Elevated plasma levels of CXCL16 in severe COVID-19 patients.

Genome-wide association studies have recently identified 3p21.31, with lead variant pointing to the CXCR6 gene, as the strongest thus far reported susceptibility risk locus for severe manifestation of COVID-19. In order the determine its role, we measured plasma levels of Chemokine (C-X-C motif) ligand 16 (CXCL16) in the plasma of COVID-19 hospitalized patients. CXCL16 interacts with CXCR6 promoting chemotaxis or cell adhesion. The CXCR6/CXCL16 axis mediates homing of T cells to the lungs in disease and hyper-expression is associated with localised cellular injury. To characterize the CXCR6/CXCL16 axis in the pathogenesis of severe COVID-19, plasma concentrations of CXCL16 collected at baseline from 115 hospitalized COVID-19 patients participating in ODYSSEY COVID-19 clinical trial were assessed together with a set of controls. We report elevated levels of CXCL16 in a cohort of COVID-19 hospitalized patients. Specifically, we report significant elevation of CXCL16 plasma levels in association with severity of COVID-19 (as defined by WHO scale) (P-value < 0.02). Our current study is the largest thus far study reporting CXCL16 levels in COVID-19 hospitalized patients (with whole-genome sequencing data available). The results further support the significant role of the CXCR6/CXCL16 axis in the immunopathogenesis of severe COVID-19 and warrants further studies to understand which patients would benefit most from targeted treatments.

Assessing the potential correlation of polymorphisms in the IL6R with relative IL6 elevation in severely ill COVID-19 patients'.

BACKGROUND: Elevated Interleukin-6 (IL-6) may play an important role in the pathophysiology of COVID-19 yet attenuated response is not seen across all severe patients. We aimed to determine the effect of IL-6 baseline levels and other clinical variables on mortality and outcomes in hospitalized COVID-19 patients as well as to explore genetic variants associated with attenuated IL-6 response. METHODS: Baseline IL-6 cytokine levels were measured in hospitalized patients participating in ongoing ODYSSEY phase 3 randomized study of tradipitant and placebo in hospitalized patients with severe COVID-19 who are receiving supplemental oxygen support. Furthermore blood samples for whole genome sequencing analysis were collected from 150 participants. RESULTS: We report significantly elevated IL-6 in COVID-19 infected hospitalized patients, n = 100 (p-value < 0.0001) when compared to controls n = 324. We also report a significantly increased level of IL-6 (p-value < 0.01) between the severe and mild COVID-19 patients with severity defined on a WHO scale. Excessive IL-6 plasma levels correlate with higher mortality (p-value 0.001). Additionally, based on our classification analysis, combination of IL-6 elevation and high levels of serum glucose can identify highest risk-group of COVID19 patients. Furthermore, we explore the role of genetic regulatory variants affecting baseline IL-6 levels specifically in COVID-19 patients. We have directly tested the association between variants in the IL6 and IL6R gene region and IL6 plasma levels. We provide results for a common IL-6 variant previously associated with pneumonia, rs1800795, and rs2228145 that was previously shown to affect IL-6 plasma levels, as well as report on novel variants associated with IL-6 plasma levels detected in our study patients. CONCLUSIONS: While it is unlikely that "cytokine storm" is the norm in severe COVID19, baseline elevations above 150 pg/ml may be associated with worst outcomes and as such may warrant treatment considerations. So far no clinical studies used IL-6 baseline assessment to stratify the patient population participating in clinical studies. We believe that careful examination and interpretation of the IL-6 levels and genetic variants can help to determine a patient population with a potentially very robust clinical response to IL-6 inhibition. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04326426.

Validation of the motion sickness severity scale: Secondary analysis of a randomized, double-blind, placebo-controlled study of a treatment for motion sickness.

BACKGROUND: Motion sickness is characterized by nausea and vomiting among a constellation of symptoms. Symptom severity is dynamic and distressing. Most validated motion sickness scales are time-intensive and effortful, with alternative scales having uncertain performance or non-specific measures. A validated instrument allowing for facile, rapid assessment of core motion sickness symptom severity would therefore be valuable. We assessed the performance of the Motion Sickness Severity Scale (MSSS), a six-item questionnaire designed to measure real-time motion sickness symptoms. METHODS: MSSS construct validity was assessed as a secondary analysis of data from 63 healthy participants without antiemetic treatment in a clinical trial (Unique Identifier = NCT03772340) conducted to evaluate the safety and efficacy of Tradipitant-a novel neurokinin-1 receptor antagonist-in the treatment of motion sickness. Clinical outcome assessments included the MSSS, the Patient Global Impression of Severity (PGI-S), and the Motion Sickness Assessment Questionnaire (MSAQ). The performance of the MSSS through Pearson correlation coefficients, within-group analysis of variance, empirical cumulative distribution functions, and Kolmogorov-Smirnov tests. RESULTS: The MSSS correlated very highly with the PGI-S (r = 0.93, p-value<0.0001) and highly with the MSAQ (r = 0.83, p-value<0.0001). Mean MSSS scores between increasing PGI-S severity levels increased significantly in all four increments (None-to-Mild: p-value = 0.006, Mild-to-Moderate: p-value<0.0001, Moderate-to-Severe: p-value = 0.006, Severe-to-Very-Severe: p-value = 0.002). There were statistically significant differences in MSSS score distributions stratified by PGI-S severity level, with higher MSSS scores associated with higher PGI-S severity levels and lower MSSS scores associated with lower PGI-S severity levels. DISCUSSION: The MSSS is a valid instrument for the assessment of the core motion sickness symptoms and is reflective of global disease severity. Implementation of the MSSS and comparable simplified, short questionnaires in motion sickness research will provide rapid and accurate measures of disease severity. These measures will enable further elucidation of motion sickness as an illness and inform the development and evaluation of motion sickness therapies.

Once-daily tasimelteon (VEC-162) for jet lag following transmeridian travel: A multicenter, randomized, double-blind, placebo-controlled trial.

Jet Lag Disorder is a Circadian Rhythm Sleep-Wake Disorder resulting from a misalignment of the endogenous circadian clock and the sleep and wake pattern required by a change in time zone. Jet lag is most severe following eastward travel. This multicenter, randomized, placebo-controlled clinical trial (JET) assessed the physiological mechanism of jet lag induced by a real-life transmeridian flight and evaluated the efficacy of tasimelteon-a circadian regulator acting as a dual melatonin receptor agonist, in the treatment of Jet Lag Disorder (JLD). Tasimelteon-treated participants slept 76 min longer on Night 3 during their second trip (evaluation phase) as compared to their first (observational phase). Over the three travel nights evaluated, transmeridian jet travelers in the tasimelteon group slept 131 min more (TST2/3) than those in the placebo group. The JET study demonstrated clinically meaningful improvements in nighttime sleep and daytime alertness in both objective and subjective measures as well as global functioning after a real-world flight. These results suggest that tasimelteon can be an effective therapeutic tool to treat JLD in the context of transmeridian travel.

Loss-of-function mutations in IFNAR2 in COVID-19 severe infection susceptibility.

Recent COVID-19 (coronavirus disease 2019) host genetics studies suggest enrichment of mutations in genes involved in the regulation of type I and type III interferon (IFN) immunity in patients with severe COVID-19 infection. We performed whole-genome sequencing analysis of samples obtained from patients participating in the ongoing ODYSSEY phase 3 study of hospitalised patients with severe COVID-19 infection receiving supplemental oxygen support. We focused on burden testing of categories of rare and common loss-of-function (LOF) variants in all of the IFN pathway genes, specifically with MAF < 0.1% and MAF < 1%. In a model including LOF and missense variants (MAF < 1%), we report a significant signal in both INFAR1 and IFNAR2. We report carriers of rare variants in our COVID-19 cohort, including a stop-gain IFNAR2 (NM_000874:exon9:c.C966A:p.Y322X) amongst carriers of several other IFNAR rare nonsynonymous variants. Furthermore, we report an increased allelic frequency of common IFNAR2 variants in our data, reported also by the COVID-19 Host Genetics Initiative.

Efficacy of Tasimelteon (HETLIOZ®) in the Treatment of Jet Lag Disorder Evaluated in an 8-h Phase Advance Model; a Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

Background: Most travelers experience Jet Lag Disorder (JLD) symptoms due to misalignment of their circadian rhythms with respect to the new time zone. We assessed the efficacy and safety of tasimelteon (HETLIOZ®) in healthy participants using a laboratory model of JLD induced by an 8-h phase advance of the sleep-wake cycle (JET8 Study). We hypothesized that tasimelteon treatment in participants experiencing JLD would cause increased sleep time, increased next-day alertness, and reduced next-day sleepiness. Methods: We undertook a randomized, double-blind, placebo-controlled trial in 12 US clinical research sleep centers. We screened healthy adults ages 18-73 years, who were eligible for the randomization phase of JET8 if they typically went to bed between 21:00 and 01:00, slept between 7 and 9 h each night, and slept at a consistent bedtime. We used block randomization stratified by site to assign participants (1:1) to receive a single oral dose of tasimelteon (20 mg) or placebo 30 min before their 8-h phase-advanced bedtime. The primary endpoint was Total Sleep Time in the first 2/3 of the night (TST2/3), which was measured by polysomnography during the 8-h sleep episode, and assessed in the intent-to-treat population. The trial is completed and registered with ClinicalTrials.gov, NCT03373201. Results: Between October 16, 2017 and January 17, 2018, we screened 607 healthy participants for JET8, of whom 320 (53%) were assigned to receive tasimelteon (n = 160) or placebo (n = 160). Tasimelteon treatment increased TST2/3 (primary endpoint) by 60.3 min (95%CI 44.0 to 76.7, P < 0.0001) and whole night TST by 85.5 min (95% CI 64.3 to 106.6, P < 0.0001), improved next day alertness, next day sleepiness, and shortened latency to persistent sleep by -15.1 min (95% CI -26.2 to -4.0, P = 0.0081). Conclusion: A single dose of tasimelteon improves the primary symptoms of JLD, including nighttime insomnia and next day functioning among participants in a laboratory model of JLD simulating eastward trans-meridian travel by inducing an 8-h phase advance of the sleep-wake cycle.

Tradipitant in the Treatment of Motion Sickness: A Randomized, Double-Blind, Placebo-Controlled Study.

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.