Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Undiagnosed Phenylketonuria Can Exist Everywhere: Results From an International Survey

peer reviewedMany countries do not have a newborn screening (NBS) program, and immigrants from such countries are at risk for late diagnosis of phenylketonuria (PKU). In this international survey, 52 of 259 patients (20%) with late diagnosed PKU were immigrants, and 145 of the 259 (55%) were born before NBS or in a location without NBS. © 2021 The Author

Severe Asthma Standard-of-Care Background Medication Reduction With Benralizumab: ANDHI in Practice Substudy

peer reviewedBackground: The phase IIIb, randomized, parallel-group, placebo-controlled ANDHI double-blind (DB) study extended understanding of the efficacy of benralizumab for patients with severe eosinophilic asthma. Patients from ANDHI DB could join the 56-week ANDHI in Practice (IP) single-arm, open-label extension substudy. Objective: Assess potential for standard-of-care background medication reductions while maintaining asthma control with benralizumab. Methods: Following ANDHI DB completion, eligible adults were enrolled in ANDHI IP. After an 8-week run-in with benralizumab, there were 5 visits to potentially reduce background asthma medications for patients achieving and maintaining protocol-defined asthma control with benralizumab. Main outcome measures for non–oral corticosteroid (OCS)-dependent patients were the proportions with at least 1 background medication reduction (ie, lower inhaled corticosteroid dose, background medication discontinuation) and the number of adapted Global Initiative for Asthma (GINA) step reductions at end of treatment (EOT). Main outcomes for OCS-dependent patients were reductions in daily OCS dosage and proportion achieving OCS dosage of 5 mg or lower at EOT. Results: For non–OCS-dependent patients, 53.3% (n = 208 of 390) achieved at least 1 background medication reduction, increasing to 72.6% (n = 130 of 179) for patients who maintained protocol-defined asthma control at EOT. A total of 41.9% (n = 163 of 389) achieved at least 1 adapted GINA step reduction, increasing to 61.8% (n = 110 of 178) for patients with protocol-defined EOT asthma control. At ANDHI IP baseline, OCS dosages were 5 mg or lower for 40.4% (n = 40 of 99) of OCS-dependent patients. Of OCS-dependent patients, 50.5% (n = 50 of 99) eliminated OCS and 74.7% (n = 74 of 99) achieved dosages of 5 mg or lower at EOT. Conclusions: These findings demonstrate benralizumab's ability to improve asthma control, thereby allowing background medication reduction. © 202

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Marqueurs de sévérité et marqueurs prédictifs de réponse au traitement dans l’asthme sévère

International audienceAsthma is a multifactorial disease with complex pathophysiology. Knowledge of its immunopathology and inflammatory mechanisms is progressing and has led to the development over recent years of increasingly targeted therapeutic strategies. The objective of this review is to pinpoint the different predictive markers of asthma severity and therapeutic response. Obesity, nasal polyposis, gastroesophageal reflux disease and intolerance to aspirin have all been considered as clinical markers associated with asthma severity, as have functional markers such as bronchial obstruction, low FEV1, small daily variations in FEV1, and high FeNO. While sinonasal polyposis and allergic comorbidities are associated with better response to omalizumab, nasal polyposis or long-term systemic steroid use are associated with better response to antibodies targeting the IL5 pathway. Elevated total IgE concentrations and eosinophil counts are classic biological markers regularly found in severe asthma. Blood eosinophils are predictive biomarkers of response to anti-IgE, anti-IL5, anti-IL5R and anti-IL4R biotherapies. Dupilumab is particularly effective in a subgroup of patients with marked type 2 inflammation (long-term systemic corticosteroid therapy, eosinophilia≥150/μl or FENO>20 ppb). Chest imaging may help to identify severe patients by seeking out bronchial wall thickening and bronchial dilation. Study of the patient's environment is crucial insofar as exposure to tobacco, dust mites and molds, as well as outdoor and indoor air pollutants (cleaning products), can trigger asthma exacerbation. Wider and more systematic use of markers of severity or response to treatment could foster increasingly targeted and tailored approaches to severe asthma.L’asthme est une maladie multifactorielle dont la physiopathologie est complexe. Les connaissances de l’immunopathologie et des mécanismes inflammatoires ont progressé permettant ces dernières années, le développement de stratégies thérapeutiques de plus en plus ciblées.L’objectif de cette revue est de décrire les différents marqueurs prédictifs de la sévérité de l’asthme et de la réponse thérapeutique. Sur le plan clinique, l’obésité, la polypose nasale, le reflux gastro-œsophagien, l’intolérance à l’aspirine ont été décrits comme des marqueurs associés à la sévérité de l’asthme.Des marqueurs fonctionnels tels qu’une obstruction bronchique, un VEMS bas, de faibles variations journalières de VEMS et une FeNO élevé ont également été décrits comme associés à la sévérité de l’asthme. La polypose naso-sinusienne et les comorbidités allergiques sont associées à une meilleure réponse à l’omalizumab alors que la polypose nasale ou l’utilisation d’une corticothérapie systémique au long cours est associée à une meilleure réponse aux anticorps dirigés contre la voie de l’IL5. Des concentrations d’IgE totales et un taux d’éosinophiles élevés sont des marqueurs biologiques classiquement retrouvés dans l’asthme sévère. L’éosinophilie sanguine est un biomarqueur permettant de prédire la réponse aux biothérapies anti-IgE, anti-IL5, anti-IL5R et anti-IL4R. Le dupilumab s’est révélé efficace en particulier dans le sous-groupe de patients présentant une inflammation de type 2 marquée (corticothérapie systémique au long cours, éosinophilie≥150/μl ou FENO>20 ppb). L’imagerie thoracique pourrait également contribuer à identifier des patients sévères par la recherche d’un épaississement de la paroi bronchique et une dilatation des bronches. L’étude de l’environnement est cruciale puisque des allergènes et des polluants aggravent la maladie asthmatique.Une utilisation plus large et systématique des marqueurs de sévérité ou de réponse au traitement pourrait permettre une approche de plus en plus précise et personnalisée

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease

Condoms And Contexts: Profiles Of Sexual Risk And Safety Among Young Heterosexually Active Men

Heterosexual men\u27s sexual safety behavior is important to controlling the U.S. epidemic of sexually transmitted infections (STIs), including human immunodeficiency virus (HIV). While sexual safety is often treated as a single behavior, such as condom use, it can also be conceptualized as resulting from multiple factors. Doing so can help us achieve more nuanced understandings of sexual risk and safety within partner-related contexts. We used latent class analysis with data collected online from 18- to 25-year-old heterosexually active U.S. men (n = 432) to empirically derive a typology of the patterns of sexual safety strategies they employed. Indicators were sexual risk-reduction strategies used in the past year with the most recent female sex partner: condom use, discussing sexual histories, STI testing, agreeing to be monogamous, and discussing birth control. We identified four subgroups: Risk Takers (12%), Condom Reliers (25%), Multistrategists (28%), and Relationship Reliers (35%). Partner-related context factorsÑnumber of past-year sex partners, relationship commitment, and sexual concurrencyÑpredicted subgroup membership. Findings support tailoring STI prevention to men\u27s sexual risk-safety subgroups. Interventions should certainly continue to encourage condom use but should also include information on how partner-related context factors and alternate sexual safety strategies can help men reduce risk for themselves and their partners