Impact of COVID-19 on primary care contacts with children and young people in England: longitudinal trends study 2015–2020

BACKGROUND: The NHS response to COVID-19 altered provision and access to primary care. AIM: To examine the impact of COVID-19 on GP contacts with children and young people (CYP) in England. DESIGN AND SETTING: A longitudinal trends analysis was undertaken using electronic health records from the Clinical Practice Research Datalink (CPRD) Aurum database. METHOD: All CYP aged 90%). Remote contacts more than doubled, increasing most in infants (over 2.5-fold). Total contacts for respiratory illnesses fell by 74% whereas contacts for common non-transmissible conditions shifted largely to remote contacts, mitigating the total fall (31%). CONCLUSION: During the COVID-19 pandemic, CYP's contact with GPs fell, particularly for face-to-face assessments. This may be explained by a lower incidence of respiratory illnesses because of fewer social contacts and changing health-seeking behaviour. The large shift to remote contacts mitigated total falls in contacts for some age groups and for common non-transmissible conditions

Protocol for developing a core outcome set for evaluating school-based physical activity interventions in primary schools.

INTRODUCTION:Primary school-based physical activity interventions, such as The Daily Mile initiative, have the potential to increase children's physical activity levels over time, which is associated with a variety of health benefits. Comparing interventions or combining results of several studies of a single intervention is challenging because previous studies have examined different outcomes or used different measures that are not feasible or relevant for researchers in school settings. The development and implementation of a core outcome set (COS) for primary school-based physical activity interventions would ensure outcomes important to those involved in implementing and evaluating interventions are standardised. METHODS AND ANALYSIS:Our aim is to develop a COS for studies of school-based physical activity interventions. We will achieve this by undertaking a four-stage process:(1) identify a list of outcomes assessed in studies through a systematic review of international literature; (2) establish domains from these outcomes to produce questionnaire items; (3) prioritise outcomes through a two-stage Delphi survey with four key stakeholder groups (researchers, public health professionals, educators and parents), where stakeholders rate the importance of each outcome on a 9-point Likert scale (consensus that the outcomes should be included in the COS will be determined as 70% or more of all stakeholders scoring the outcome 7%-9% and 15% or less scoring 1 to 3); (4) achieve consensus on a final COS in face-to-face meetings with a sample of stakeholders and primary school children. ETHICS AND DISSEMINATION:We have received ethical approval from Imperial College London (ref: 19IC5428). The results of this study will be disseminated via conference presentations/public health meetings, peer-reviewed publications and through appropriate media channels. TRIAL REGISTRATION NUMBER:Core Outcome Measures in Effectiveness Trials Initiative (COMET) number: 1322

Comparative analysis of small-molecule limk1/2 inhibitors: chemical synthesis, biochemistry, and cellular activity

LIM domain kinases 1 and 2 (LIMK1 and LIMK2) regulate actin dynamics and subsequently key cellular functions such as proliferation and migration. LIMK1 and LIMK2 phosphorylate and inactivate cofilin leading to increased actin polymerization. As a result, LIMK inhibitors are emerging as a promising treatment strategy for certain cancers and neurological disorders. High-quality chemical probes are required if the role of these kinases in health and disease is to be understood. To that end, we report the results of a comparative assessment of 17 reported LIMK1/2 inhibitors in a variety of in vitro enzymatic and cellular assays. Our evaluation has identified three compounds (TH-257, LIJTF500025, and LIMKi3) as potent and selective inhibitors suitable for use as in vitro and in vivo pharmacological tools for the study of LIMK function in cell biology

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

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)

Developing a core outcome set for physical activity interventions in primary schools: a modified-Delphi study.

Funder: National Institute for Health Research (NIHR)OBJECTIVES: To develop a core outcome set (COS) for physical activity interventions in primary schools. DESIGN: Modified-Delphi study. SETTING: The UK and international. PARTICIPANTS: 104 participants from four stakeholder groups (educators, public health professionals, health researchers, parents); 16 children (aged 8-9 years) from 1 London primary school. INTERVENTIONS: Physical activity interventions. METHODS: Four-stage process: (1) outcomes extracted from relevant studies identified from an umbrella review and a focus group; (2) list of outcomes produced and domains established; (3) stakeholders completed a two-round Delphi survey by rating (Round 1) and re-rating (Round 2) each outcome on a nine-point Likert Scale from 'not important' to 'critical': a>70% participant threshold identified the outcomes rated 'critical' to measure, and outcomes important to children were identified through a workshop; and (4) a stakeholder meeting to achieve consensus of the outcomes to include in the COS. RESULTS: In total, 74 studies were extracted from 53 reviews. A list of 50 outcomes was produced and three domains were established: 'physical activity and health' (16 outcomes), 'social and emotional health' (22 outcomes) and 'educational performance' (12 outcomes). 104 participants completed survey Round 1; 65 participants completed both rounds. In total, 13 outcomes met the threshold; children identified 8 outcomes. Fourteen outcomes achieved consensus to produce the COS: five outcomes for physical activity and health (diet (varied and balanced), energy, fitness, intensity of physical activity, sleep (number of hours)); seven outcomes for social and emotional health (anxiety, depression, enjoyment, happiness, self-esteem, stress, well-being); and two outcomes for educational performance (concentration, focus). CONCLUSIONS: We have developed the first COS for physical activity interventions in primary schools in consultation with those interested in the development and application of an agreed standardised set of outcomes. Future studies including these outcomes will reduce heterogeneity across studies. TRIAL REGISTRATION NUMBER: Core Outcome Measures in Effectiveness Trials Initiative registration number 1322; Results

Complement Activation in Arterial and Venous Thrombosis is Mediated by Plasmin

Thrombus formation leading to vaso-occlusive events is a major cause of death, and involves complex interactions between coagulation, fibrinolytic and innate immune systems. Leukocyte recruitment is a key step, mediated partly by chemotactic complement activation factors C3a and C5a. However, mechanisms mediating C3a/C5a generation during thrombosis have not been studied. In a murine venous thrombosis model, levels of thrombin–antithrombin complexes poorly correlated with C3a and C5a, excluding a central role for thrombin in C3a/C5a production. However, clotweight strongly correlated with C5a, suggesting processes triggered during thrombosis promote C5a generation. Since thrombosis elicits fibrinolysis,we hypothesized that plasmin activates C5 during thrombosis. In vitro, the catalytic efficiency of plasmin-mediated C5a generation greatly exceeded that of thrombin or factor Xa, but was similar to the recognized complement C5 convertases. Plasmin-activated C5 yielded a functional membrane attack complex (MAC). In an arterial thrombosis model, plasminogen activator administration increased C5a levels. Overall, these findings suggest plasmin bridges thrombosis and the immune response by liberating C5a and inducing MAC assembly. These new insights may lead to the development of strategies to limit thrombus formation and/or enhance resolutionMedicine, Faculty ofNon UBCMedicine, Department ofReviewedFacult