TITLE: Randomised Controlled Trial of Intravenous Nafamostat Mesylate in COVID pneumonitis: Phase 1b/2a Experimental Study to Investigate Safety, Pharmacokinetics and Pharmacodynamics

Despite the success of vaccines and selected repurposed treatments, COVID-19 is likely to remain a global health problem and further chemotherapeutics are required. Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials without characterisation of Pharmacokinetics (PK)/Pharmacodynamics (PD) including safety in COVID-19. One such drug is Nafamostat Mesylate (Nafamostat), a synthetic serine protease inhibitor with anticoagulant and anti-inflammatory properties. Preclinical data has demonstrated that it is has potent antiviral activity against SARS-CoV-2 by directly inhibiting the transmembrane protease serine 2 (TMPRSS2) dependent stage of host cell entry. MethodsWe present the findings of a phase Ib/II open label, platform randomised controlled trial (RCT), exploring the safety of intravenous Nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), Nafamostat or an alternative therapy. Secondary endpoints included clinical endpoints such as number of oxygen free days and clinical improvement/ deterioration, PK/PD, thromboelastometry, D Dimers, cytokines, immune cell flow cytometry and viral load. ResultsData is reported from 42 patients, 21 of which were randomly assigned to receive intravenous Nafamostat. The Nafamostat group developed significantly higher plasma creatinine levels, more adverse events and a lower number of oxygen free days. There were no other statistically significant differences in the primary or secondary endpoints between Nafamostat and SoC. PK data demonstrated that intravenous Nafamostat was rapidly broken down to inactive metabolites. We observed an antifibrinolytic profile, and no significant anticoagulant effects in thromboelastometry. Participants in the Nafamostat group had higher D Dimers compared to SoC. There were no differences in cytokine profile and immune cell phenotype and viral loads between the groups. ConclusionIn hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous Nafamostat. Given the number of negative trials with repurposed drugs, our experimental medicine trial highlights the value of PK/PD studies prior to selecting drugs for efficacy trials. Given the mechanism of action, further evaluation of Nafamostat delivered via a different route may be warranted. This trial demonstrates the importance of experimental trials in new disease entities such as COVID-19 prior to selecting drugs for larger trials.

Whole genome sequencing identifies multiple loci for critical illness caused by COVID-19

Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care1 or hospitalisation2;3;4 following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study recruits critically-ill cases and compares their genomes with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identify 15 new independent associations with critical COVID-19, including variants within genes involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating expression of multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease. We show that comparison between critically-ill cases and population controls is highly efficient for genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. Therapeutic predictions arising from these findings require testing in clinical trials.

Genetic mechanisms of critical illness in Covid-19

The subset of patients who develop critical illness in Covid-19 have extensive inflammation affecting the lungs1 and are strikingly different from other patients: immunosuppressive therapy benefits critically-ill patients, but may harm some non-critical cases.2 Since susceptibility to life-threatening infections and immune-mediated diseases are both strongly heritable traits, we reasoned that host genetic variation may identify mechanistic targets for therapeutic development in Covid-19.3 GenOMICC (Genetics Of Mortality In Critical Care, genomicc.org) is a global collaborative study to understand the genetic basis of critical illness. Here we report the results of a genome-wide association study (GWAS) in 2244 critically-ill Covid-19 patients from 208 UK intensive care units (ICUs), representing >95% of all ICU beds. Ancestry-matched controls were drawn from the UK Biobank population study and results were confirmed in GWAS comparisons with two other population control groups: the 100,000 genomes project and Generation Scotland. We identify and replicate three novel genome-wide significant associations, at chr19p13.3 (rs2109069, p = 3.98 x 10-12), within the gene encoding dipeptidyl peptidase 9 (DPP9), at chr12q24.13 (rs10735079, p =1.65 x 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), and at chr21q22.1 (rs2236757, p = 4.99 x 10-8) in the interferon receptor gene IFNAR2. Consistent with our focus on extreme disease in younger patients with less comorbidity, we detect a stronger signal at the known 3p21.31 locus than previous studies (rs73064425, p = 4.77 x 10-30). We identify potential targets for repurposing of licensed medications. Using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease. Transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe Covid-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms, and mediators of inflammatory organ damage in Covid-19. Both mechanisms may be amenable to targeted treatment with existing drugs. Large-scale randomised clinical trials will be essential before any change to clinical practice.

The Role of Habits in Anorexia Nervosa: Where We Are and Where to Go From Here?

PURPOSE OF REVIEW: The persistent maladaptive eating behavior characteristic of anorexia nervosa (AN) can be understood as a learned habit. This review describes the cognitive neuroscience background and the existing data from research in AN. RECENT FINDINGS: Behavior is habitual after it is frequently repeated and becomes nearly automatic, relatively insensitive to outcome, and mediated by dorsal frontostriatal neural systems. There is evidence for such behavior in AN, in which restrictive intake has been related to dorsal frontostriatal systems. Other neural and neurocognitive data provide mixed findings, some of which suggest disturbances in habit systems in AN. There are compelling behavioral and neural data to suggest that habit systems may underlie the persistence of AN. The habit model needs further research, via more direct behavioral hypothesis testing and probes of the development of habitual behavior. Investigation of the habit-centered model of AN may open avenues for the development of novel treatments.

The effect of acute weight restoration on dietary fat preference in hospitalized patients with anorexia nervosa.

OBJECTIVE: Individuals with anorexia nervosa (AN) restrict fat intake. The Geiselman Food Preference Questionnaire-I© (FPQ) is a validated self-report instrument that yields a fat preference score (>100 = high fat preference, <100 = low fat preference). The goal of the study was to assess the utility of the FPQ in patients with AN. SPECIFIC AIMS: (1) to examine change in fat preference scores before and after weight restoration in hospitalized patients; and (2) to compare patients' scores before and after weight restoration to scores from healthy participants (HPs). METHOD: The FPQ was completed by 88 patients and 115 HPs. RESULTS: Compared with HPs, patients had significantly lower fat preference scores before (74.03 ± 32.03 vs. 102.93 ± 16.89, P < 0.001) and after (81.51 ± 26.89 vs. 102.92 ± 16.89, P < 0.001) weight restoration. Fat preference scores increased with weight gain (74.03 + 32.03 vs. 81.51 + 26.89, P < 0.01) but did not normalize in AN. DISCUSSION: Acutely weight restored patients continue to endorse decreased preference for high fat foods. The FPQ may be a useful metric by which to assess improvements in diet during treatment. Further study is warranted to validate the FPQ against observed food intake in AN. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2017; 50:148-151).

Striatal dopamine type 2 receptor availability in anorexia nervosa.

The neurobiology of anorexia nervosa remains incompletely understood. Here we utilized PET imaging with the radiotracer [(11)C]raclopride to measure striatal dopamine type 2 (D2) receptor availability in patients with anorexia nervosa. 25 women with anorexia nervosa who were receiving treatment in an inpatient program participated, as well as 25 control subjects. Patients were scanned up to two times with the PET tracer [(11)C]raclopride: once while underweight, and once upon weight restoration. Control subjects underwent one PET scan. In the primary analyses, there were no significant differences between underweight patients (n=21) and control subjects (n=25) in striatal D2 receptor binding potential. Analysis of subregions (sensorimotor striatum, associative striatum, limbic striatum) did not reveal differences between groups. In patients completing both scans (n=15), there were no detectable changes in striatal D2 receptor binding potential after weight restoration. In this sample, there were no differences in striatal D2 receptor binding potential between patients with anorexia nervosa and control subjects. Weight restoration was not associated with a change in striatal D2 receptor binding. These findings suggest that disturbances in reward processing in this disorder are not attributable to abnormal D2 receptor characteristics, and that other reward-related neural targets may be of greater relevance.

Adolescent-adult discrepancies on the eating disorder examination: a function of developmental stage or severity of illness?

OBJECTIVE: Across studies, adolescents score lower on measures of eating disorder pathology than adults, but it is unclear whether such findings reflect discrepancies inherent to site/study or true developmental differences. The aim of this study was to determine whether age predicts subscale and diagnostic scores of the Eating Disorder Examination (EDE) in adolescents and adults with anorexia nervosa (AN) admitted to a single research center within the same period of time. METHOD: The sample consisted of 16 adolescent and 20 adult consecutive admissions to parallel, age-specific, research-based AN treatment programs. Participants completed a baseline evaluation at admission that included the EDE, depression measures, and global assessment of functioning scales. RESULTS: Age significantly predicted EDE scores in univariate regression analyses. However, in multivariate models that included severity indices of general and specific psychopathology as covariates, age was no longer a significant predictor of severity of eating disorder symptoms. DISCUSSION: This study adds to the growing body of data showing lower scores on the EDE for adolescents with AN relative to their adult counterparts, while eliminating potential site confounds. Results indicate that the higher adult scores may be carried in part by a more overall severe and chronic general clinical profile.

Expectancies, dietary restraint, and test meal intake among undergraduate women.

This study investigated the relationship between self-reported dietary restraint and expectancies about caloric content on test meal consumption among undergraduate women. Participants completed two test meal sessions during which they were asked to consume as much milkshake from a covered opaque container as they wished. In one session, participants were instructed that the milkshake was made with high-calorie ingredients, and in the other that the milkshake was made with low-calorie ingredients. The milkshakes in both sessions were actually made with the same ingredients. Participants' mean consumption was less on the low-calorie instruction day (402 g) than on the high-calorie instruction day (382 g), but the difference was not statistically significant. In addition, few significant relationships were observed between dietary restraint measures and total intake on either the low- or high-calorie instruction days. Thus, this study supports a growing body of literature indicating that scores on measures of dietary restraint are not related to the actual restriction of food intake.