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

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

peer reviewe

A Recurrent Misdiagnosed and Maltreated Case of Keratosis Obturans

Keratosis obturans is an obscure entity characterized by accumulation of desquamated keratinous material in the bony portion of the external auditory canal. Patients with this condition typically present with severe otalgia, conductive hearing loss, and global widening of the external auditory canal. We present a case of keratosis obturans that was misdiagnosed as impacted wax. The case was diagnosed and managed by microscope-guided examination with the patient under general anesthesia

Robotic Assistance for Minimally Invasive Cervical Pedicle Instrumentation: Report on Feasibility and Safety

International audienceBackgroundAccurate screw placement remains challenging, especially in the cervical spine. We present our first experience of minimally invasive posterior cervical and upper thoracic pedicle screw fixation in the lower cervical spine.MethodsThis study reports a case series of patients, undergoing posterior percutaneous pedicle fixation using Cirq robotic assistance coupled to the Airo intraoperative computed tomography scan and Brainlab navigation system. Routine computed tomography was performed on postoperative day 2 to evaluate pedicle screw placement. The effective dose was calculated.ResultsBetween February 2020 and December 2020, 7 patients (4 men and 3 women) were treated. The mean age was 58.8 years (range, 29–75 years). Fixation was performed with a cannulated PASS OCT Reconstruction System (Medicrea). Overall, 28 screws were placed within cervical and upper thoracic pedicles. According to the Neo and Heary classification, 85.7% were rated as acceptable and 14.3% as poor. The radiation dose received by the patient was 9.1 mSv (range, 7.7–10.6 mSv). The radiation dose received by the surgical staff was 0 mSv. The postoperative course was excellent.ConclusionsPosterior miniopen fixation using Cirq robotic assistance coupled with an intraoperative computed tomography navigation system is a major innovation that can improve the accuracy of pedicle screw positioning, with acceptable patient radiation and reduced surgical team exposure

Long‐term cognitive outcome after radiosurgery in epileptic hypothalamic hamartomas and review of the literature

International audienc

Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking

Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function

SARS-CoV-2 vaccination modelling for safe surgery to save lives: data from an international prospective cohort study

Background: Preoperative SARS-CoV-2 vaccination could support safer elective surgery. Vaccine numbers are limited so this study aimed to inform their prioritization by modelling. Methods: The primary outcome was the number needed to vaccinate (NNV) to prevent one COVID-19-related death in 1 year. NNVs were based on postoperative SARS-CoV-2 rates and mortality in an international cohort study (surgical patients), and community SARS-CoV-2 incidence and case fatality data (general population). NNV estimates were stratified by age (18-49, 50-69, 70 or more years) and type of surgery. Best- and worst-case scenarios were used to describe uncertainty. Results: NNVs were more favourable in surgical patients than the general population. The most favourable NNVs were in patients aged 70 years or more needing cancer surgery (351; best case 196, worst case 816) or non-cancer surgery (733; best case 407, worst case 1664). Both exceeded the NNV in the general population (1840; best case 1196, worst case 3066). NNVs for surgical patients remained favourable at a range of SARS-CoV-2 incidence rates in sensitivity analysis modelling. Globally, prioritizing preoperative vaccination of patients needing elective surgery ahead of the general population could prevent an additional 58 687 (best case 115 007, worst case 20 177) COVID-19-related deaths in 1 year. Conclusion: As global roll out of SARS-CoV-2 vaccination proceeds, patients needing elective surgery should be prioritized ahead of the general population

COVID-19 Host Genetics Initiative. A first update on mapping the human genetic architecture of COVID-19

The COVID-19 pandemic continues to pose a major public health threat, especially in countries with low vaccination rates. To better understand the biological underpinnings of SARS-CoV-2 infection and COVID-19 severity, we formed the COVID-19 Host Genetics Initiative1. Here we present a genome-wide association study meta-analysis of up to 125,584 cases and over 2.5 million control individuals across 60 studies from 25 countries, adding 11 genome-wide significant loci compared with those previously identified2. Genes at new loci, including SFTPD, MUC5B and ACE2, reveal compelling insights regarding disease susceptibility and severity.</p