Convergent evidence that ZNF804A is a regulator of pre-messenger RNA processing and gene expression

Genome-wide association studies have linked common variation in ZNF804A with an increased risk of schizophrenia. However, little is known about the biology of ZNF804A and its role in schizophrenia. Here, we investigate the function of ZNF804A using a variety of complementary molecular techniques. We show that ZNF804A is a nuclear protein that interacts with neuronal RNA splicing factors and RNA-binding proteins including RBFOX1, which is also associated with schizophrenia, CELF3/4, components of the ubiquitin-proteasome system and the ZNF804A paralog, GPATCH8. GPATCH8 also interacts with splicing factors and is localized to nuclear speckles indicative of a role in pre-messenger RNA (mRNA) processing. Sequence analysis showed that GPATCH8 contains ultraconserved, alternatively spliced poison exons that are also regulated by RBFOX proteins. ZNF804A knockdown in SH-SY5Y cells resulted in robust changes in gene expression and pre-mRNA splicing converging on pathways associated with nervous system development, synaptic contact, and cell adhesion. We observed enrichment (P = 1.66 × 10–9) for differentially spliced genes in ZNF804A-depleted cells among genes that contain RBFOX-dependent alternatively spliced exons. Differentially spliced genes in ZNF804A-depleted cells were also enriched for genes harboring de novo loss of function mutations in autism spectrum disorder (P = 6.25 × 10–7, enrichment 2.16) and common variant alleles associated with schizophrenia (P = .014), bipolar disorder and schizophrenia (P = .003), and autism spectrum disorder (P = .005). These data suggest that ZNF804A and its paralogs may interact with neuronal-splicing factors and RNA-binding proteins to regulate the expression of a subset of synaptic and neurodevelopmental genes

Estimating global injuries morbidity and mortality : methods and data used in the Global Burden of Disease 2017 study

Background While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. Methods In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. Results GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. Conclusions GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.Peer reviewe

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

Functional analysis of TCF4 missense mutations that cause Pitt-Hopkins syndrome

Pitt–Hopkins syndrome (PTHS) is a rare developmental disorder associated with severe mental retardation, facial abnormalities, and intermittent hyperventilation. Autosomal dominant PTHS is caused by mutations in the transcription factor 4 (TCF4) gene, whereas NRXN1 and CNTNAP2 mutations are associated with autosomal recessive PTHS. To determine the impact of missense mutations on TCF4 function, we tested a panel of PTHS-associated mutations using a range of quantitative techniques. Mutations in the basic helix-loop-helix (bHLH) domain of TCF4 alter the subnuclear localization of the mutant protein and can attenuate homo- and heterodimer formation in homogenous time-resolved fluorescence (HTRF) assays. By contrast, mutations proximal to the bHLH domain do not alter the location of TCF4 or impair heterodimer formation. In addition, we show that TCF4 can transactivate the NRXN1β and CNTNAP2 promoters in luciferase assays. Here we find variable, context-specific deficits in the ability of the different PTHS-associated TCF4 mutants to transactivate these promoters when coexpressed with different bHLH transcription factors. These data demonstrate that PTHS-associated missense mutations can have multiple effects on the function of the protein, and suggest that TCF4 may modulate the expression of NRXN1 and CNTNAP2 thereby defining a regulatory network in PTHS

Response to an unsolicited intervention offer to persons aged >/= 75 years after screening positive for depressive symptoms: a qualitative study

Item does not contain fulltextBACKGROUND: Screening can increase detection of clinically relevant depressive symptoms, but screen-positive persons are not necessarily willing to accept a subsequent unsolicited treatment offer. Our objective was to explore limiting and motivating factors in accepting an offer to join a "coping with depression" course, and perceived needs among persons aged >/=75 years who screened positive for depressive symptoms in general practice. METHODS: In a randomized controlled trial, in which 101 persons who had screened positive for depressive symptoms were offered a "coping with depression" course, a sample of 23 persons were interviewed, of whom five (22%) accepted the treatment offer. Interview transcripts were coded independently by two researchers. RESULTS: All five individuals who accepted a place on the course felt depressed and/or lonely and had positive expectations about the course. The main reasons for declining to join the course were: not feeling depressed, or having negative thoughts about the course effect, concerns about group participation, or about being too old to change and learn new things. Although perceived needs to relieve depressive symptoms largely matched the elements of the course, most of those who had been screened were not (yet) prepared to accept an intervention offer. Many expressed the need to discuss this treatment decision with their general practitioner. CONCLUSIONS: Although the unsolicited treatment offer closely matched the perceived needs of people screening positive for depressive symptoms, only those who combined feelings of being depressed or lonely with positive expectations about the offered course accepted it. Treatment should perhaps be more individually tailored to the patient's motivational stage towards change, a process in which general practitioners can play an important role