A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Lopinavir pharmacokinetics in COVID-19 patients

International audienceThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, in late 2019. Therapeutic solutions are currently being tested for COVID-19, the SARS-CoV-2-associated pneumonia. Ritonavir-boosted lopinavir is included in the investigational therapies. A recent in vitro study reported that lopinavir inhibits SARS-CoV-2 replication with a 50% effective concentration (EC50) of 16 720 ng/mL.1Here we describe lopinavir pharmacokinetics in COVID-19 patients treated with ritonavir-boosted lopinavir at the Nantes University Hospital, France

Hepatitis A and B vaccine uptake and immunisation among men who have sex with men seeking PrEP: a substudy of the ANRS IPERGAY trial

Vaccination against hepatitis A virus (HAV) and hepatitis B virus (HBV) is recommended in men who have sex with men (MSM). We assessed HAV and HBV vaccine uptake in the nonimmune participants and their immunisation during follow-up of the ANRS IPERGAY (Intervention Préventive de l'Exposition aux Risques avec et pour les Gays) pre-exposure prophylaxis (PrEP) trial. During the ANRS IPERGAY trial among MSM (NCT 01473472), vaccination against HAV and HBV was offered free of charge to all nonimmune participants at baseline. We assessed anti-HAV IgGs and anti-hepatitis B surface (HBs) antibodies (Abs) at baseline, 1-3 months after each vaccine dose and on the last followup visit. Vaccination uptake and immunisation were analysed in non-immune participants with at least 6 months of follow-up after the 1st vaccine dose. A total of 427 MSM with a median age of 34.8 years were analysed. Median follow-up was 2.2 years (Q1-Q3, 1.6-2.9). Absence of anti-HAV IgG at baseline (50.4%, 215/427) was associated with younger age (p=0.0001). Among HAV non-immune participants, 96.1% (197/205) received one or more vaccine doses and 91.0% (172/189) received two vaccine doses. Among HBV non-immune participants, 97.6 % (81/83) received one or more vaccine doses and 78.4% (58/74) received three doses. On the last-visit sample, anti-HAV IgG and anti-HBs Abs were respectively detected in 94.8% (95% CI 90.0% to 97.7%) and 79.6% (95% CI 66.5% to 89.4%) of participants with complete vaccination and in 80.0% (95% CI 51.9% to 95.7%) and 40.0% (95% CI 16.3% to 67.7%) of participants with incomplete vaccination. Vaccine acceptability against HAV and HBV infections was very high in MSM starting PrEP. Immunisation was high in participants with a full vaccination scheme. Physicians must consider PrEP visits as major opportunities to propose and complete HAV and HBV vaccination in at-risk non-immune subjects

Hepatitis A and B vaccine uptake and immunisation among men who have sex with men seeking PrEP: a substudy of the ANRS IPERGAY trial

Vaccination against hepatitis A virus (HAV) and hepatitis B virus (HBV) is recommended in men who have sex with men (MSM). We assessed HAV and HBV vaccine uptake in the nonimmune participants and their immunisation during follow-up of the ANRS IPERGAY (Intervention Préventive de l'Exposition aux Risques avec et pour les Gays) pre-exposure prophylaxis (PrEP) trial. During the ANRS IPERGAY trial among MSM (NCT 01473472), vaccination against HAV and HBV was offered free of charge to all nonimmune participants at baseline. We assessed anti-HAV IgGs and anti-hepatitis B surface (HBs) antibodies (Abs) at baseline, 1-3 months after each vaccine dose and on the last followup visit. Vaccination uptake and immunisation were analysed in non-immune participants with at least 6 months of follow-up after the 1st vaccine dose. A total of 427 MSM with a median age of 34.8 years were analysed. Median follow-up was 2.2 years (Q1-Q3, 1.6-2.9). Absence of anti-HAV IgG at baseline (50.4%, 215/427) was associated with younger age (p=0.0001). Among HAV non-immune participants, 96.1% (197/205) received one or more vaccine doses and 91.0% (172/189) received two vaccine doses. Among HBV non-immune participants, 97.6 % (81/83) received one or more vaccine doses and 78.4% (58/74) received three doses. On the last-visit sample, anti-HAV IgG and anti-HBs Abs were respectively detected in 94.8% (95% CI 90.0% to 97.7%) and 79.6% (95% CI 66.5% to 89.4%) of participants with complete vaccination and in 80.0% (95% CI 51.9% to 95.7%) and 40.0% (95% CI 16.3% to 67.7%) of participants with incomplete vaccination. Vaccine acceptability against HAV and HBV infections was very high in MSM starting PrEP. Immunisation was high in participants with a full vaccination scheme. Physicians must consider PrEP visits as major opportunities to propose and complete HAV and HBV vaccination in at-risk non-immune subjects

Hepatitis A and B vaccine uptake and immunisation among men who have sex with men seeking PrEP: a substudy of the ANRS IPERGAY trial

Vaccination against hepatitis A virus (HAV) and hepatitis B virus (HBV) is recommended in men who have sex with men (MSM). We assessed HAV and HBV vaccine uptake in the nonimmune participants and their immunisation during follow-up of the ANRS IPERGAY (Intervention Préventive de l'Exposition aux Risques avec et pour les Gays) pre-exposure prophylaxis (PrEP) trial. During the ANRS IPERGAY trial among MSM (NCT 01473472), vaccination against HAV and HBV was offered free of charge to all nonimmune participants at baseline. We assessed anti-HAV IgGs and anti-hepatitis B surface (HBs) antibodies (Abs) at baseline, 1-3 months after each vaccine dose and on the last followup visit. Vaccination uptake and immunisation were analysed in non-immune participants with at least 6 months of follow-up after the 1st vaccine dose. A total of 427 MSM with a median age of 34.8 years were analysed. Median follow-up was 2.2 years (Q1-Q3, 1.6-2.9). Absence of anti-HAV IgG at baseline (50.4%, 215/427) was associated with younger age (p=0.0001). Among HAV non-immune participants, 96.1% (197/205) received one or more vaccine doses and 91.0% (172/189) received two vaccine doses. Among HBV non-immune participants, 97.6 % (81/83) received one or more vaccine doses and 78.4% (58/74) received three doses. On the last-visit sample, anti-HAV IgG and anti-HBs Abs were respectively detected in 94.8% (95% CI 90.0% to 97.7%) and 79.6% (95% CI 66.5% to 89.4%) of participants with complete vaccination and in 80.0% (95% CI 51.9% to 95.7%) and 40.0% (95% CI 16.3% to 67.7%) of participants with incomplete vaccination. Vaccine acceptability against HAV and HBV infections was very high in MSM starting PrEP. Immunisation was high in participants with a full vaccination scheme. Physicians must consider PrEP visits as major opportunities to propose and complete HAV and HBV vaccination in at-risk non-immune subjects

Utility of hyposmia and hypogeusia for the diagnosis of COVID-19

International audience[No abstract available