Functional cardiac MRI in preterm and term newborns.

Published versio

NHS CHECK: protocol for a cohort study investigating the psychosocial impact of the COVID-19 pandemic on healthcare workers

INTRODUCTION: The COVID-19 pandemic has had profound effects on the working lives of healthcare workers (HCWs), but the extent to which their well-being and mental health have been affected remains unclear. This longitudinal cohort study aims to recruit a cohort of National Health Service (NHS) HCWs, conducting surveys at regular intervals to provide evidence about the prevalence of symptoms of mental disorders, and investigate associated factors such as occupational contexts and support interventions available. METHODS AND ANALYSIS: All staff, students and volunteers working in the 18 participating NHS Trusts in England will be sent emails inviting them to complete a survey at baseline, with email invitations for the follow-up surveys sent 6 months and 12 months later. Opening in late April 2020, the baseline survey collects data on demographics, occupational/organisational factors, experiences of COVID-19, validated measures of symptoms of poor mental health (eg, depression, anxiety, post-traumatic stress disorder), and constructs such as resilience and moral injury. These surveys will be complemented by in-depth psychiatric interviews with a sample of HCWs. Qualitative interviews will also be conducted, to gain deeper understanding of the support programmes used or desired by staff, and facilitators and barriers to accessing such programmes. ETHICS AND DISSEMINATION: Ethical approval for the study was granted by the Health Research Authority (reference: 20/HRA/210, IRAS: 282686) and local Trust Research and Development approval. Cohort data are collected via Qualtrics online survey software, pseudonymised and held on secure university servers. Participants are aware that they can withdraw from the study at any time, and there is signposting to support services if participants feel they need it. Only those consenting to be contacted about further research will be invited to participate in further components. Findings will be rapidly shared with NHS Trusts, and via academic publications in due course

Projections of the current and future disease burden of hepatitis C virus infection in Malaysia

The prevalence of hepatitis C virus (HCV) infection in Malaysia has been estimated at 2.5% of the adult population. Our objective, satisfying one of the directives of the WHO Framework for Global Action on Viral Hepatitis, was to forecast the HCV disease burden in Malaysia using modelling methods.An age-structured multi-state Markov model was developed to simulate the natural history of HCV infection. We tested three historical incidence scenarios that would give rise to the estimated prevalence in 2009, and calculated the incidence of cirrhosis, end-stage liver disease, and death, and disability-adjusted life-years (DALYs) under each scenario, to the year 2039. In the baseline scenario, current antiviral treatment levels were extended from 2014 to the end of the simulation period. To estimate the disease burden averted under current sustained virological response rates and treatment levels, the baseline scenario was compared to a counterfactual scenario in which no past or future treatment is assumed.In the baseline scenario, the projected disease burden for the year 2039 is 94,900 DALYs/year (95% credible interval (CrI): 77,100 to 124,500), with 2,002 (95% CrI: 1340 to 3040) and 540 (95% CrI: 251 to 1,030) individuals predicted to develop decompensated cirrhosis and hepatocellular carcinoma, respectively, in that year. Although current treatment practice is estimated to avert a cumulative total of 2,200 deaths from DC or HCC, a cumulative total of 63,900 HCV-related deaths is projected by 2039.The HCV-related disease burden is already high and is forecast to rise steeply over the coming decades under current levels of antiviral treatment. Increased governmental resources to improve HCV screening and treatment rates and to reduce transmission are essential to address the high projected HCV disease burden in Malaysia

Prevalence of post-traumatic stress disorder and common mental disorders in health-care workers in England during the COVID-19 pandemic: a two-phase cross-sectional study

BACKGROUND: Previous studies on the impact of the COVID-19 pandemic on the mental health of health-care workers have relied on self-reported screening measures to estimate the point prevalence of common mental disorders. Screening measures, which are designed to be sensitive, have low positive predictive value and often overestimate prevalence. We aimed to estimate prevalence of common mental disorders and post-traumatic stress disorder (PTSD) among health-care workers in England using diagnostic interviews. METHODS: We did a two-phase, cross-sectional study comprising diagnostic interviews within a larger multisite longitudinal cohort of health-care workers (National Health Service [NHS] CHECK; n=23 462) during the COVID-19 pandemic. In the first phase, health-care workers across 18 NHS England Trusts were recruited. Baseline assessments were done using online surveys between April 24, 2020, and Jan 15, 2021. In the second phase, we selected a proportion of participants who had responded to the surveys and conducted diagnostic interviews to establish the prevalence of mental disorders. The recruitment period for the diagnostic interviews was between March 1, 2021 and Aug 27, 2021. Participants were screened with the 12-item General Health Questionnaire (GHQ-12) and assessed with the Clinical Interview Schedule-Revised (CIS-R) for common mental disorders or were screened with the 6-item Post-Traumatic Stress Disorder Checklist (PCL-6) and assessed with the Clinician Administered PTSD Scale for DSM-5 (CAPS-5) for PTSD. FINDINGS: The screening sample contained 23 462 participants: 2079 participants were excluded due to missing values on the GHQ-12 and 11 147 participants due to missing values on the PCL-6. 243 individuals participated in diagnostic interviews for common mental disorders (CIS-R; mean age 42 years [range 21-70]; 185 [76%] women and 58 [24%] men) and 94 individuals participated in diagnostic interviews for PTSD (CAPS-5; mean age 44 years [23-62]; 79 [84%] women and 15 [16%] men). 202 (83%) of 243 individuals in the common mental disorders sample and 83 (88%) of 94 individuals in the PTSD sample were White. GHQ-12 screening caseness for common mental disorders was 52·8% (95% CI 51·7-53·8). Using CIS-R diagnostic interviews, the estimated population prevalence of generalised anxiety disorder was 14·3% (10·4-19·2), population prevalence of depression was 13·7% (10·1-18·3), and combined population prevalence of generalised anxiety disorder and depression was 21·5% (16·9-26·8). PCL-6 screening caseness for PTSD was 25·4% (24·3-26·5). Using CAPS-5 diagnostic interviews, the estimated population prevalence of PTSD was 7·9% (4·0-15·1). INTERPRETATION: The prevalence estimates of common mental disorders and PTSD in health-care workers were considerably lower when assessed using diagnostic interviews compared with screening tools. 21·5% of health-care workers met the threshold for diagnosable mental disorders, and thus might benefit from clinical intervention. FUNDING: UK Medical Research Council; UCL/Wellcome; Rosetrees Trust; NHS England and Improvement; Economic and Social Research Council; National Institute for Health and Care Research (NIHR) Biomedical Research Centre at the Maudsley and King's College London (KCL); NIHR Protection Research Unit in Emergency Preparedness and Response at KCL

A systematic review of outcomes reported inpediatric perioperative research: A report from the Pediatric Perioperative Outcomes Group

The Pediatric Perioperative Outcomes Group (PPOG) is an international collaborative of clinical investigators and clinicians within the subspecialty of pediatric anesthesiology and perioperative care which aims to use COMET (Core Outcomes Measures in Effectiveness Trials) methodology to develop core outcome sets for infants, children, and young people that are tailored to the priorities of the pediatric surgical population. Focusing on four age‐dependent patient subpopulations determined a priori for core outcome set development: (a) neonates and former preterm infants (up to 60 weeks postmenstrual age); (b) infants (>60 weeks postmenstrual age—1‐13‐<18 years), we conducted a systematic review of outcomes reported in perioperative studies that include participants within age‐dependent pediatric subpopulations. Our review of pediatric perioperative controlled trials published from 2008 to 2018 identified 724 articles reporting 3192 outcome measures. The proportion of published trials and the most frequently reported outcomes varied across predetermined age‐groups. Outcomes related to patient comfort, particularly pain and analgesic requirement, were the most frequent domain for infants, children, and adolescents. Clinical indicators, particularly cardiorespiratory or medication‐related adverse events, were the most common outcomes for neonates and infants <60 weeks and were the second most frequent domain at all other ages. Neonates and infants <60 weeks of age were significantly under‐represented in perioperative trials. Patient‐centered outcomes, healthcare utilization, and bleeding/transfusion‐related outcomes were less often reported. In most studies, outcomes were measured in the immediate perioperative period, with the duration often restricted to the postanesthesia care unit or the first 24 postoperative hours. The outcomes identified with this systematic review will be combined with patient‐centered outcomes identified through a subsequent stakeholder engagement study to arrive at a core outcome set for each age‐specific group

Lives saved with vaccination for 10 pathogens across 112 countries in a pre-COVID-19 world.

BackgroundVaccination is one of the most effective public health interventions. We investigate the impact of vaccination activities for Haemophilus influenzae type b, hepatitis B, human papillomavirus, Japanese encephalitis, measles, Neisseria meningitidis serogroup A, rotavirus, rubella, Streptococcus pneumoniae, and yellow fever over the years 2000-2030 across 112 countries.MethodsTwenty-one mathematical models estimated disease burden using standardised demographic and immunisation data. Impact was attributed to the year of vaccination through vaccine-activity-stratified impact ratios.ResultsWe estimate 97 (95%CrI[80, 120]) million deaths would be averted due to vaccination activities over 2000-2030, with 50 (95%CrI[41, 62]) million deaths averted by activities between 2000 and 2019. For children under-5 born between 2000 and 2030, we estimate 52 (95%CrI[41, 69]) million more deaths would occur over their lifetimes without vaccination against these diseases.ConclusionsThis study represents the largest assessment of vaccine impact before COVID-19-related disruptions and provides motivation for sustaining and improving global vaccination coverage in the future.FundingVIMC is jointly funded by Gavi, the Vaccine Alliance, and the Bill and Melinda Gates Foundation (BMGF) (BMGF grant number: OPP1157270 / INV-009125). Funding from Gavi is channelled via VIMC to the Consortium's modelling groups (VIMC-funded institutions represented in this paper: Imperial College London, London School of Hygiene and Tropical Medicine, Oxford University Clinical Research Unit, Public Health England, Johns Hopkins University, The Pennsylvania State University, Center for Disease Analysis Foundation, Kaiser Permanente Washington, University of Cambridge, University of Notre Dame, Harvard University, Conservatoire National des Arts et Métiers, Emory University, National University of Singapore). Funding from BMGF was used for salaries of the Consortium secretariat (authors represented here: TBH, MJ, XL, SE-L, JT, KW, NMF, KAMG); and channelled via VIMC for travel and subsistence costs of all Consortium members (all authors). We also acknowledge funding from the UK Medical Research Council and Department for International Development, which supported aspects of VIMC's work (MRC grant number: MR/R015600/1).JHH acknowledges funding from National Science Foundation Graduate Research Fellowship; Richard and Peggy Notebaert Premier Fellowship from the University of Notre Dame. BAL acknowledges funding from NIH/NIGMS (grant number R01 GM124280) and NIH/NIAID (grant number R01 AI112970). The Lives Saved Tool (LiST) receives funding support from the Bill and Melinda Gates Foundation.This paper was compiled by all coauthors, including two coauthors from Gavi. Other funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication

Iodine Atoms: A New Molecular Feature for the Design of Potent Transthyretin Fibrillogenesis Inhibitors

The thyroid hormone and retinol transporter protein known as transthyretin (TTR) is in the origin of one of the 20 or so known amyloid diseases. TTR self assembles as a homotetramer leaving a central hydrophobic channel with two symmetrical binding sites. The aggregation pathway of TTR into amiloid fibrils is not yet well characterized but in vitro binding of thyroid hormones and other small organic molecules to TTR binding channel results in tetramer stabilization which prevents amyloid formation in an extent which is proportional to the binding constant. Up to now, TTR aggregation inhibitors have been designed looking at various structural features of this binding channel others than its ability to host iodine atoms. In the present work, greatly improved inhibitors have been designed and tested by taking into account that thyroid hormones are unique in human biochemistry owing to the presence of multiple iodine atoms in their molecules which are probed to interact with specific halogen binding domains sitting at the TTR binding channel. The new TTR fibrillogenesis inhibitors are based on the diflunisal core structure because diflunisal is a registered salicylate drug with NSAID activity now undergoing clinical trials for TTR amyloid diseases. Biochemical and biophysical evidence confirms that iodine atoms can be an important design feature in the search for candidate drugs for TTR related amyloidosis

Vasomotion and Neurovascular Coupling in the Visual Thalamus In Vivo

Spontaneous contraction and relaxation of arteries (and in some instances venules) has been termed vasomotion and has been observed in an extensive variety of tissues and species. However, its functions and underlying mechanisms are still under discussion. We demonstrate that in vivo spectrophotometry, measured simultaneously with extracellular recordings at the same locations in the visual thalamus of the cat, reveals vasomotion, measured as an oscillation (0.14hz) in the recorded oxyhemoglobin (OxyHb) signal, which appears spontaneously in the microcirculation and can last for periods of hours. During some non-oscillatory periods, maintained sensory stimulation evokes vasomotion lasting ∼30s, resembling an adaptive vascular phenomenon. This oscillation in the oxyhaemoblobin signal is sensitive to pharmacological manipulation: it is inducible by chloralose anaesthesia and it can be temporarily blocked by systemic administration of adrenaline or acetylcholine (ACh). During these oscillatory periods, neurovascular coupling (i.e. the relationship between local neural activity and the rate of blood supply to that location) appears significantly altered. This raises important questions with regard to the interpretation of results from studies currently dependent upon a linear relationship between neural activity and blood flow, such as neuroimaging

Risk factors and prognosis of young stroke. The FUTURE study: A prospective cohort study. Study rationale and protocol

Contains fulltext : 98322.pdf (postprint version ) (Open Access)BACKGROUND: Young stroke can have devastating consequences with respect to quality of life, the ability to work, plan or run a family, and participate in social life. Better insight into risk factors and the long-term prognosis is extremely important, especially in young stroke patients with a life expectancy of decades. To date, detailed information on risk factors and the long-term prognosis in young stroke patients, and more specific risk of mortality or recurrent vascular events, remains scarce. METHODS/DESIGN: The FUTURE study is a prospective cohort study on risk factors and prognosis of young ischemic and hemorrhagic stroke among 1006 patients, aged 18-50 years, included in our study database between 1-1-1980 and 1-11-2010. Follow-up visits at our research centre take place from the end of 2009 until the end of 2011. Control subjects will be recruited among the patients' spouses, relatives or social environment. Information on mortality and incident vascular events will be retrieved via structured questionnaires. In addition, participants are invited to the research centre to undergo an extensive sub study including MRI. DISCUSSION: The FUTURE study has the potential to make an important contribution to increase the knowledge on risk factors and long-term prognosis in young stroke patients. Our study differs from previous studies by having a maximal follow-up of more than 30 years, including not only TIA and ischemic stroke but also hemorrhagic stroke, the addition of healthy controls and prospectively collect data during an extensive follow-up visit. Completion of the FUTURE study may provide better information for treating physicians and patients with respect to the prognosis of young stroke.8 p

A TRPV Channel Modulates C. elegans Neurosecretion, Larval Starvation Survival, and Adult Lifespan

For most organisms, food is only intermittently available; therefore, molecular mechanisms that couple sensation of nutrient availability to growth and development are critical for survival. These mechanisms, however, remain poorly defined. In the absence of nutrients, newly hatched first larval (L1) stage Caenorhabditis elegans halt development and survive in this state for several weeks. We isolated mutations in unc-31, encoding a calcium-activated regulator of neural dense-core vesicle release, which conferred enhanced starvation survival. This extended survival was reminiscent of that seen in daf-2 insulin-signaling deficient mutants and was ultimately dependent on daf-16, which encodes a FOXO transcription factor whose activity is inhibited by insulin signaling. While insulin signaling modulates metabolism, adult lifespan, and dauer formation, insulin-independent mechanisms that also regulate these processes did not promote starvation survival, indicating that regulation of starvation survival is a distinct program. Cell-specific rescue experiments identified a small subset of primary sensory neurons where unc-31 reconstitution modulated starvation survival, suggesting that these neurons mediate perception of food availability. We found that OCR-2, a transient receptor potential vanilloid (TRPV) channel that localizes to the cilia of this subset of neurons, regulates peptide-hormone secretion and L1 starvation survival. Moreover, inactivation of ocr-2 caused a significant extension in adult lifespan. These findings indicate that TRPV channels, which mediate sensation of diverse noxious, thermal, osmotic, and mechanical stimuli, couple nutrient availability to larval starvation survival and adult lifespan through modulation of neural dense-core vesicle secretion