ActEarly: a City Collaboratory approach to early promotion of good health and wellbeing.

Economic, physical, built, cultural, learning, social and service environments have a profound effect on lifelong health. However, policy thinking about health research is dominated by the 'biomedical model' which promotes medicalisation and an emphasis on diagnosis and treatment at the expense of prevention. Prevention research has tended to focus on 'downstream' interventions that rely on individual behaviour change, frequently increasing inequalities. Preventive strategies often focus on isolated leverage points and are scattered across different settings. This paper describes a major new prevention research programme that aims to create City Collaboratory testbeds to support the identification, implementation and evaluation of upstream interventions within a whole system city setting. Prevention of physical and mental ill-health will come from the cumulative effect of multiple system-wide interventions. Rather than scatter these interventions across many settings and evaluate single outcomes, we will test their collective impact across multiple outcomes with the goal of achieving a tipping point for better health. Our focus is on early life (ActEarly) in recognition of childhood and adolescence being such critical periods for influencing lifelong health and wellbeing

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Facebook Live: Mental Health and BIPOC Social & Cultural Differences

Speaking out about the inequities surrounding mental health services for minorities is a beginning to finding solutions. In this discussion, our panelists will talk about how their own communities and lives have been affected, and ideas for how we can work together to make it better

Neonatal exposure to hypoxia induces early arterial stiffening via activation of lysyl oxidases

Abstract Hypoxia in the neonatal period is associated with early manifestations of adverse cardiovascular health in adulthood including higher risk of hypertension and atherosclerosis. We hypothesize that this occurs due to activation of lysyl oxidases (LOXs) and the remodeling of the large conduit vessels, leading to early arterial stiffening. Newborn C57Bl/6 mice were exposed to hypoxia (FiO2 = 11.5%) from postnatal day 1 (P1) to postnatal day 11 (P11), followed by resumption of normoxia. Controls were maintained in normoxia. Using in vivo (pulse wave velocity; PWV) and ex vivo (tensile testing) arterial stiffness indexes, we determined that mice exposed to neonatal hypoxia had significantly higher arterial stiffness compared with normoxia controls by young adulthood (P60), and it increased further by P120. Echocardiography performed at P60 showed that mice exposed to hypoxia displayed a compensated dilated cardiomyopathy. Western blotting revelated that neonatal hypoxia accelerated age‐related increase in LOXL2 protein expression in the aorta and elevated LOXL2 expression in the PA at P11 with a delayed decay toward normoxic controls. In the heart and lung, gene and protein expression of LOX/LOXL2 were upregulated at P11, with a delayed decay when compared to normoxic controls. Neonatal hypoxia results in a significant increase in arterial stiffness in early adulthood due to aberrant LOX/LOXL2 expression. This suggests an acceleration in the mechanical decline of the cardiovascular system, that contributes to increased risk of hypertension in young adults exposed to neonatal hypoxia that may increase susceptibility to further insults

Engaging Researchers with Data Management

Effective Research Data Management (RDM) is a key component of research integrity and reproducible research, and its importance is increasingly emphasised by funding bodies, governments, and research institutions around the world. However, many researchers are unfamiliar with RDM best practices, and research support staff are faced with the diffi cult task of delivering support to researchers across diff erent disciplines and career stages. What strategies can institutions use to solve these problems? Engaging Researchers with Data Management is an invaluable collection of 24 case studies, drawn from institutions across the globe, that demonstrate clearly and practically how to engage the research community with RDM. These case studies together illustrate the variety of innovative strategies research institutions have developed to engage with their researchers about managing research data. Each study is presented concisely and clearly, highlighting the essential ingredients that led to its success and challenges encountered along the way. By interviewing key staff about their experiences and the organisational context, the authors of this book have created an essential resource for organisations looking to increase engagement with their research communities. This handbook is a collaboration by research institutions, for research institutions. It aims not only to inspire and engage, but also to help drive cultural change towards betier data management. It has been writien for anyone interested in RDM, or simply, good research practice

Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy

Clinical presentation of congenital heart disease is heterogeneous, making identification of the disease-causing genes and their genetic pathways and mechanisms of action challenging. By using in vivo electrocardiography, transthoracic echocardiography and microcomputed tomography imaging to screen 3,894 single-gene-null mouse lines for structural and functional cardiac abnormalities, here we identify 705 lines with cardiac arrhythmia, myocardial hypertrophy and/or ventricular dilation. Among these 705 genes, 486 have not been previously associated with cardiac dysfunction in humans, and some of them represent variants of unknown relevance (VUR). Mice with mutations in Casz1, Dnajc18, Pde4dip, Rnf38 or Tmem161b genes show developmental cardiac structural abnormalities, with their human orthologs being categorized as VUR. Using UK Biobank data, we validate the importance of the DNAJC18 gene for cardiac homeostasis by showing that its loss of function is associated with altered left ventricular systolic function. Our results identify hundreds of previously unappreciated genes with potential function in congenital heart disease and suggest causal function of five VUR in congenital heart disease