The Relationship between Concurrent Substance Use Disorders and Eating Disorders with Personality Disorders

Objective: The current pilot study investigated whether patients with concurrent substance use disorders and eating disorders (SUD and ED) who experienced a reduction in SUD and ED symptoms following treatment for SUD and ED also experienced a reduction in personality disorder (PD) symptoms. Method: Twenty patients with SUD and ED and PD were assessed pre and post treatment using clinical interviews, self-report questionnaires, and a therapist questionnaire on DSM-IV-TR symptoms for PD. Results: Symptoms for the personality disorders were reduced following treatment. This reduction was correlated with a decrease in the number of symptoms of ED at post treatment. Discussion: Chronic concurrent SUD and ED may make it difficult to separate PD symptoms from co-occurring disorders. Many features attributed to PDs may be reduced when problematic substance use and disordered eating are addressed, a fact that may increase clinician and patients’optimism about therapeutic change

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

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

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

The effectiveness and cost-effectiveness of a stepped care intervention for alcohol use disorders in primary care: a pilot study

Background Screening for alcohol use disorders identifies a wide range of needs, varying from hazardous and harmful drinking to alcohol dependence. Stepped care offers a potentially resource-efficient way of meeting these needs, but requires evaluation in a randomised controlled trial. Aims To evaluate the feasibility, effectiveness and cost-effectiveness of opportunistic screening and a stepped care intervention in primary care. Method A total of 1794 male primary care attendees at six practices in South Wales were screened using the Alcohol Use Disorders Identification Test (AUDIT). Of these, 112 participants who scored 8 or more on the AUDIT and who consented to enter the study were randomised to receive either 5 minutes of minimal intervention delivered by a practice nurse (control group) or stepped care intervention consisting of three successive steps (intervention group): a single session of behaviour change counselling delivered by a practice nurse; four 50-minute sessions of motivational enhancement therapy delivered by a trained alcohol counsellor; and referral to a community alcohol treatment agency. Results Both groups reduced alcohol consumption 6 months after randomisation with a greater, although not significant, improvement for the stepped care intervention. Motivation to change was greater following the stepped care intervention. The stepped care intervention resulted in greater cost savings compared with the minimal intervention. Conclusions Stepped care was feasible to implement in the primary care setting and resulted in greater cost savings compared with minimal intervention

RNA Interference-Mediated Silencing of Mitotic Kinesin KIF14 Disrupts Cell Cycle Progression and Induces Cytokinesis Failure

KIF14 is a microtubule motor protein whose elevated expression is associated with poor-prognosis breast cancer. Here we demonstrate KIF14 accumulation in mitotic cells, where it associated with developing spindle poles and spindle microtubules. Cells at later stages of mitosis were characterized by the concentration of KIF14 at the midbody. Time-lapse microscopy revealed that strong RNA interference (RNAi)-mediated silencing of KIF14 induced cytokinesis failure, causing several rounds of endoreduplication and resulting in multinucleated cells. Additionally, less efficacious KIF14-specific short interfering RNAs (siRNAs) induced multiple phenotypes, all of which resulted in acute apoptosis. Our data demonstrate the ability of siRNA-mediated silencing to generate epiallelic hypomorphs associated with KIF14 depletion. Furthermore, the link we observed between siRNA efficacy and phenotypic outcome indicates that distinct stages during cell cycle progression are disrupted by the differential modulation of KIF14 expression