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

Evidence for BRAF mutation and variable levels of microsatellite instability in a syndrome of familial colorectal cancer

Background & Aims: Recently, an alternative pathway of tumorigenesis has been identified in the colorectum associated with serrated precursor lesions, variable levels of microsatellite instability (MSI-V), and driven in part by activating mutations in the BRAF proto-oncogene (V599E). Somatic BRAF mutations in hereditary nonpolyposis colon cancer (HNPCC) are rarely observed. Here, we discuss their role in the development of other familial colorectal cancers (CRC). We studied non-FAP, non-HNPCC CRC families characterized by tumors that varied in their level of MSI between individual members. Methods: A subset of tumors from a total of 55 collected (25 polyp and 30 cancers) from 43 individuals across 11 families underwent pathology review, examination for V599E using allele-specific polymerase chain reaction, and for methylation of the MINT31 CpG island. Results: All MSI-V families met the current revised Bethesda Guidelines and 6 of 11 (55%) met the Amsterdam I criteria. V599E was observed in 12 of 19 (63%) polyps and 14 of 20 (70%) cancers (4 of 4 high MSI, 2 of 4 low MSI, and 8 of 12 stable MSI), a significant increase over HNPCC (0 of 15 or 0%), and unselected CRC (30 of 197 or 15.2%) (P < .05). Eight of the 10 (80%) cancers that underwent analysis showed hypermethylation of MINT31. CRCs showed early age at onset and were more likely to show a serrated architecture than unselected CRCs (P < .05). Conclusion: These data provide evidence that the families described here represent a syndrome of familial CRC that is distinct from HNPCC. High levels of BRAF mutation and MINT31 hypermethylation suggest an origin in the serrated pathway of CRC development

De MMPI-2-Restructured Form: Een nieuwe standaard in de psychologische diagnostiek?

Item does not contain fulltextDe MMPI-2- Restructured Form (MMPI-2-RF) is een kortere versie van de bekende MMPI-2. De MMPI-2-RF is in de VS al in gebruik en zal in de loop van volgend jaar ook beschikbaar komen voor het Nederlands taalgebied. De test is op een geheel nieuwe wijze vormgegeven en bevat eengroot aantal nieuwe schalen die beter aansluiten bij moderne dimensionele modellen van psychopathologie en persoonlijkheid. In onderhavig artikel wordt de aanloop naar deze nieuwe test geschetst en zal er worden ingegaan op de meetpretentie en interpretatie van de schalen uit deze test. Voorts wordt er aandacht besteed aan de positie van de MMPI-2-RF ten opzichte van de MMPI-2.7 p

Betonelementen ontworpen volgens niet-lineaire methodes: Gedrag in gebruikstoestand

info:eu-repo/semantics/publishe

Impact of new traumatic or stressful life-events on preexisting PTSD in traumatized refugees : results of a longitudinal study: results of a longitudinal study

Background: A significant proportion of trauma survivors experience an additional critical life event in the aftermath. These renewed experiences of traumatic and stressful life events may lead to an increase in trauma-related mental health symptoms. Method: In a longitudinal study, the effects of renewed experiences of a trauma or stressful life event were examined. For this purpose, refugees seeking asylum in Germany were assessed for posttraumatic stress symptoms (PTS), Posttraumatic Stress Diagnostic Scale (PDS), anxiety, and depression (Hopkins Symptom Checklist [HSCL-25]) before treatment start as well as after 6 and 12 months during treatment (N=46). Stressful life events and traumatic events were recorded monthly. If a new event happened, PDS and HSCL were additionally assessed directly afterwards. Mann–Whitney U-tests were performed to calculate the differences between the group that experienced an additional critical event (stressful vs. trauma) during treatment (n=23) and the group that did not (n=23), as well as differences within the critical event group between the stressful life event group (n=13) and the trauma group (n=10). Results: Refugees improved significantly during the 12-month period of our study, but remained severely distressed. In a comparison of refugees with a new stressful life event or trauma, significant increases in PTS, anxiety, and depressive symptoms were found directly after the experience, compared to the group without a renewed event during the 12 months of treatment. With regard to the different critical life events (stressful vs. trauma), no significant differences were found regarding overall PTS, anxiety, and depression symptoms. Only avoidance symptoms increased significantly in the group experiencing a stressful life event. Conclusion: Although all clinicians should be aware of possible PTS symptom reactivation, especially those working with refugees and asylum seekers, who often experience new critical life events, should understand symptom fluctuation and address it in treatment

Enhancing Psychosis-Spectrum Nosology Through an International Data Sharing Initiative.

The latent structure of schizotypy and psychosis-spectrum symptoms remains poorly understood. Furthermore, molecular genetic substrates are poorly defined, largely due to the substantial resources required to collect rich phenotypic data across diverse populations. Sample sizes of phenotypic studies are often insufficient for advanced structural equation modeling approaches. In the last 50 years, efforts in both psychiatry and psychological science have moved toward (1) a dimensional model of psychopathology (eg, the current Hierarchical Taxonomy of Psychopathology [HiTOP] initiative), (2) an integration of methods and measures across traits and units of analysis (eg, the RDoC initiative), and (3) powerful, impactful study designs maximizing sample size to detect subtle genomic variation relating to complex traits (the Psychiatric Genomics Consortium [PGC]). These movements are important to the future study of the psychosis spectrum, and to resolving heterogeneity with respect to instrument and population. The International Consortium of Schizotypy Research is composed of over 40 laboratories in 12 countries, and to date, members have compiled a body of schizotypy- and psychosis-related phenotype data from more than 30000 individuals. It has become apparent that compiling data into a protected, relational database and crowdsourcing analytic and data science expertise will result in significant enhancement of current research on the structure and biological substrates of the psychosis spectrum. The authors present a data-sharing infrastructure similar to that of the PGC, and a resource-sharing infrastructure similar to that of HiTOP. This report details the rationale and benefits of the phenotypic data collective and presents an open invitation for participation