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Recent advances in automation have fostered the development of unattended data collection services at a handful of synchrotron facilities worldwide. At the Swiss Light Source, the installation of new high-throughput sample changers at all three macromolecular crystallography beamlines and the commissioning of the Fast Fragment and Compound Screening pipeline created a unique opportunity to automate data acquisition. Here, the DA+ microservice software stack upgrades, implementation of an automatic loop-centering service and deployment of the Smart Digital User (SDU) software for unattended data collection are reported. The SDU software is the decision-making software responsible for communications between services, sample and device safety, sample centering, sample alignment with grid based X-ray diffraction and, finally, data collection.

ObjectivesThe inflammatory protein calprotectin (MRP8/14) has been identified as a promising biomarker of treatment response in rheumatoid arthritis (RA). Our aim was to test MRP8/14 as a biomarker of response to tumour necrosis factor (TNF)-inhibitors in the largest RA cohort to date and to compare with C-reactive protein (CRP).MethodsSerum MRP8/14 was measured in 470 patients with RA about to commence treatment with adalimumab (n=196) or etanercept (n=274). Additionally, MRP8/14 was measured in the 3-month sera of 179 adalimumab-treated patients. Response was determined using European League against Rheumatism (EULAR) response criteria calculated using the traditional 4-component (4C) DAS28-CRP and alternate validated versions using 3-component (3C) and 2-component (2C), clinical disease activity index (CDAI) improvement criteria and change in individual outcome measures. Logistic/linear regression models were fitted for response outcome.ResultsIn the 3C and 2C models, patients with RA were 1.92 (CI: 1.04 to 3.54) and 2.03 (CI: 1.09 to 3.78) times more likely to be classified as EULAR responders if they had high (75th quartile) pre-treatment levels of MRP8/14 compared with low (25th quartile). No significant associations were observed for the 4C model. When only using CRP as a predictor, in the 3C and 2C analyses, patients above the 75th quartile were 3.79 (CI: 1.81 to 7.93) and 3.58 (CI: 1.74 to 7.35) times more likely to be EULAR responders and addition of MRP8/14 did not significantly improve model fit (p values=0.62 and 0.80, respectively). No significant associations were observed in the 4C analysis. Exclusion of CRP from the outcome measure (CDAI) did not result in any significant associations with MRP8/14 (OR 1.00 (CI: 0.99 to 1.01), suggesting that the associations were due to the correlation with CRP and that there is no additional utility of MRP8/14 beyond use of CRP in patients with RA starting TNFi therapy.ConclusionBeyond correlation with CRP, we found no evidence to suggest that MRP8/14 explains additional variability in response to TNFi in patients with RA over and above CRP alone.

Corrected excess Gibbs energies of the liquid solutions in the ACl-ThCl4 (A = Li, Na, K), as well as revised standard enthalpies of formation and standard entropies of the intermediate phases occurring in the binary systems, are presented [...]

Anti-programmed cell death protein 1 (PD1) antibodies, pembrolizumab and nivolumab, alone or in combination with ipilimumab, have become standard treatment for melanoma and multiple other malignancies. Neurological adverse effects are rare and have not been well characterized to date. Patients who developed neurological adverse effects while being treated with PD1, alone or in combination with ipilimumab, were retrospectively identified from 10 cancer centers. Fifty-eight patients were included, and the median time from treatment initiation to development of neurological adverse effects was 7 weeks (range, 1-86.5 weeks). Thirty-seven (64%) toxicities affected the peripheral nervous system. Fifty (86%) patients were treated with corticosteroids, with 22 (37%) patients requiring further immunomodulation including intravenous immunoglobulin (16), plasmapheresis (7), mycophenolate mofetil (4), cyclophosphamide (1), and rituximab (1). Twenty-seven (46%) had a complete resolution of their neurological symptoms, and two (4%) patients died secondary to complications from their neurological adverse effects. The response rate of the cancer to immunotherapy was 78%, and the median progression free survival was not reached. Neurological adverse effects can occur with PD1 treatment, do not appear to impact treatment response, but may be irreversible or worsen in some patients. Management may require immunomodulation beyond corticosteroids.

COG-UK is supported by funding from the MRC part of UK Research & Innovation, the National Institute of Health Research (Grant code MC_PC_19027), and Genome Research Limited, operating as the Welcome Sanger Institute. Background The first epidemic wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Scotland resulted in high case numbers and mortality in care homes. In Lothian, over one-third of care homes reported an outbreak, while there was limited testing of hospital patients discharged to care homes. Aim To investigate patients discharged from hospitals as a source of SARS-CoV-2 introduction into care homes during the first epidemic wave. Methods A clinical review was performed for all patients discharges from hospitals to care homes from 1st March 2020 to 31st May 2020. Episodes were ruled out based on coronavirus disease 2019 (COVID-19) test history, clinical assessment at discharge, whole-genome sequencing (WGS) data and an infectious period of 14 days. Clinical samples were processed for WGS, and consensus genomes generated were used for analysis using Cluster Investigation and Virus Epidemiological Tool software. Patient timelines were obtained using electronic hospital records. Findings In total, 787 patients discharged from hospitals to care homes were identified. Of these, 776 (99%) were ruled out for subsequent introduction of SARS-CoV-2 into care homes. However, for 10 episodes, the results were inconclusive as there was low genomic diversity in consensus genomes or no sequencing data were available. Only one discharge episode had a genomic, time and location link to positive cases during hospital admission, leading to 10 positive cases in their care home. Conclusion The majority of patients discharged from hospitals were ruled out for introduction of SARS-CoV-2 into care homes, highlighting the importance of screening all new admissions when faced with a novel emerging virus and no available vaccine. Publisher PDF

Supplementary Figure 1 - PDF files 2472K, Expression of cell surface markers throughout CLL PBMC

Purpose: Despite advances in the treatment of chronic lymphocytic leukemia (CLL), the disease remains incurable with standard therapies and relapse is inevitable. A growing body of evidence indicates that alterations in the adhesion properties of neoplastic cells play a pivotal role in the development and progression of CLL.Experimental Design: The expression of 71 cell surface molecules was examined on CLL peripheral blood mononuclear cells (PBMCs) over 3 weeks in culture. The most highly upregulated marker, CD62L, was examined further for expression on CD5+/CD19+ CLL cells in vitro and in lymph node and bone marrow biopsies. The prosurvival role of CD62L was examined using a functional blocking antibody and therapeutic potential evaluated by comparison with current chemotherapy agents.Results: Blocking CD62L resulted in apoptosis of CLL cells but not PBMCs from healthy donors suggesting a novel role for CD62L in CLL cell survival. The beneficial effect of coculturing CLL cells with bone marrow stromal cells or endothelial cells does not protect CLL cells from anti-CD62L–related toxicity. Moreover, combining fludarabine or mafosfamide with the anti-CD62L in vitro produced an additive effect both with and without stromal cells.Conclusion: This is the first reported data showing that blocking the activation and homing marker, CD62L, regulates CLL cell survival in vitro. These data also suggest that therapeutic antibodies against CD62L may provide additional clinical benefit to patients with CLL receiving current standard chemotherapy protocols. Clin Cancer Res; 19(20); 5675–85. ©2013 AACR.

Supplementary Figure Legends - PDF files 57K, Figure Legends

Supplementary Table 2 - PDF files 77K, CD markers used in phenotype screen

Supplementary Figure 3 - PDF files 1469K, Correlation of CD62L antibody toxicity and clinical parameters

Supplementary Table 1 - PDF files 69K, Patient Data

We provide some natural history notes on the Pampas Fox Lycalopex gymnocercus from the Paraguayan Chaco. Information is presented on diet, distribution (with the first formal documentation of the species in the Oriental region), local beliefs, mortality, and possible play behavior. Photographic documentation of the existence of sarcoptic mange in wild foxes in the Paraguayan Chaco is also provided.

In 2015, Edward Snowden recommended that ordinary citizens use adblocking software and an encryption-oriented privacy extension for their web browser to protect against surveillance. This paper critically explores how the development of privacy extension software for web browsers can be situated in relation to privacy advocacy. Privacy advocates are individuals who act on behalf of the citizenry to speak to governments and corporations about how our data are collected and processed. While the Snowden revelations began in 2013 and the Cambridge Analytica scandal broke in 2018, privacy extensions remain underexplored in the literature on privacy advocacy. This paper shares findings from ethnographically informed interviews conducted with thirty developers and other knowledgeable experts who created twenty-six named privacy extensions. The privacy extensions explored included anti-tracking, hypertext transfer protocol secure (HTTPS), and privacy policy and password-related functionalities. Although privacy extensions are an imperfect set of tools to protect privacy, we argue that production of this software demonstrates an array of privacy advocacy strategies. Privacy extensions can be scaffolded upon previous resistance moves to surveillance by individuals, while also sometimes intersecting with traditional and expanded notions of collective action in the digital age.

Living with a child who has a life-limiting condition (LLC) is likely to have a major impact on all family members. There is a need to have a clearer understanding of the nature and extent of this impact on parents and well-siblings. The current study aimed to investigate the psychosocial functioning of well-siblings and parents living with a child with an LLC. Further, the study aimed to assess the resilience resources of both well-siblings and parents, giving consideration to how these relate to psychosocial functioning.Participants included 48 well-siblings (6-21 years) and 42 parents of children with LLCs. Parents and well-siblings independently completed validated measures of child and adult functioning and personal resilience. Parents provided demographic information about the patient and family.The emotional, social and school functioning of well-siblings in the current study was found to be significantly poorer than published norms (all p's .01). Parental self-reported depression, anxiety and stress scores were also all significantly poorer than published norms (all p's .01). There was negligible agreement between well-sibling self-reported functioning and parental proxy-report of the well-siblings functioning (all r's .126, all p's .464). Sibling self-reported resilience was positively correlated with each of the measures of psychosocial functioning (all r's .318, p's .05). Parental resilience was significantly negatively correlated with depressive symptoms (r = -.369, p .05) and anxiety symptoms (r = -.473, p .01) but not stress scores (r = -.074, p = .644).Family members living with a child who has an LLC were found to have significantly poorer psychosocial functioning than published norms. Although one cannot infer a causal direction from the current study, greater self-reported well-sibling and parental resilience were associated with aspects of better self-reported psychosocial functioning. Future studies should assess the impact of psychosocial interventions aimed at enhancing the resilience and functioning of both well-siblings and parents.

BackgroundPoor mental well-being is a major issue for young people and is likely to have long-term negative consequences. The contribution of nutrition is underexplored. We, therefore, investigated the association between dietary choices and mental well-being among schoolchildren.MethodsData from 7570 secondary school and 1253 primary school children in the Norfolk Children and Young People Health and Well-being Survey, open to all Norfolk schools during October 2017, were analysed. Multivariable linear regression was used to measure the association between nutritional factors and mental well-being assessed by the Warwick-Edinburgh Mental Well-being Scale for secondary school pupils, or the Stirling Children’s Well-being Scale for primary school pupils. We adjusted all analyses for important covariates including demographic, health variables, living/home situation and adverse experience variables.ResultsIn secondary school analyses, a strong association between nutritional variables and well-being scores was apparent. Higher combined fruit and vegetable consumption was significantly associated with higher well-being: well-being scores were 3.73 (95% CI 2.94 to 4.53) units higher in those consuming five or more fruits and vegetables (pConclusionThese findings suggest that public health strategies to optimise the mental well-being of children should include promotion of good nutrition.

This article shares findings from a study that explored factors contributing to the development of a social work professional identity, with a particular focus on social work students undertaking field education placements in mental health settings. Social work identity is not well recognised or articulated by experienced practitioners, nor does it appear to be adequately emphasised in social work education and training programmes. There is limited research on social work identity in mental health settings and even less pertaining to students’ efforts to construct a professional identity in such paradigmatically unfamiliar environments. This qualitative study explored how students understand, experience and articulate their developing professional identity in mental health settings. Participants were interviewed towards the completion of seventy-day (500-hour) field placements. Findings highlight that students struggled to relate to the concept of a ‘social work identity’ and were unable to articulate what it might be or involve. Students were more at ease describing specific roles they performed during their placement. However, analysis of their reflections on what they observed, what they did during placement, and reflective or integrative opportunities, provided rich descriptions of a range of the factors contributing to and influencing their developing social work identity.

Background The formulation of expert opinion guidelines has several sources of bias that may adversely affect their quality. To minimize bias, guideline creators must use rigorous methodology. There has been no appraisal of the methodologic quality of basic critical care echocardiography (BCCE) training/education guidelines. Research Question What is the methodologic quality of expert guidelines/recommendations on BCCE training? Study Design and Methods The review was performed by a multidisciplinary team including intensive care specialists, a hospital scientist, a trainee, a nurse sonographer, and a public health expert. Four databases (PubMed, OVID-Embase, Clarivate Analytics Web of Science, and Google Scholar) were searched on July 31, 2020, to identify guidelines on BCCE training/education. Every guideline was assessed subjectively for the degree of detail of the recommendations and assessed objectively by using the AGREE-II critical appraisal tool for clinical practice guidelines to generate a scaled domain score. A score ≥ 75% in every domain was the cut off for guidelines to be used without modifications. Results From 4,288 abstracts screened, 24 guidelines met the inclusion criteria. Very few guidelines made clear recommendations regarding introductory courses: physics (n = 6 [25%]), instrumentation (n = 5 [20.8%]), image acquisition theory (n = 6 [25%]), course curriculum (n = 5 [[20.8%]), pre-course/post-course tests (n = 1 [4.2%]), minimum course duration (n = 6 [25%]), or trainer qualifications (n = 5 [20.8%]). Very few provided clear recommendations for longitudinal competence programs: clinically indicated scans (n = 8 [33.3%]), logbook (n = 14 [58.3%]), image storage (n = 9 [37.5%]), formative assessment (n = 6 [25%]), minimum scan numbers (n = 14 [58.3%]), image acquisition competence (n = 3 [12.5%]), image interpretation competence (n = 2 [8.3%]), and credentialing/certification (n = 3 [12.5%]). Five guidelines (20.8%) attained a scaled overall AGREE-II score ≥ 75%. One guideline (4.2%) attained scores ≥ 75% in every domain. Interpretation The methodologic appraisal of BCCE-training guidelines showed widespread deficiencies in guideline formulation processes. The impact of these deficiencies on the validity of the recommendations requires further evaluation in longitudinal studies.

Introduction Knee replacement (KR) is a clinically proven procedure typically offered to patients with severe knee osteoarthritis (OA) to relieve pain and improve quality of life. However, artificial joints fail over time, requiring revision associated with higher mortality and inferior outcomes. With more young people presenting with knee OA and increasing life expectancy, there is an unmet need to postpone time to first KR. Knee joint distraction (KJD), the practice of using external fixators to open up knee joint space, is proposed as potentially effective to preserve the joint following initial studies in the Netherlands, however, has not been researched within an NHS setting. The KARDS trial will investigate whether KJD is non-inferior to KR in terms of patient-reported postoperative pain 12 months post-surgery. Methods and analysis KARDS is a phase III, multicentre, pragmatic, open-label, individually randomised controlled non-inferiority trial comparing KJD with KR in patients with severe knee OA, employing a hybrid-expertise design, with internal pilot phase and process evaluation. 344 participants will be randomised (1:1) to KJD or KR. The primary outcome measure is the Knee Injury and Osteoarthritis Outcomes Score (KOOS) pain domain score at 12 months post-operation. Secondary outcome measures include patient-reported overall KOOS, Pain Visual Analogue Scale and Oxford Knee Scores, knee function assessments, joint space width, complications and further interventions over 24 months post-operation. Per patient cost difference between KR and KJD and cost per quality-adjusted life year (QALY) gained over 24 months will be estimated within trial, and incremental cost per QALY gained over 20 years by KJD relative to KR predicted using decision analytic modelling. Ethics and dissemination Ethics approval was obtained from the Research Ethics Committee (REC) and Health Research Authority (HRA). Trial results will be disseminated at clinical conferences, through relevant patient groups and published in peer-reviewed journals. Trial registration number NCT14879004;recruitment opened April 2021.

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with heterogeneous aetiology and a complex genetic background. Effective therapies are therefore likely to act on convergent pathways such as dysregulated energy metabolism, linked to multiple neurodegenerative diseases including ALS.MethodsActivity of the glycolysis enzyme phosphoglycerate kinase 1 (PGK1) was increased genetically or pharmacologically using terazosin in zebrafish, mouse and ESC-derived motor neuron models of ALS. Multiple disease phenotypes were assessed to determine the therapeutic potential of this approach, including axon growth and motor behaviour, survival and cell death following oxidative stress.FindingsWe have found that targeting a single bioenergetic protein, PGK1, modulates motor neuron vulnerability in vivo. In zebrafish models of ALS, overexpression of PGK1 rescued motor axon phenotypes and improved motor behaviour. Treatment with terazosin, an FDA-approved compound with a known non-canonical action of increasing PGK1 activity, also improved these phenotypes. Terazosin treatment extended survival, improved motor phenotypes and increased motor neuron number in Thy1-hTDP-43 mice. In ESC-derived motor neurons expressing TDP-43M337V, terazosin protected against oxidative stress-induced cell death and increased basal glycolysis rates, while rescuing stress granule assembly.InterpretationOur data demonstrate that terazosin protects motor neurons via multiple pathways, including upregulating glycolysis and rescuing stress granule formation. Repurposing terazosin therefore has the potential to increase the limited therapeutic options across all forms of ALS, irrespective of disease cause.

Mapping accessible chromatin across time scales can give insights into its dynamic nature, for example during cellular differentiation and tissue or organism development. Analysis of such data can be utilised to identify functional cis-regulatory elements (CRE) and transcription factor binding sites and, when combined with transcriptomics, can reveal gene regulatory networks (GRNs) of expressed genes. Chromatin accessibility mapping is a powerful approach and can be performed using ATAC-sequencing (ATAC-seq), whereby Tn5 transposase inserts sequencing adaptors into genomic DNA to identify differentially accessible regions of chromatin in different cell populations. It requires low sample input and can be performed and analysed relatively quickly compared with other methods. The data generated from ATAC-seq, along with other genomic approaches, can help uncover chromatin packaging and potential cis-regulatory elements that may be responsible for gene expression. Here, we describe the ATAC-seq approach and give examples from mainly vertebrate embryonic development, where such datasets have identified the highly dynamic nature of chromatin, with differing landscapes between cellular precursors for different lineages.

Objective Major trauma is associated with blood loss and hypothermia. It is common to replace lost fluid with red cells stored at 2-6°C, and/or colloid/crystalloid fluid stored at ambient temperature, thus increasing hypothermia risk. At trauma and medical retrieval sites, mains electricity powered fluid warmers cannot be generally used. Latent heat provides an alternate practical method of portable temperature-controlled intravenous fluid warming. This work investigates the safety and efficacy of a fluid warmer powered by latent heat. Methods Twenty-five haematology patients received red cell transfusions, one through a fluid warmer, using latent heat from a super-cooled liquid and one without warming. Temperature of donor red cell units was measured after passing through fluid warmers. Blood samples were collected from red cell units and patients, prior and after each transfusion. These were tested for haemolysis markers (plasma haemoglobin, potassium, lactate dehydrogenase, bilirubin) and for traces of super-cooled liquid. Patient physiological parameters (oxygen saturation, pulse, temperature, blood pressure, respiration) were monitored during each transfusion. Results Patient's physiological signs remained stable and no transfusion reactions were observed during warm transfusions. Latent heat fluid warmers increased the temperature of red cell units to approximately 35°C. There were no significant differences in haemolysis markers following warmed and unwarmed transfusions, and no contamination of red cell units by super-cooled liquid was detected. Conclusion The latent heat fluid warmer was shown to safely warm transfused blood in a controlled clinical setting.

Objectives. The clinical progression of JIA is unpredictable. Knowing who will develop severe disease could facilitate rapid intensification of therapies. We use genetic variants conferring susceptibility to JIA to predict disease outcome measures. Methods. A total of 713 JIA patients with genotype data and core outcome variables (COVs) at diagnosis (baseline) and 1 year follow-up were identified from the Childhood Arthritis Prospective Study (CAPS). A weighted genetic risk score (GRS) was generated, including all single nucleotide polymorphisms (SNPs) previously associated with JIA susceptibility (P-value, Versus Arthritis 20542 22084 20621, Centre for Epidemiology Versus Arthritis (UK) 21755, National Institute for Health Research (NIHR), Manchester Academic Health Sciences Centre (MAHSC), CLUSTER consortium, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) MR/R013926/1, Great Ormond Street Hospital Children's Charity VS0518, Olivia's Vision, NIHR GOSH BRC, 'UK's Experimental Arthritis Treatment Centre for Children by Versus Arthritis 20621, NIHR GOSH Biomedical Research Centre, British Society for Rheumatology (BSR)

Background: \ud The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes.\ud \ud Methods: \ud This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status.\ud \ud Findings: \ud Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years [IQR 17–43]) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio [HR] 2·26 [95% CI 1·32–3·89]). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 [1·08–1·95]). Most patients were unvaccinated (32 078 [74·0%] across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 [95% CI 0·47–8·05] and for hospital admission or emergency care attendance 1·58 [0·69–3·61]) were similar to the HRs for unvaccinated patients (2·32 [1·29–4·16] and 1·43 [1·04–1·97]; p=0·82 for both) but the precision for the vaccinated subgroup was low.\ud \ud Interpretation: \ud This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant.\ud \ud Funding: \ud Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research.

BackgroundMandatory vaccination has been mooted to combat falling childhood vaccine uptake rates in England. This study investigated parental preferences for a mandatory vaccination scheme.MethodsDiscrete choice experiment. Six attributes were investigated: vaccine (MMR, 6-in-1), child age group (2 years and older, 5 years and older), incentive (£130 cash incentive for parent, £130 voucher incentive for child, no incentive), penalty (£450 fine, parent not able to claim Child Benefits for an unvaccinated child, unvaccinated child not able to attend school or day care), ability to opt out (medical exemption only, medical and religious belief exemption), and compensation scheme (not offered, offered). Mixed effects conditional logit regression models were used to investigate parental preferences and relative importance of attributes.FindingsParticipants were 1,001 parents of children aged 5 years and under (53% female, mean age=33·6 years, SD=7·1, 84% white British). Parental preferences were mostly based on incentives (slight preference for cash pay-out for the parent versus a voucher for the child) and penalties (preference for schemes that did not allow unvaccinated children to attend school or day care and those that withheld financial benefits for parents of unvaccinated children). Parents also preferred schemes that: offered a compensation scheme, mandated the 6-in-1 vaccine, mandated vaccination in children aged 2 years and older, and that offered only medical exemptions.InterpretationResults can inform policymakers’ decisions about how best to implement a mandatory childhood vaccination scheme in England.FundingData collection was funded by a British Academy/Leverhulme Small Research Grants (SRG1920\101118).Research in contextEvidence before this studyUptake of childhood vaccines in high-income countries has decreased in recent years. Making vaccination mandatory has the potential to increase uptake. There is no standard approach to mandatory vaccination schemes. Research suggests that the cultural context will affect perceived acceptability of vaccine laws. Mandatory vaccination has been mooted in England as a way to increase vaccine uptake. However, there is no recent research investigating parental preferences for how a mandatory vaccine scheme could be implemented.Added value of this studyWe used a discrete choice experiment to investigate English parents’ preferences for a mandatory vaccination scheme. Variables included were parameters that are likely to be considered by policymakers if a mandatory vaccination scheme were to be proposed.Implications of all the available evidenceStudy results indicate that parents prefer mandatory vaccination schemes that offer financial incentives for vaccination. The penalty imposed for missing a vaccine dose, and the inclusion of a compensation scheme for severe adverse effects also influenced preferences. These results can be used to inform policy should a mandatory vaccination scheme be proposed in England.

Continuous developments in cryogenic X-ray crystallography have provided most of our knowledge of 3D protein structures, which has recently been further augmented by revolutionary advances in cryoEM. However, a single structural conformation identified at cryogenic temperatures may introduce a fictitious structure as a result of cryogenic cooling artefacts, limiting the overview of inherent protein physiological dynamics, which play a critical role in the biological functions of proteins. Here, a room-temperature X-ray crystallographic method using temperature as a trigger to record movie-like structural snapshots has been developed. The method has been used to show how TL00150, a 175.15 Da fragment, undergoes binding-mode changes in endothiapepsin. A surprising fragment-binding discrepancy was observed between the cryo-cooled and physiological temperature structures, and multiple binding poses and their interplay with DMSO were captured. The observations here open up new promising prospects for structure determination and interpretation at physiological temperatures with implications for structure-based drug discovery.

Positron emission tomography (PET) is an imaging technique that detects radiolabelled drugs, which have been injected into the body. PET uses radioisotopes which emit energy in the form of positrons (β+). As the positron interacts with the surrounding tissue, it subsequently forms two gamma rays (γ) of equal energy (511 keV) in opposite directions. These gamma rays can then be detected by external detectors and used to produce a 3D image. A number of corrections are applied to improve image quality and respiratory gating methods can be used to correct for respiratory motion. Hybrid imaging also allows fused data for anatomical localisation and attenuation correction.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections were rising during early summer 2021 in many countries as a result of the Delta variant. We assessed reverse transcription polymerase chain reaction swab positivity in the Real-time Assessment of Community Transmission–1 (REACT-1) study in England. During June and July 2021, we observed sustained exponential growth with an average doubling time of 25 days, driven by complete replacement of the Alpha variant by Delta and by high prevalence at younger, less-vaccinated ages. Prevalence among unvaccinated people [1.21% (95% credible interval 1.03%, 1.41%)] was three times that among double-vaccinated people [0.40% (95% credible interval 0.34%, 0.48%)]. However, after adjusting for age and other variables, vaccine effectiveness for double-vaccinated people was estimated at between ~50% and ~60% during this period in England. Increased social mixing in the presence of Delta had the potential to generate sustained growth in infections, even at high levels of vaccination.

Cancer patients experience numerous distressing symptoms and concerns across the course of their illness, which negatively influence their quality of life. Regardless of cancer type, unmanaged symptoms can lead to adverse downstream consequences. Patient Reported Outcome Measures (PROMs) can be used to inform patient care and lead to targeted symptom management but simply gathering this information does not improve outcomes for the patient. Patient generated information must be easy for the clinicians to access and interpret if it is to be used to inform care delivery in ambulatory oncology facilities. This pragmatic work responded to this need. One Canadian provincial ambulatory oncology jurisdiction implemented digital tracking of PROMs over time in the provincial Electronic Medical Record (EMR) to support full integration of PROMs into standard care workflows and processes. Due to an inability within the EMR for direct patient entry, a hybrid data-entry was designed where the patient completes a paper-based PROM in the waiting room, and after clinical review, a clinician documents this along with their clinical assessment in the EMR. Several digital dashboards were developed which report PROMs data at the micro (individual), meso (clinic) and macro (program) levels. Using PROMs routinely in these provincial practice settings has numerous benefits including enhanced patient-clinician communication, assisting with problem detection, management of symptoms, and improving outcomes for patients. There are over 60,000 unique patients represented in our PROMs database, and over 300,000 unique screening events captured. The PROMs data is now used at all levels of the provincial cancer jurisdiction to provide targeted person centred care (micro), to staff appropriately at a clinic or program level (meso), and for capacity planning for provincial programs (macro). A new provincial EMR is currently being implemented which has an associated patient portal. Based on the success of this work, integration of direct entry of PROMs by the patient prior to the appointment and an associated workflow for symptom management is underway in this jurisdiction.

The gastrointestinal system anomalies in the newborn infants are not uncommon and are due to either embryogenesis defects or intrauterine vascular accidents resulting in a compromise of fetal blood circulation to specific system organs. The symptoms generally present within first 1–2 days of life and are mostly referable to intestinal obstruction, manifesting as vomiting, feeding difficulty and distension of abdomen. Other defects may have distinct signs and symptoms and variable time of onset. Some defects may be diagnosed antenatally during prenatal maternal care. The investigations include radiography, magnetic resonance imaging and ultrasound and in a majority of cases clinical presentation and plain radiography may provide adequate diagnostic information. The outcomes of surgical repair are variable and depend upon the original pathological defect. Here, the common anomalies are described with their clinical presentation, surgical repair techniques and outcomes.

When graduates of Australian social work courses embark on a career in mental health, the systems they enter are complex, fragmented and evolving. Emerging practitioners will commonly be confronted by the loneliness, social exclusion, poverty and prejudice experienced by people living with mental distress, however, social work practice may not be focused on these factors. Instead, in accordance with the dominant biomedical perspective, symptom and risk management may predominate. Frustration with the limitations evident in this approach has seen the United Nations call for the transformation of mental health service delivery. Recognising paradigmatic influences on mental health social work may lead to a more considered enactment of person centred, recovery and rights-based approaches. This paper compares and contrasts influences of neo-liberalism, critical theory, human rights and post-structuralism on mental health social work practice. In preparing social work practitioners to recognise the influence of, and work more creatively with, intersecting paradigms, social work educators strive to foster a transformative approach to mental health practice that straddles discourses.

AIMS Identifying significant miRNAs that are either under or overexpressed in hypoxia compared to normoxia in glioma cells. Further exploring the effect and role of hypoxia on miR-92a-3p and miR-149-5p in gliomas in apoptotic and cellular senescence pathways. METHOD A range of glioma cells were used for screening, including primary cell lines: GIN28 and GIN31; low-grade cell lines: LGG19 and LGG24; a paediatric cell line: SF188 and a commercially available glioblastoma cell line U87. These cells were cultured at both 1% (hypoxia) and 20% (normoxia) oxygen levels. Screening of miRNAs was achieved by quantitative polymerase chain reaction (qPCR) using miRNA specific primers. Knockdowns/in were achieved by transfecting with miR-92a-3p and miR-149-5p mimics and inhibitors. Caspase-glo assay was used to assess the effect of hypoxia on apoptosis. RESULTS A range of miRNAs were differentially expressed in hypoxia in a range of glioma cell lines. miRNA 92a-3p and miR-149-5p were found to be downregulated and upregulated respectively in primary gliomablastoma cells in hypoxia compared to normoxia. These particular miRNAs are also found to have multiple targets in apoptosis and cellular senescence. CONCLUSION The screening of 90 miRNAs among the different categories of gliomas highlighted multiple miRNAs that were significant in hypoxia compared to normoxia. Using primary cell lines have identified hypoxia-affected miRNAs in glioblastomas. This discovery will increase our knowledge and understanding of the hypoxia effect on miRNAs which may aid and direct targeted therapy to conquer hypoxia in glioblastomas.

The Internal Dosimetry User Group (IDUG) is an independent, non-profit group of medical professionals dedicated to the promotion of dosimetry in molecular radiotherapy ( www.IDUG.org.uk ). The Ionising Radiation (Medical Exposure) Regulations 2017, IR(ME)R, stipulate a requirement for optimisation and verification of molecular radiotherapy treatments, ensuring doses to non-target organs are as low as reasonably practicable. For many molecular radiotherapy treatments currently undertaken within the UK, this requirement is not being fully met. The growth of this field is such that we risk digressing further from IR(ME)R compliance potentially delivering suboptimal therapies that are not in the best interest of our patients. For this purpose, IDUG proposes ten points of action to aid in the successful implementation of this legislation. We urge stakeholders to support these proposals and ensure national provision is sufficient to meet the criteria necessary for compliance, and for the future advancement of molecular radiotherapy within the UK.

The structural, thermochemical, and thermophysical properties of the NaF–ThF4 fuel system were studied with experimental methods and molecular dynamics (MD) simulations. Equilibrium MD (EMD) simulations using the polarizable ion model were performed to calculate the density, molar volume, thermal expansion, mixing enthalpy, heat capacity, and distribution of [ThFn]m− complexes in the (Na,Th)Fx melt over the full concentration range at various temperatures. The phase equilibria in the 10–50 mol % ThF4 and 85–95 mol % ThF4 regions of the NaF–ThF4 phase diagram were measured using differential scanning calorimetry, as were the mixing enthalpies at 1266 K of (NaF/ThF4) = (0.8:0.2), (0.7:0.3) mixtures. Furthermore, the β-Na2ThF6 and NaTh2F9 compounds were synthesized and subsequently analyzed with the use of X-ray diffraction. The heat capacities of both compounds were measured in the temperature ranges (2–271 K) and (2–294 K), respectively, by thermal relaxation calorimetry. Finally, a CALPHAD model coupling the structural and thermodynamic data was developed using both EMD and experimental data as input and a quasichemical formalism in the quadruplet approximation. Here, 7- and 8-coordinated Th4+ cations were introduced on the cationic sublattice alongside a 13-coordinated dimeric species to reproduce the chemical speciation, as calculated by EMD simulations and to provide a physical description of the melt.

The COVID-19 pandemic has spread rapidly throughout the world. In the UK, the initial peak was in April 2020; in the county of Norfolk (UK) and surrounding areas, which has a stable, low-density population, over 3200 cases were reported between March and August 2020. As part of the activities of the national COVID-19 Genomics Consortium (COG-UK) we undertook whole genome sequencing of the SARS-CoV-2 genomes present in positive clinical samples from the Norfolk region. These samples were collected by four major hospitals, multiple minor hospitals, care facilities and community organizations within Norfolk and surrounding areas. We combined clinical metadata with the sequencing data from regional SARS-CoV-2 genomes to understand the origins, genetic variation, transmission and expansion (spread) of the virus within the region and provide context nationally. Data were fed back into the national effort for pandemic management, whilst simultaneously being used to assist local outbreak analyses. Overall, 1565 positive samples (172 per 100 000 population) from 1376 cases were evaluated; for 140 cases between two and six samples were available providing longitudinal data. This represented 42.6 % of all positive samples identified by hospital testing in the region and encompassed those with clinical need, and health and care workers and their families. In total, 1035 cases had genome sequences of sufficient quality to provide phylogenetic lineages. These genomes belonged to 26 distinct global lineages, indicating that there were multiple separate introductions into the region. Furthermore, 100 genetically distinct UK lineages were detected demonstrating local evolution, at a rate of ~2 SNPs per month, and multiple co-occurring lineages as the pandemic progressed. Our analysis: identified a discrete sublineage associated with six care facilities; found no evidence of reinfection in longitudinal samples; ruled out a nosocomial outbreak; identified 16 lineages in key workers which were not in patients, indicating infection control measures were effective; and found the D614G spike protein mutation which is linked to increased transmissibility dominates the samples and rapidly confirmed relatedness of cases in an outbreak at a food processing facility. The large-scale genome sequencing of SARS-CoV-2-positive samples has provided valuable additional data for public health epidemiology in the Norfolk region, and will continue to help identify and untangle hidden transmission chains as the pandemic evolves.