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Issue Title: Advances in Pharmacophores and 3-D Screening This paper describes the extension of our earlier multiobjective method for generating plausible pharmacophore hypotheses to incorporate partial matches. Diverse sets of molecules rarely adopt exactly the same binding mode, and so allowing the identification of partial matches allows our program to be applied to larger and more diverse datasets. The method explores the conformational space of a series of ligands simultaneously with their alignment using a multiobjective genetic algorithm (MOGA). The principles of Pareto ranking are used to evolve a diverse set of pharmacophore hypotheses that are optimised on conformational energy of the ligands, the goodness of the overlay and the volume of the overlay. A partial match is defined as a pharmacophoric feature that is present in at least two, but not all, of the ligands in the set. The number of ligands that map to a given pharmacophore point is taken into account when evaluating an overlay. The method is applied to a number of test cases extracted from the Protein Data Bank (PDB) where the true overlay is known.[PUBLICATION ABSTRACT]

Pharmacophore methods provide a way of establishing a structure activity relationship for a series of known active ligands. Often, there are several plausible hypotheses that could explain the same set of ligands and, in such cases, it is important that the chemist is presented with alternatives that can be tested with different synthetic compounds. Existing pharmacophore methods involve either generating an ensemble of conformers and considering each conformer of each ligand in turn or exploring conformational space on-the-fly. The ensemble methods tend to produce a large number of hypotheses and require considerable effort to analyse the results, whereas methods that vary conformation on-the-fly typically generate a single solution that represents one possible hypothesis, even though several might exist. We describe a new method for generating multiple pharmacophore hypotheses with full conformational flexibility being explored on-the-fly. The method is based on multiobjective evolutionary algorithm techniques and is designed to search for an ensemble of diverse yet plausible overlays which can then be presented to the chemist for further investigation.

This paper describes the extension of our earlier multi-objective method for generating plausible pharmacophore hypotheses to incorporate partial matches. Diverse sets of molecules rarely adopt exactly the same binding mode, and so allowing the identification of partial matches allows our program to be applied to larger and more diverse datasets. The method explores the conformational space of a series of ligands simultaneously with their alignment using a multi-objective genetic algorithm (MOGA). The principles of Pareto ranking are used to evolve a diverse set of pharmacophore hypotheses that are optimised on conformational energy of the ligands, the goodness of the overlay and the volume of the overlay. A partial match is defined as a pharmacophoric feature that is present in at least two, but not all, of the ligands in the set. The number of ligands that map to a given pharmacophore point is taken into account when evaluating an overlay. The method is applied to a number of test cases extracted from the Protein Data Bank (PDB) where the true overlay is known.

AbstractObjectiveTo estimate the real world effectiveness of the Pfizer-BioNTech BNT162b2 and Oxford-AstraZeneca ChAdOx1-S vaccines against confirmed covid-19 symptoms (including the UK variant of concern B.1.1.7), admissions to hospital, and deaths.DesignTest negative case-control study.SettingCommunity testing for covid-19 in England.Participants156 930 adults aged 70 years and older who reported symptoms of covid-19 between 8 December 2020 and 19 February 2021 and were successfully linked to vaccination data in the National Immunisation Management System.InterventionsVaccination with BNT162b2 or ChAdOx1-S.Main outcome measuresPrimary outcomes were polymerase chain reaction confirmed symptomatic SARS-CoV-2 infections, admissions to hospital for covid-19, and deaths with covid-19.ResultsParticipants aged 80 years and older vaccinated with BNT162b2 before 4 January 2021 had a higher odds of testing positive for covid-19 in the first nine days after vaccination (odds ratio up to 1.48, 95% confidence interval 1.23 to 1.77), indicating that those initially targeted had a higher underlying risk of infection. Vaccine effectiveness was therefore compared with the baseline post-vaccination period. Vaccine effects were noted 10 to 13 days after vaccination, reaching a vaccine effectiveness of 70% (95% confidence interval 59% to 78%), then plateauing. From 14 days after the second dose a vaccination effectiveness of 89% (85% to 93%) was found compared with the increased baseline risk. Participants aged 70 years and older vaccinated from 4 January (when ChAdOx1-S delivery commenced) had a similar underlying risk of covid-19 to unvaccinated individuals. With BNT162b2, vaccine effectiveness reached 61% (51% to 69%) from 28 to 34 days after vaccination, then plateaued. With ChAdOx1-S, effects were seen from 14 to 20 days after vaccination, reaching an effectiveness of 60% (41% to 73%) from 28 to 34 days, increasing to 73% (27% to 90%) from day 35 onwards. On top of the protection against symptomatic disease, a further 43% (33% to 52%) reduced risk of emergency hospital admission and 51% (37% to 62%) reduced risk of death was observed in those who had received one dose of BNT162b2. Participants who had received one dose of ChAdOx1-S had a further 37% (3% to 59%) reduced risk of emergency hospital admission. Follow-up was insufficient to assess the effect of ChAdOx1-S on mortality. Combined with the effect against symptomatic disease, a single dose of either vaccine was about 80% effective at preventing admission to hospital with covid-19 and a single dose of BNT162b2 was 85% effective at preventing death with covid-19.ConclusionVaccination with either one dose of BNT162b2 or ChAdOx1-S was associated with a significant reduction in symptomatic covid-19 in older adults, and with further protection against severe disease. Both vaccines showed similar effects. Protection was maintained for the duration of follow-up (>6 weeks). A second dose of BNT162b2 was associated with further protection against symptomatic disease. A clear effect of the vaccines against the B.1.1.7 variant was found.

IntroductionThe emergence of the novel respiratory SARS-CoV-2 and subsequent COVID-19 pandemic have required rapid assimilation of population-level data to understand and control the spread of infection in the general and vulnerable populations. Rapid analyses are needed to inform policy development and target interventions to at-risk groups to prevent serious health outcomes. We aim to provide an accessible research platform to determine demographic, socioeconomic and clinical risk factors for infection, morbidity and mortality of COVID-19, to measure the impact of COVID-19 on healthcare utilisation and long-term health, and to enable the evaluation of natural experiments of policy interventions.Methods and analysisTwo privacy-protecting population-level cohorts have been created and derived from multisourced demographic and healthcare data. The C20 cohort consists of 3.2 million people in Wales on the 1 January 2020 with follow-up until 31 May 2020. The complete cohort dataset will be updated monthly with some individual datasets available daily. The C16 cohort consists of 3 million people in Wales on the 1 January 2016 with follow-up to 31 December 2019. C16 is designed as a counterfactual cohort to provide contextual comparative population data on disease, health service utilisation and mortality. Study outcomes will: (a) characterise the epidemiology of COVID-19, (b) assess socioeconomic and demographic influences on infection and outcomes, (c) measure the impact of COVID-19 on short -term and longer-term population outcomes and (d) undertake studies on the transmission and spatial spread of infection.Ethics and disseminationThe Secure Anonymised Information Linkage-independent Information Governance Review Panel has approved this study. The study findings will be presented to policy groups, public meetings, national and international conferences, and published in peer-reviewed journals.

Compassionate conservation focuses on 4 tenets: first, do no harm; individuals matter; inclusivity of individual animals; and peaceful coexistence between humans and animals. Recently, compassionate conservation has been promoted as an alternative to conventional conservation philosophy. We believe examples presented by compassionate conservationists are deliberately or arbitrarily chosen to focus on mammals; inherently not compassionate; and offer ineffective conservation solutions. Compassionate conservation arbitrarily focuses on charismatic species, notably large predators and megaherbivores. The philosophy is not compassionate when it leaves invasive predators in the environment to cause harm to vastly more individuals of native species or uses the fear of harm by apex predators to terrorize mesopredators. Hindering the control of exotic species (megafauna, predators) in situ will not improve the conservation condition of the majority of biodiversity. The positions taken by so-called compassionate conservationists on particular species and on conservation actions could be extended to hinder other forms of conservation, including translocations, conservation fencing, and fertility control. Animal welfare is incredibly important to conservation, but ironically compassionate conservation does not offer the best welfare outcomes to animals and is often ineffective in achieving conservation goals. Consequently, compassionate conservation may threaten public and governmental support for conservation because of the limited understanding of conservation problems by the general public. La conservación compasiva se enfoca en cuatro principios: no causar daño; los individuos importan; la integración de los animales individualmente; y la coexistencia pacífica entre los humanos u los animales. Recientemente, la conservación compasiva ha sido promovida como una alternativa a la filosofía convencional de la conservación. Creemos que los ejemplos presentados por los conservacionistas compasivos han sido elegidos arbitraria o deliberadamente por estar enfocados en los mamíferos; por ser inherentes y no compasivos; y por ofrecer soluciones de conservación poco efectivas. La conservación compasiva se enfoca arbitrariamente en las especies carismáticas, principalmente los grandes depredadores y los megaherbívoros. La filosofía no es compasiva cuando deja que los depredadores invasores dentro del ambiente causen daño a un vasto número de individuos nativos o usa el miedo al daño por superdepredadores para aterrorizar a los mesodepredadores. El entorpecimiento del control de especies exóticas (megafauna, depredadores) in situ no mejorará las condiciones de conservación de la mayoría de la biodiversidad, incluso si los conservacionistas compasivos no dañan a los individuos exóticos. Las posiciones que toman los llamados conservacionistas compasivos sobre especies particulares y sobre las acciones de conservación podrían extenderse para entorpecer otros tipos de conservación, incluyendo las reubicaciones, el encercado para la conservación yel control de la fertilidad. El bienestar animal es increíblemente importante para la conservación e irónicamente, la conservación compasiva no ofrece los mejores resultados de bienestar para los animales y comúnmente es poco efectiva en el logro de los objetivos de conservación. Como consecuencia, la conservación compasiva puede poner en peligro el apoyo público y del gobierno que tiene la conservación debido al entendimiento poco limitado que tiene el público general sobre los problemas de conservación. 同理心保护注重四项原则: 不制造伤害、心系每一条生命、不排斥每ー种动物，以及人与动物和平共处。 目前，同理心保护已经被推崇为传统保护哲学的替代选择。然而，我们认为同理心保护主义者有意或武断地挑选 了哺乳动物作为范例，这在本质上并不具备同理心，且他们提供的保护方案也不实际。同理心保护常常不加判断 地只关注明星物种，尤其是大型食肉动物和食草动物;若是保留环境中的入侵食肉动物，从而对原生种造成巨大 伤害，抑或是利用顶级捕食者来威慑中等食肉动物，这样的保护理念实际上都没有同理心。即便同理心保护主义 者没有直接伤害外来物种的个体，阻止对外来物种（大型动物、食肉动物) 的就地种群控_ ，也不能改善组成生 物多祥性的大部分物种的保护情況。所谓的同理心保护主义者对特定物种或是特定保护行动所采取的立场，甚 至会阻碍其它形式的保护，如迁地保护、围栏保护和繁殖控制等。动物福利对保护极为重要，然而讽刺的是，同 理心保护不仅没有给动物提供最优的福利条件，还通常不利于实现保护目标。因此，鉴于公众对保护问题的认知 有限同理心保护可能会威胁到公众和政府对保护的支持。

To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance ( P  < 2.5 × 10 −6 ), including five new risk genes ( NAV3 , ITSN1 , MARK2 , SCAF1 and HNRNPUL2 ). The association of NAV3 with autism risk is primarily driven by rare inherited loss-of-function (LoF) variants, with an estimated relative risk of 4, consistent with moderate effect. Autistic individuals with LoF variants in the four moderate-risk genes ( NAV3 , ITSN1 , SCAF1 and HNRNPUL2 ; n  = 95) have less cognitive impairment than 129 autistic individuals with LoF variants in highly penetrant genes ( CHD8, SCN2A, ADNP, FOXP1 and SHANK3 ) (59% vs 88%, P  = 1.9 × 10 −6 ). Power calculations suggest that much larger numbers of autism cases are needed to identify additional moderate-risk genes. An integrated analysis of de novo and inherited coding variants in 42,607 individuals with autism spectrum disorder identifies 60 risk genes of which five have not previously been associated with neurodevelopmental disorders.

IntroductionPrevention of fragility fractures, a source of significant economic and personal burden, is hindered by poor uptake of fracture prevention medicines. Enhancing communication of scientific evidence and elicitation of patient medication-related beliefs has the potential to increase patient commitment to treatment. The Improving uptake of Fracture Prevention drug treatments (iFraP) programme aims to develop and evaluate a theoretically informed, complex intervention consisting of a computerised web-based decision support tool, training package and information resources, to facilitate informed decision-making about fracture prevention treatment, with a long-term aim of improving informed treatment adherence. This protocol focuses on the iFraP Development (iFraP-D) work.Methods and analysisThe approach to iFraP-D is informed by the Medical Research Council complex intervention development and evaluation framework and the three-step implementation of change model. The context for the study is UK fracture liaison services (FLS), which enact secondary fracture prevention. An evidence synthesis of clinical guidelines and Delphi exercise will be conducted to identify content for the intervention. Focus groups with patients, FLS clinicians and general practitioners and a usual care survey will facilitate understanding of current practice, and investigate barriers and facilitators to change. Design of the iFraP intervention will be informed by decision aid development standards and theories of implementation, behaviour change, acceptability and medicines adherence. The principles of co-design will underpin all elements of the study through a dedicated iFraP community of practice including key stakeholders and patient advisory groups. In-practice testing of the prototype intervention will inform revisions ready for further testing in a subsequent pilot and feasibility randomised trial.Ethics and disseminationEthical approval was obtained from North West—Greater Manchester West Research Ethics Committee (19/NW/0559). Dissemination and knowledge mobilisation will be facilitated through national bodies and networks, publications and presentations.Trial registration numberresearchregistry5041.

There is a need for better understanding of the risk of thrombocytopenic, haemorrhagic, thromboembolic disorders following first, second and booster vaccination doses and testing positive for SARS-CoV-2. Self-controlled cases series analysis of 2.1 million linked patient records in Wales between 7th December 2020 and 31st December 2021. Outcomes were the first diagnosis of thrombocytopenic, haemorrhagic and thromboembolic events in primary or secondary care datasets, exposure was defined as 0–28 days post-vaccination or a positive reverse transcription polymerase chain reaction test for SARS-CoV-2. 36,136 individuals experienced either a thrombocytopenic, haemorrhagic or thromboembolic event during the study period. Relative to baseline, our observations show greater risk of outcomes in the periods post-first dose of BNT162b2 for haemorrhagic (IRR 1.47, 95%CI: 1.04–2.08) and idiopathic thrombocytopenic purpura (IRR 2.80, 95%CI: 1.21–6.49) events; post-second dose of ChAdOx1 for arterial thrombosis (IRR 1.14, 95%CI: 1.01–1.29); post-booster greater risk of venous thromboembolic (VTE) (IRR-Moderna 3.62, 95%CI: 0.99–13.17) (IRR-BNT162b2 1.39, 95%CI: 1.04–1.87) and arterial thrombosis (IRR-Moderna 3.14, 95%CI: 1.14–8.64) (IRR-BNT162b2 1.34, 95%CI: 1.15–1.58). Similarly, post SARS-CoV-2 infection the risk was increased for haemorrhagic (IRR 1.49, 95%CI: 1.15–1.92), VTE (IRR 5.63, 95%CI: 4.91, 6.4), arterial thrombosis (IRR 2.46, 95%CI: 2.22–2.71). We found that there was a measurable risk of thrombocytopenic, haemorrhagic, thromboembolic events after COVID-19 vaccination and infection.

2018/19 was the first season of introduction of a newly licensed adjuvanted influenza vaccine (aTIV) for adults aged 65 years and over and the sixth season in the roll-out of a childhood influenza vaccination programme with a quadrivalent live attenuated influenza vaccine (LAIV). The season saw mainly A(H1N1)pdm09 and latterly A(H3N2) circulation. End-of-season adjusted vaccine effectiveness (aVE) estimates against laboratory confirmed influenza infection in primary care were calculated using the test negative case control method adjusting for key confounders. End-of-season aVE was 44.3% (95% CI: 26.8, 57.7) against all laboratory-confirmed influenza; 45.7% (95% CI: 26.0, 60.1) against influenza A(H1N1)pdm09 and 35.1% (95% CI: −3.7,59.3) against A(H3N2). Overall aVE was 49.9% (95%CI: −13.7, 77.9) for all those ≥ 65 years of age and 62.0% (95% CI: 3.4, 85.0) for those who received aTIV. Overall aVE for 2–17 year olds receiving LAIV was 48.6% (95% CI: −4.4, 74.7). The paper provides evidence of overall significant influenza VE in 2018/19, most notably against influenza A(H1N1)pdm09, however, as seen in 2017/18, there was reduced, non-significant VE against A(H3N2). aTIV provided significant protection for those 65 years of age and over.