Data availabilitySummary statistics generated by COVID-19 Host Genetics Initiative are available online (https://www.covid19hg.org/results/r6/). The analyses described here use the freeze 6 data. The COVID-19 Host Genetics Initiative continues to regularly release new data freezes. Summary statistics for samples from individuals of non-European ancestry are not currently available owing to the small individual sample sizes of these groups, but the results for 23 loci lead variants are reported in Supplementary Table 3. Individual-level data can be requested directly from the authors of the contributing studies, listed in Supplementary Table 1.

c. polymeropoulos, G. Birznieks & M. H. polymeropoulos the genetic background of Atopic Dermatitis (AD) with chronic pruritus is complex. Filaggrin (FLG) is an essential gene in the epidermal barrier formation s. Loss-of-function (Lof) variants in FLG associated with skin barrier dysfunction constitute the most well-known genetic risk factor for AD. in this study, we focused on the frequency and effect of FLG loss-of-function variants in association with self-reported age-of-onset of AD. The dataset consisted of 386 whole-genome sequencing (WGS) samples. We observe a significant association between FLG Lof status and age-of-onset, with earlier age of onset of AD observed in the FLG LOF carrier group (p-value 0.0003, Wilcoxon two-sample test). We first tested this on the two most prevalent FLG variants. Interestingly, the effect is even stronger when considering all detected FLG Lof variants. Having two or more FLG Lof variants associates with the onset of AD at 2 years of age. In this study, we have shown enrichment of rare variants in the EDC region in cases compared with controls. Age-of-onset analysis shows not only the effect of the FLG and likely eDc variants in terms of the heightened risk of AD, but foremost enables to predict early-onset, lending further credence to the penetrance and causative effect of the identified variants. Understanding the genetic background and risk of early-onset is suggestive of skin barrier dysfunction etiology of AD with chronic pruritus Atopic dermatitis (AD) is a chronic, inflammatory skin disease with an estimated prevalence of 7.3% in the US 1. The genetic background of chronic pruritus in AD is complex. The heritability of AD is estimated to be around 75% 2. Interestingly, when one or both parents have AD the risk of a child developing AD is higher than the risk of developing other atopic conditions, such as asthma and allergic rhinitis 3. This suggests that there are genetic factors specific to AD beyond those for general atopy 4. One of the main functions of the skin is to act as a barrier between the individual and the environment, preventing water loss and at the same time preventing pathogen and allergen entry 5. Skin barrier dysfunction is a key clinical feature of AD, as this facilitates penetration of allergens, immunological dysfunction, and consequently an increased risk of developing eczema 5,6. The skin barrier dysfunction has been associated with the etiology of the itch-scratch cycle. Genes encoding skin barrier proteins have been shown to play a role in the heritability of AD 7,8. FLG is the most studied gene in AD. Loss of function (LOF) variants resulting in aberrant FLG production, constitute the best-known AD gene-association and have been shown to predispose individuals to AD 5,8. FLG initially synthesizes profilaggrin, which is then transformed to FLG monomers which interact with intermediate filaments in the stratum corneum (SC), causing such to aggregate into dense parallel arrays of macrofilaments. This promotes cellular compaction and keratin cros...

Introduction: Novel therapies are needed for the treatment of motion sickness given the inadequate relief and bothersome and dangerous adverse effects of currently approved therapies. Neurokinin-1 (NK1) receptor antagonists have the potential to be effective in improving the symptoms of motion sickness, given the involvement of Substance P in nauseogenic and emetic pathways and the expression of NK1 receptors in the gastrointestinal system. Here we evaluated the efficacy of tradipitant, a novel NK1 receptor antagonist, in preventing motion sickness in variable sea conditions. Methods: A total of 126 adults participated in the Motion Sifnos study. Groups of participants were assigned to one of seven boat trips lasting ∼4 h on the Pacific Ocean. Participants were randomized 1:1 to tradipitant 170 mg or placebo and completed the Motion Sickness Severity Scale (MSSS) every 30 min, in addition to other assessments. Severity of motion sickness was assessed with the incidence of vomiting and the MSSS. Results: Participants on tradipitant had a significantly lower incidence of vomiting as compared to those on placebo across all boat trips (tradipitant = 17.5%, placebo = 39.7%, p = 0.0039). For trips exposed to rough sea conditions, the difference in the incidence of vomiting between the groups was more dramatic (tradipitant = 15.79%, placebo = 72.22%, p= 0.0009). Across these trips, motion sickness symptoms were significantly lower in the tradipitant group compared to the placebo group (tradipitant = 3.19, placebo = 4.57, p = 0.0235). Discussion: Tradipitant has the potential to be an effective therapy for the prevention of vomiting and treatment of nausea in people with motion sickness.

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Purpose To assess the efficacy of tasimelteon to improve sleep in Smith–Magenis syndrome (SMS). Methods A 9-week, double-blind, randomized, two-period crossover study was conducted at four US clinical centers. Genetically confirmed patients with SMS, aged 3 to 39, with sleep complaints participated in the study. Patients were assigned to treatment with tasimelteon or placebo in a 4-week crossover study with a 1-week washout between treatments. Eligible patients participated in an open-label study and were followed for >3 months. Results Improvement of sleep quality (DDSQ50) and total sleep time (DDTST50) on the worst 50% of nights were primary endpoints. Secondary measures included actigraphy and behavioral parameters. Over three years, 52 patients were screened, and 25 patients completed the randomized portion of the study. DDSQ50 significantly improved over placebo (0.4, p = 0.0139), and DDTST50 also improved (18.5 minutes, p = 0.0556). Average sleep quality (0.3, p = 0.0155) and actigraphy-based total sleep time (21.1 minutes, p = 0.0134) improved significantly, consistent with the primary outcomes. Patients treated for ≥90 days in the open-label study showed persistent efficacy. Adverse events were similar between placebo and tasimelteon. Conclusion Tasimelteon safely and effectively improved sleep in SMS.