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

Lurasidone for adolescents with complex mental disorders: A case series

Objectives: Lurasidone is a new second generation (atypical) antipsychotic agent with unique receptor affinity and side-effect profiles, but limited literature is available on its use in adolescent populations. Contrasting with research treatment trials which typically recruit patients by stringent selection criteria, this case series examined the effects and tolerability of using lurasidone in adolescents within real-life clinical settings in treating complex cases who had not responded to other therapy options. Methods: We conducted a retrospective case-note audit of 6 adolescents aged 14 to 17 years old attending community child and adolescent mental health services (CAMHS) who were prescribed lurasidone. Results: Lurasidone had been prescribed for a range of “hard-to-manage” conditions with complex comorbidities, in adolescents in relation to specific use of lurasidone on the basis of clinical and pharmacological indications after exhausting more conventional treatment options. Case-note review suggested response to lurasidone was clinically positive in 3 cases, equivocal/marginal in 2 cases, and ineffective in 1 case. There were no cases of poor tolerance or adverse effects. Notably, positive responses for depressive and irritable mood symptoms were specifically recorded by prescribing clinicians, indicative of benefits on symptom improvement. No lurasidone attributed weight gain, galactorrhoea, metabolic abnormalities, sexual dysfunction or intolerance were reported. Pro-cognitive effects were not detected; but our findings were constrained by the non-systematic and incomplete information ascertainment, typical in retrospective case-note review. Conclusion: This case series provides preliminary data supporting lurasidone’s potential use in adolescents of complex clinical needs (but without a clinical diagnosis of bipolar disorder) within real-life clinical settings. Lurasidone appears to show a weight-sparing effect, in addition to improving mood symptoms in some cases. Lurasidone deserves further study for its use in the adolescent population (outside the remit of FDA) given its potential more favorable risk-benefit profile in young people. The favorable tolerability appear to be borne out by the pharmacodynamic predictions in our complex patients who would be excluded in formal clinical trial studies

Toxicity of chlorpyrifos and chlorpyrifos oxon in a transgenic mouse model of the human paraoxonase (PON1) Q192R polymorphism

Objectives The Q192R polymorphism of paraoxonase (PON1) has been shown to affect hydrolysis of organophosphorus compounds. The Q192 and R192 alloforms exhibit equivalent catalytic efficiencies of hydrolysis for diazoxon, the oxon form of the pesticide (DZ). However, the R192 alloform has a higher catalytic efficiency of hydrolysis than does the Q192 alloform for chlorpyrifos oxon (CPO), the oxon form of the pesticide chlorpyrifos (CPS). The current study examined the relevance of these observations for in-vivo exposures to chlorpyrifos and chlorpyrifos oxon. Methods Using a transgenic mouse model we examined the relevance of the Q192R polymorphism for exposure to CPS and CPO in vivo. Transgenic mice were generated that expressed either human PON1(Q192) or PON1(R192) at equivalent levels, in the absence of endogenous mouse PON1. Dose-response and time course experiments were performed on adult mice exposed dermally to CPS or CPO. Morbidity and acetylcholinesterase (AChE) activity in the brain and diaphragm were determined in the first 24 h following exposure. Results Mice expressing PON1(Q192) were significantly more sensitive to CPO, and to a lesser extent CPS, than were mice expressing PON1(R192). The time course of inhibition following exposure to 1.2 mg/kg CPO revealed maximum inhibition of brain AChE at 6-12 h, with PON1(R192), PON1(Q192), and PON1(-/-) mice exhibiting 40, 70 and 85% inhibition, respectively, relative to control mice. The effect of PON1 removal on the dose-response curve for CPS exposure was remarkably consistent with a PBPK/PD model of CPS exposure. Conclusion These results indicate that individuals expressing only the PON1(Q192) allele would be more sensitive to the adverse effects of CPO or CPS exposure, especially if they are expressing a low level of plasma PON1(Q192)

Quality and quantity: tackling non-contact attrition in a longitudinal survey

This research note describes some of the methods of reducing non-contact attrition used in the Scottish Young People's Surveys, and suggests that the type of attrition reduction method used can affect the quality of the survey sample

Role of paraoxonase (PON1)status in pesticide sensitivity: genetic and temporal determinants

Individual differences in detoxication capacities for specific organophosphorous (OP) compounds are due largely to differences in catalytic efficiency or abundance of the HDL-associated enzyme, paraoxonase (PON1). First, we provide evidence that children less than 2 years of age represent a particularly susceptible populationfor OP exposure due to low abundance of PON1 and variable onset of plasma PON1 activity. Second, we describe studies examining the neurotoxic effects of chronic, low-level OP pesticide exposure in mice. PONI knockout (PON1(-/-)) and wild-type mice were exposed chronically (PN4 to PN21) to low levels of chlorpyrifos oxon (CPO). Endpoints included cholinesterase activity, histopathology, gene expression, and behavior. Even at PN4, when PON1 levels were low in wild-type mice, PON1(-/-) mice were more sensitive to inhibition of brain cholinesterase by CPO. At PN22, and persisting as long as 4 months, chronic developmental exposure to 0.18 mg/kg/d or 0.25 mg/kg/d CPO resulted in perinuclear vacuolization of cells in a discrete area of the neocortex and irregular distribution of neurons in the cortical plate, with an increase in the number of affected cells at 0.25 mg/kg/d. Third, we describe a transgenic mouse model in which human transgenes encoding either hPON1(Q192) or hPON1(R192) were expressed at equal levels in place of mouse PONI. The developmental onset of expression followed the mouse time course and was identical for the two transgenes, allowing these mice to be used to assess the importance of the Q192R polymorphism during development. Adult mice expressing hPON1(R192) were significantly more resistant than hPON1(Q192) mice to CPO toxicity. Our studies indicate that children less than 2 years old, especially those homozygous for PON1(Q192), would be predicted to be particularly susceptible to CPO toxicit