are expected to be rarely found in the population, and these rare variants require different technologies to be studies (usually whole-exome or whole-genome sequencing). Here, we combined sequencing results from 21 cohorts across 12 countries to perform a rare variant association study. In an analysis comprising 5,085 participants with severe COVID-19 and 571,737 controls, we found that the gene for toll-like receptor 7 (TLR7) on chromosome X was an important determinant of severe COVID-19. Importantly, despite being found on a sex chromosome, this observation was consistent across both sexes.

Serum biochemical response to inhalant anesthetics in New Zealand white rabbits.

Anesthetics can affect biochemical parameters, complicating the interpretation of laboratory results and perhaps leading to erroneous diagnoses. The present study was performed to characterize variations in selected rabbit biochemical parameters after inhalant anesthetics. Twenty New Zealand White rabbits were allocated to 2 treatment groups (n = 10 animals each), which received either halothane or isoflurane. Anesthesia was induced by using a face-mask, and rabbits were intubated for maintenance of anesthesia for 30 min. Blood samples were obtained before induction and at 1, 10, 30, 60, and 120 min and 24, 48, and 72 h after intubation. Serum cholesterol, triglycerides, albumin, total proteins, total bilirubin, sodium, potassium, chloride, calcium, and phosphorus concentrations were measured by using an autoanalyzer. Administration of halothane significantly increased serum triglyceride levels and decreased serum cholesterol, albumin, total protein, and potassium levels. Isoflurane administration increased serum triglyceride, phosphorus, and chloride concentrations and decreased serum calcium and potassium levels. Caution is required in interpreting data on serum biochemical parameters from rabbits anesthetized with halothane or isoflurane.

Pituitary-adrenocortical axis, serum serotonin and biochemical response after halothane or isoflurane anaesthesia in rabbits.

To document the changes in serum serotonin, adrenocorticotrophic hormone (ACTH), corticosterone levels and select biochemical parameters in response to inhalant anaesthesia, 20 New Zealand White (NZW) rabbits were assigned to two treatment groups: halothane and isoflurane. Induction of anaesthesia was achieved using a face mask (3.5% halothane and 4.5% isoflurane in oxygen) followed by endotracheal intubation and maintenance of anaesthesia for 30 min (1.5% halothane and 2.5% isoflurane in oxygen). Blood samples were obtained before anaesthetic induction, and at 1, 10, 30, 60, 120 min and 24, 48 and 72 h after endotracheal intubation. Serum serotonin and corticosterone levels were measured by competitive enzyme immunoassay, ACTH by radioimmunoassay. Serum glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), blood urea nitrogen (BUN) and creatinine levels were measured using an automated analyser. Significant increases in serum ACTH and corticosterone levels occurred after halothane administration while serum serotonin levels did not change. An increase in serum corticosterone and serotonin levels occurred in the isoflurane group but no changes in ACTH concentrations were detected. Administration of halothane significantly increased serum glucose, ALT, AST, BUN and creatinine levels. After isoflurane administration, there was a significant increase in serum glucose, AST, BUN and creatinine levels. Based on these results, halothane stimulates the hypothalamic-pituitary-adrenal axis to a greater extent than isoflurane, but isoflurane increases serum serotonin levels. Both anaesthetic agents alter select biochemical parameters. These results should be taken into account when blood samples are evaluated in treated isoflurane or halothane anaesthetized rabbits.

Targeted ethnography as a critical step to inform cultural adaptations of HIV prevention interventions for adults with severe mental illness.

As in other countries worldwide, adults with severe mental illness (SMI) in Brazil are disproportionately infected with HIV relative to the general population. Brazilian psychiatric facilities lack tested HIV prevention interventions. To adapt existing interventions, developed only in the US, we conducted targeted ethnography with adults with SMI and staff from two psychiatric institutions in Brazil. We sought to characterize individual, institutional, and interpersonal factors that may affect HIV risk behavior in this population. We conducted 350 hours of ethnographic field observations in two mental health service settings in Rio de Janeiro, and 9 focus groups (n=72) and 16 key-informant interviews with patients and staff in these settings. Data comprised field notes and audiotapes of all exchanges, which were transcribed, coded, and systematically analyzed. The ethnography identified and/or characterized the institutional culture: (1) patients' risk behaviors; (2) the institutional setting; (3) intervention content; and (4) intervention format and delivery strategies. Targeted ethnography also illuminated broader contextual issues for development and implementation of HIV prevention interventions for adults with SMI in Brazil, including an institutional culture that did not systematically address patients' sexual behavior, sexual health, or HIV sexual risk, yet strongly impacted the structure of patients' sexual networks. Further, ethnography identified the Brazilian concept of "social responsibility" as important to prevention work with psychiatric patients. Targeted ethnography with adults with SMI and institutional staff provided information critical to the adaptation of tested US HIV prevention interventions for Brazilians with SMI.

The effects of anesthesia on the clinical chemistry of New Zealand White rabbits.

The effects of four anesthetics on various plasma biochemical parameters were investigated in the New Zealand White rabbit. Fifty animals were assigned to five treatment groups (n = 10 per group): control (1 ml normal saline intravenously [i.v.]); ketamine (10 mg/kg i.v.) with either xylazine (3 mg/kg i.v.) or diazepam (2 mg/kg i.v.); pentobarbitone (30 mg/kg i.v.); and thiopentone (20 mg/kg i.v.). Plasma cholesterol, triglycerides, lactate dehydrogenase (LDH), sodium, potassium, chloride, calcium and phosphorus concentrations were measured by an autoanalyzer. Blood samples were obtained at six time-points: before injection and at 10, 30, 60, and 120 min and 24 h after injection of the anesthetic or saline. Plasma biochemical levels were compared to control group and baseline (time 0) levels. Plasma cholesterol concentrations significantly increased in the ketamine-diazepam (P<0.01) and pentobarbitone (P<0.05) groups, whereas plasma triglycerides significantly increased in the ketamine-xylazine (P<0.01) and ketamine-diazepam (P<0.01) groups. Plasma LDH significantly increased in the ketamine-diazepam group (P<0.001) and decreased in the pentobarbitone group (P<0.01). Plasma sodium levels significantly increased after ketamine-xylazine (P<0.05), ketamine-diazepam (P<0.05), and thiopentone (P<0.05) administration; plasma potassium significantly increased after ketamine-xylazine (P<0.05) and decreased in the pentobarbitone group (P<0.05); plasma chloride (P<0.01) and phosphorus (P<0.05) significantly increased after ketamine-diazepam treatment whereas plasma calcium levels increased (P<0.05) after ketamine-xylazine injection. From the results observed so far, we concluded that plasma levels of some biochemical parameters significantly increased or decreased after anesthetic administration. Therefore, caution is required in interpreting data on plasma biochemical parameters from anesthetized rabbits, particularly during the recovery period.