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Abstract Introduction The introduction of a national evaluation of newborn screening for Severe Combined Immunodeficiency (SCID) in England triggered a change to the selective Bacillus Calmette-Guerin (BCG) vaccination programme delivery pathway, as this live attenuated vaccine is contraindicated in infants with SCID. The neonatal BCG vaccination programme is a targeted programme for infants at increased risk of tuberculosis and used to be offered shortly after birth. Since September 2021 the BCG vaccine is given to eligible infants within 28 days of birth, when the SCID screening outcome is available. We explore the experiences of those implementing the new pathway, and how they made sense of, engaged with, and appraised the change. Methods A mixed-methods evaluation was conducted between October 2022 and February 2023. This involved national online surveys with BCG commissioners and providers and qualitative semi-structured interviews with commissioners, providers, and Child Health Information System stakeholders in two urban areas. Survey data was analysed using descriptive statistics and interview data was analysed thematically. The data was triangulated using Normalization Process Theory as a guiding framework. Results Survey respondents (n = 65) and qualitative interviewees (n = 16) revealed that making sense of the new pathway was an iterative process. Some expressed a desire for more direction on how to implement the new pathway. The perceived value of the change varied from positive, ambivalent, to concerned. Some felt well-prepared and that improvements to data capture, eligibility screening, and accountably brought by the change were valuable. Others were concerned about the feasibility of the 28-day target, reductions in vaccination coverage, increased resource burden, and the outcome of the SCID evaluation. New collaborations and communities of practice were required to facilitate the change. Three main challenges in implementing the pathway and meeting the 28-day vaccination target were identified: appointment non-attendance; appointment and data systems; and staffing and resourcing. Feedback mechanisms were informal and took place in tandem with implementation. Conclusion The new NHS neonatal BCG service specification has created an effective structure for monitoring and managing the BCG vaccination programme, but further work is required to support delivery of the 28-day vaccination target and improve uptake rates.

Summary: Background: Bacille Calmette-Guérin (BCG) vaccination has off-target (non-specific) effects that are associated with protection against unrelated infections and decreased all-cause mortality in infants. We aimed to determine whether BCG vaccination prevents febrile and respiratory infections in adults. Methods: This randomised controlled phase 3 trial was done in 36 healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom. Healthcare workers were randomised to receive BCG-Denmark (single 0.1 ml intradermal injection) or no BCG in a 1:1 ratio using a web-based procedure, stratified by stage, site, age, and presence of co-morbidity. The difference in occurrence of febrile or respiratory illness were measured over 12 months (prespecified secondary outcome) using the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020, and April 1, 2021, 6828 healthcare workers were randomised to BCG-Denmark (n = 3417) or control (n = 3411; no intervention or placebo) groups. The 12-month adjusted estimated risk of ≥1 episode of febrile or respiratory illness was 66.8% in the BCG group (95% CI 65.3%–68.2%), compared with 63.4% in the control group (95% CI 61.8%–65.0%), a difference of +3.4 percentage points (95% CI +1.3% to +5.5%; p 0.002). The adjusted estimated risk of a severe episode (defined as being incapacitated for ≥3 consecutive days or hospitalised) was 19.4% in the BCG group (95% CI 18.0%–20.7%), compared with 18.8% in the control group (95% CI 17.4%–20.2%) a difference of +0.6 percentage points (95% CI −1.3% to +2.5%; p 0.6). Both groups had a similar number of episodes of illness, pneumonia, and hospitalisation. There were three deaths, all in the control group. There were no safety concerns following BCG vaccination. Interpretation: In contrast to the beneficial off-target effects reported following neonatal BCG in infants, a small increased risk of symptomatic febrile or respiratory illness was observed in the 12 months following BCG vaccination in adults. There was no evidence of a difference in the risk of severe disease. Funding: Bill & Melinda Gates Foundation, Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, the National Health and Medical Research Council, the Swiss National Science Foundation and individual donors.

Summary: Background: The COVID-19 pandemic led to the rapid development and deployment of several highly effective vaccines against SARS-CoV-2. Recent studies suggest that these vaccines may also have off-target effects on the immune system. We sought to determine and compare the off-target effects of the adenovirus vector ChAdOx1-S (Oxford-AstraZeneca) and modified mRNA BNT162b2 (Pfizer-BioNTech) vaccines on immune responses to unrelated pathogens. Methods: Prospective sub-study within the BRACE trial. Blood samples were collected from 284 healthcare workers before and 28 days after ChAdOx1-S or BNT162b2 vaccination. SARS-CoV-2-specific antibodies were measured using ELISA, and whole blood cytokine responses to specific (SARS-CoV-2) and unrelated pathogen stimulation were measured by multiplex bead array. Findings: Both vaccines induced robust SARS-CoV-2 specific antibody and cytokine responses. ChAdOx1-S vaccination increased cytokine responses to heat-killed (HK) Candida albicans and HK Staphylococcus aureus and decreased cytokine responses to HK Escherichia coli and BCG. BNT162b2 vaccination decreased cytokine response to HK E. coli and had variable effects on cytokine responses to BCG and resiquimod (R848). After the second vaccine dose, BNT162b2 recipients had greater specific and off-target cytokine responses than ChAdOx1-S recipients. Interpretation: ChAdOx1-S and BNT162b2 vaccines alter cytokine responses to unrelated pathogens, indicative of potential off-target effects. The specific and off-target effects of these vaccines differ in their magnitude and breadth. The clinical relevance of these findings is uncertain and needs further study. Funding: Bill & Melinda Gates Foundation, National Health and Medical Research Council, Swiss National Science Foundation and the Melbourne Children’s. BRACE trial funding is detailed in acknowledgements.

Summary: Background: The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) describes three primary avoidant/restrictive food intake disorder (ARFID) subtypes including sensory sensitivity, lack of interest in food or eating, and fear of aversive consequences. Studies exploring these subtypes have yielded varying results. We used latent class analysis (LCA) based on the psychopathology of ARFID in a sample of children and adolescents to empirically identify classes. Methods: We carried out a surveillance study of ARFID in collaboration with the British Paediatric Surveillance Unit (BPSU) and the Child and Adolescent Psychiatry Surveillance System (CAPSS) in the United Kingdom and the Republic of Ireland from 1st of March 2021 to 31st of March 2022. Paediatricians and child and adolescent psychiatrists were contacted monthly to report newly diagnosed cases of ARFID electronically and complete a detailed clinical questionnaire. Cases aged 5–18 years were included. LCA was performed specifying 1–6 classes and likelihood-based tests for model selection. The Bayesian Information Criterion (BIC), the Akaike Information Criterion (AIC) and the Sample-Size Adjusted BIC were used to determine the most parsimonious model. Analysis of variance (ANOVA) and χ2 tests were used to compare the characteristics of the identified classes. A multinomial logistic regression (MLR) was performed to investigate predicting factors for the latent classes. Findings: We identified 319 children and adolescents with ARFID. LCA revealed four distinct classes which were labelled as Fear subtype, Lack of Interest subtype, Sensory subtype, and Combined subtype. The probability of being classified as these were 7.2% (n = 23), 25.1% (n = 80), 29.5% (n = 94) and 38.2% (n = 122), respectively. Age at diagnosis, sex, weight loss, distress associated with eating, and autism spectrum disorder diagnosis were identified as predictors of class membership. Interpretation: LCA identified four different classes in a sample of children and adolescents with ARFID. The Combined Subtype, a mixed presentation was the most common. The other three classes resembled the subtypes described in the literature. Clinicians should be aware of these different presentations of ARFID as they may benefit from different clinical interventions. Funding: This study was funded by the Former EMS Ltd (charity number 1098725, registered October 9th 2017).

This investigation focusses on the use of two wall-resolved LES approaches for the simulation of the buoyancy driven flow in a differentially heated square cavity, aiming to advance understanding of the flow phenomena involved. The study also assesses the predictive accuracy and cost-effectiveness of LES for natural convection flows. This assessment is pursued through comparisons of the resulting predictions, and also of their computational requirements, with those for DNS, produced in an earlier study, and those of a number of URANS models produced during the current investigation. URANS models tested here include both high- and low-Reynolds-number schemes. In the case of the high-Reynolds-number models a recently developed numerical variant of the Analytical Wall Function (AWF) has been employed to account for the effects of near-wall turbulence. Both LES approaches result in predictions that are close to those of the DNS but have considerably more modest resource requirements. The URANS approaches, which have the lowest resource requirements, for key parameters such as the local Nusselt number are not as accurate as the LES approaches and their performance is highly dependent on the turbulence model employed. Surprisingly, the simplest of the low-Re models employed, the Launder–Sharma two-equation model, is reasonably close to the DNS data. The approach that requires the least computational resource, the high-Re model with the recent version of the AWF, also offers a promising URANS route. Simulations were also conducted to investigate the flow behaviour at a Rayleigh number that is an order of magnitude higher than that of the available DNS. At such high Rayleigh number, at which the phenomena are of close relevance to cooling loops of nuclear reactors, comparisons are performed between the LES and the high-Re AWF combination. The findings show that as the Rayleigh number increases, the turbulence levels become stronger, but these are confined to more refined structures within the thinner near-wall boundary layers.

Abstract Background Transcriptional regulation is a key aspect of environmental stress responses. Heat stress induces transcriptional memory, i.e., sustained induction or enhanced re-induction of transcription, that allows plants to respond more efficiently to a recurrent HS. In light of more frequent temperature extremes due to climate change, improving heat tolerance in crop plants is an important breeding goal. However, not all heat stress-inducible genes show transcriptional memory, and it is unclear what distinguishes memory from non-memory genes. To address this issue and understand the genome and epigenome architecture of transcriptional memory after heat stress, we identify the global target genes of two key memory heat shock transcription factors, HSFA2 and HSFA3, using time course ChIP-seq. Results HSFA2 and HSFA3 show near identical binding patterns. In vitro and in vivo binding strength is highly correlated, indicating the importance of DNA sequence elements. In particular, genes with transcriptional memory are strongly enriched for a tripartite heat shock element, and are hallmarked by several features: low expression levels in the absence of heat stress, accessible chromatin environment, and heat stress-induced enrichment of H3K4 trimethylation. These results are confirmed by an orthogonal transcriptomic data set using both de novo clustering and an established definition of memory genes. Conclusions Our findings provide an integrated view of HSF-dependent transcriptional memory and shed light on its sequence and chromatin determinants, enabling the prediction and engineering of genes with transcriptional memory behavior.

Summary: Background: Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. Methods: In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1 mL of BCG-Denmark corresponding to 2−8 x 105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n = 38) or control (n = 46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27–2.82, p = 0.02) than the control group (hazard ratio 0.54, 95% CI 0.32–0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69–3.12, p = 0.003; hazard ratio 0.45, 95% CI 0.26–0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p = 0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3–2.6%, p = 0.02). There were no safety concerns. Interpretation: BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore. Funding: Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.

Patients with recurrent acute pancreatitis (RAP) are at significant risk of developing early chronic pancreatitis (CP), which progresses into irreversible, end-stage CP with severe symptoms. There is no specific therapy in RAP or in early CP that may hinder disease progression. The pathogenesis of CP is complex and involves interactions among multiple cell types, including pancreatic acinar, ductal, and stellate cells (PSC). Therefore, it is pivotal to identify common pathogenic pathways in these cells that could be targeted pharmacologically. The Orai1-mediated store-operated Ca2+ entry (SOCE) is a ubiquitous signaling mechanism that may become overactivated in pathological states resulting in intracellular Ca2+ overload. In this study, we used ex vivo and in vivo preclinical disease models to demonstrate that Orai1 inhibition prevents progression of RAP and early CP. The selective Orai1 inhibitor CM5480 restored the expression of SOCE-associated regulatory factor in acinar cells, prevented uncontrolled Ca2+ elevation, protected acinar and ductal functions, mitigated immune cell infiltration, and diminished PSC activation, proliferation, and migration. We suggest that the overactivation of Orai1 is a crucial pathogenetic event in the progression of early CP and that inhibition of Orai1 could prevent the development of end-stage CP.

Introduction Patients with episodes of supraventricular tachycardia (SVT), a common heart arrhythmia, are often attended by ambulance services. International guidelines advocate treatment with the Valsalva manoeuvre (VM), but this simple physical treatment has a low success rate, with most patients requiring conveyance to hospital. The Valsalva Assist Device (VAD) is a simple device that might help practitioners and patients perform a more effective VM and reduce the need for patients to be taken to hospital.Methods and analysis This stepped wedge cluster randomised controlled trial, conducted within a UK ambulance service, compares the current standard VM with a VAD-delivered VM in stable adult patients presenting to the ambulance service with SVT. The primary outcome is conveyance to hospital; secondary outcomes measures include cardioversion rates, duration of ambulance care and number of subsequent episodes of SVT requiring ambulance service care. We plan to recruit approximately 800 patients, to have 90% power to detect an absolute reduction in conveyance rate of 10% (from 90% to 80%) between the standard VM (control) and VAD-delivered VM (intervention). Such a reduction in conveyance would benefit patients, the ambulance service and receiving emergency departments. It is estimated potential savings would pay for devices for the entire ambulance trust within 7 months.Ethics and dissemination The study has been approved by the Oxford Research Ethics Committee (reference 22/SC/0032). Dissemination will be through peer-reviewed journal publication, presentation at national and international conferences and by the Arrhythmia Alliance, a patient support charity.Trial registration number ISRCTN16145266.

Abstract Background Nutritional rehabilitation for patients with anorexia nervosa involves balancing the need for weight gain whilst mitigating the risk of refeeding syndrome. Graded caloric increases and restriction of calories from carbohydrate have been used to minimise the risk of developing refeeding hypophosphatemia. There is little evidence to support the recommended nutrient composition, specifically the recommended carbohydrate intake that is safe in this population. The aim of this pilot study was to compare the effect of a low and a standard carbohydrate feeding protocol on serum phosphate levels in children and adolescents with anorexia nervosa. Methods A pilot study of 23 children and adolescents with anorexia nervosa admitted for medical stabilisation to the adolescent ward of a tertiary hospital was undertaken. Participants were commenced on an oral feeding protocol and were randomly allocated to isocaloric meal plans that were either low carbohydrate (

Vast amounts of publicly licensed classical music resources are housed within many different repositories on the Web encompassing richly diverse facets of information—including bibliographical and biographical data, digitized images of music notation, music score encodings, audiovisual performance recordings, derived feature data, scholarly commentaries, and listener reactions. While these varied perspectives ought to contribute to greater holistic understanding of the music objects under consideration, in practice, such repositories are typically minimally connected. The TROMPA project aims to improve this situation by interconnecting and enriching public-domain music repositories. This is achieved, on the one hand, by the application of automated, cutting-edge Music Information Retrieval techniques, and on the other, by the development of contribution mechanisms enabling users to integrate their expertise. Information within established repositories is interrelated with data generated by the project within a data infrastructure whose design is guided by the FAIR principles of data management and stewardship: making music information Findable, Accessible, Interoperable, and Reusable. We provide an overview of challenges of description, identification, representation, contribution, and reliability toward applying the FAIR principles to music information, and outline TROMPA's implementational approach to overcoming these challenges. This approach applies a graph-based data infrastructure to interrelate information hosted in different repositories on the Web within a unifying data model (a 'knowledge graph'). Connections are generated across different representations of music content beyond the catalogue level, for instance connecting note elements within score encodings to corresponding moments in performance time-lines. Contributions of user data are supported via privacy-first mechanisms that retain control of such data with the contributing user. Provenance information is captured throughout, supporting reproducibility and re-use of the data both within and outside the context of the project.

Introduction: As the world continues to urbanize, particularly in low- and middle-income countries, understanding the barriers and effective interventions to improve urban immunization equity is critical to achieving both Immunization Agenda 2030 targets and the Sustainable Development Goals. Approximately 25 million children missed one or more doses of the diphtheria, tetanus and pertussis (DTP3) vaccine in 2021 and it is estimated that close to 30% of the world’s children missing the first dose of DTP, known as zero-dose, live in urban and peri-urban settings. Methods: The aim of this research is to improve understanding of urban immunization equity through a qualitative review of mixed method studies, urban immunization strategies and funding proposals across more than 70 urban areas developed between 2016 and 2020, supported by Gavi, the Vaccine Alliance. These research studies and strategies created a body of evidence regarding the barriers to vaccination in urban settings and potential interventions relevant to low- and middle-income countries (LMICs) with a focus on the vaccination of urban poor, populations of concern and residents of informal settlements. Through the document review we identified common challenges to achieving equitable coverage in urban areas and mapped proposed interventions. Results: We identified 70 documents as part of the review and categorized results across (1) social determinants of health, (2) immunization service-delivery barriers and (3) quality of services. Barriers and solutions identified in the documents were categorized in these thematic areas, drawing information from results in more than 21 countries. Conclusion: Populations of concern such as migrants, refugees, residents of informal settlements and the urban poor face barriers to accessing care which include poor availability and quality of service. Example solutions proposed to these challenges include tailored delivery strategies, improved use of digital data collection and child-friendly services. More research is required on the efficacy of the proposed interventions identified and on gender-specific dynamics in urban poor areas affecting equitable immunization coverage.

As SARS-CoV-2 infections continue to cause hospital admissions around the world, there is a continued need to accurately assess those at highest risk of death to guide resource use and clinical management. The ISARIC 4C mortality score provides mortality risk prediction at admission to hospital based on demographic and physiological parameters. Here we evaluate dynamic use of the 4C score at different points following admission. Score components were extracted for 6,373 patients admitted to Barts Health NHS Trust hospitals between 1st August 2020 and 19th July 2021 and total score calculated every 48 hours for 28 days. Area under the receiver operating characteristic (AUC) statistics were used to evaluate discrimination of the score at admission and subsequent inpatient days. Patients who were still in hospital at day 6 were more likely to die if they had a higher score at day 6 than others also still in hospital who had the same score at admission. Discrimination of dynamic scoring in those still in hospital was superior with the area under the curve 0.71 (95% CI 0.69–0.74) at admission and 0.82 (0.80–0.85) by day 8. Clinically useful changes in the dynamic parts of the score are unlikely to be associated with subject-level measurements. Dynamic use of the ISARIC 4C score is likely to provide accurate and timely information on mortality risk during a patient’s hospital admission.

Background: The expansion of available vaccines in recent years has increased the overall costs of the vaccine program and put pressure on providers responsible for vaccination. In England in 2016–17, GP practices responsible for vaccinating their local population were paid £227 million. However, the costs to general practice of delivering the program and the factors influencing these costs are unknown. Therefore, the aim of this study was to evaluate the costs of delivering the routine vaccination program at GP practices in England, to identify organizational factors impacting costs, and to compare these to the funding received. Methods: Time Driven Activity Based Costing was undertaken at a convenience sample of nine geographically and socio-economically diverse GP practices in 2017–2018. Cost data were gathered for the preceding year using a survey and clinical and administrative staff kept activity logs for a 2-week period. Results: The mean cost of delivering a childhood vaccination appointment was £18.20 (range £9.71-£25.97) and an adult appointment cost £14.05 (range £7.59-£20.88), of which 75% was for staff, 24% for facility costs and 1% for consumables. Organizational factors contributing to lower costs include: shorter length of allocated appointment; greater use of administrative and reception staff; lower working time for practice manager and practice nurse; and use of health-care assistants for adult vaccinations. The costs identified are lower than payments at all practices. Conclusions: Funding received for vaccination activities was higher than costs at included practices. Several organizational factors have been identified that impact on program delivery costs that could be modified.

HIV co-receptor tropism determination is essential before prescribing the CCR5 antagonist maraviroc. British HIV Association guidelines suggest tropism testing may remain valid for only 90 days in antiretroviral-naïve patients. We aimed to determine the accuracy of this figure. Tropism was assessed in 26 antiretroviral-naïve patients with ongoing viral replication, sampled yearly from first clinic visit. The V3 region of HIV-1 was sequenced in triplicate, then tropism predicted using the Geno2Pheno system. Baseline tropism prediction remained valid for a median of 52 months (range 7-81). For 19/26 individuals baseline tropism remained unchanged throughout a median of 54 months follow-up; 18 R5 tropic and 1 X4 tropic. In seven patients (27%) baseline tropism switched at least once (range 1-4 switches) during follow-up; however, their baseline tropism prediction remained valid for a median of 45 months. Co-receptor tropism in treatment-naïve patients with ongoing viral replication appears highly stable over time, suggesting that baseline genotypic tropism prediction may be valid for a longer duration in patients delaying ART initiation. In this study, baseline tropism prediction remained valid for a median of 52 months, suggesting current guidelines recommending repeat testing after 90 days may be excessively conservative in their assessment of tropism stability. [ABSTRACT FROM AUTHOR]

Background and purpose: Dose escalation has improved cancer outcomes for patients with localized prostate cancer. Targeting subprostatic tumor regions for dose intensification may further improve outcomes. Apparent Diffusion Coefficient (ADC) maps may enable early radiation response assessment and dose adaptation. This study was a proof-of-principle investigation of early changes in ADC radiomics features for patients undergoing radiotherapy with dose escalation to the gross tumor volume (GTV). Materials and methods: Fifty-nine patients were enrolled on a prospective tumor dose-escalation trial. Multi-parametric MRI was performed at baseline and week six, corresponding to the time of peak ADC change. GTV and prostate contours were deformably registered between baseline and week six T2-weighted images, and applied to ADC maps, to account for diminished image contrast post-EBRT and possible differences in prostate gland volume, shape, and orientation. A total of 101 radiomics features were tested for significant change post-EBRT using two-tailed Student’s t-test. All ADC features of the prostate and GTV volumes were correlated using Pearson’s coefficient (p

Abstract Background The vaccine system in England underwent radical changes in 2013 following the implementation of the Health and Social Care Act. There have since been multi-year decreases in coverage of many vaccines. Healthcare professionals have reported finding the new system fragmented and challenging. This study aims to produce a logic model of the new system and evaluate the available evidence for interventions to improve coverage. Methods We undertook qualitative document analysis to develop the logic model using process evaluation methods. We performed a systematic review by searching 12 databases with a broad search strategy to identify interventions studied in England conducted between 2006 and 2016 and evaluated their effectiveness. We then compared the evidence base to the logic model. Results We analysed 83 documents and developed a logic model describing the core inputs, processes, activities, outputs, outcomes and impacts of the new vaccination system alongside the programmatic assumptions for each stage. Of 9,615 unique articles, we screened 624 abstracts, 45 full-text articles, and included 16 studies: 8 randomised controlled trials and 8 quasi-experimental studies. Four studies suggest that modifications to the contracting and incentive systems can increase coverage, but changes to other programme inputs (e.g. human or capital resources) were not evaluated. Four multi-component intervention studies modified activities and outputs from within a GP practice to increase coverage, but were part of campaigns or projects. Thus, many potentially modifiable factors relating to routine programme implementation remain unexplored. Reminder/recall systems are under-studied in England; incentive payments to adolescents may be effective; and only two studies evaluated carer information. Conclusions The evidence base for interventions to increase immunisation coverage in the new system in England are limited by a small number of studies and by significant risk of bias. Several areas important to primary care remain unexplored as targets for interventions, especially modification to organisational management.

Background & Aims: The incidence of primary liver cancer (PLC) is increasing in Western Europe. To understand trends over time and the current burden in the UK, a detailed analysis of the epidemiology of PLC and its subtypes was conducted. Methods: Data on PLCs diagnosed during 1997–2017 were obtained from population-based, nationwide registries in the UK. European age-standardised incidence (ASR) and incidence-based mortality rates (ASMR) per 100,000 person-years were calculated overall and by sex and UK-nation. Annual percentage change in rates was estimated using Joinpoint regression. One-, 2-, and 5-year age-standardised net survival was estimated. Results: A total of 82,024 PLCs were diagnosed. Both hepatocellular carcinoma (HCC) incidence and mortality rates trebled (ASR 1.8–5.5 per 100,000, ASMR 1.3–4.0). The rate of increase appeared to plateau around 2014/2015. Scottish men consistently had the highest HCC incidence rates. PLC survival increased, driven by a substantial increase in the proportion that are HCC (as prognosis is better than other PLCs) and in HCC survival (change in 1-year survival 24–47%). Intrahepatic cholangiocarcinoma was the most common PLC in women and 1-year survival improved from 22.6% to 30.5%. Conclusions: PLC incidence has been increasing rapidly but, as most risk factors are modifiable, it is largely a preventable cancer. This rate of increase has slowed in recent years, possibly attributable to effective treatment for hepatitis C. As other risk factors such as obesity and diabetes remain prevalent in the UK, it is unlikely the considerable burden of this disease will abate. While improvements in survival have been made, over half of patients are not alive after 1 year, therefore further progress in prevention, early detection, and treatment innovation are needed. Lay summary: Many more people are getting liver cancer, particularly the subtype hepatocellular carcinoma, than 20 years ago. Men in Scotland are most likely to get liver cancer and to die from it. Survival after liver cancer diagnosis is getting longer but still less than half are alive after 1 year.

Spotty liver disease (SLD) is a bacterial disease of chicken, causing mortalities and reduction in egg production, hence, contributing to economic loss in the poultry industry. The causative agent of SLD has only recently been identified as a novel Campylobacter species, Campylobacter hepaticus. Specific primers were designed from the hsp60 gene of Campylobacter hepaticus and PCR followed by high-resolution melt curve analysis was optimised to detect and differentiate three species of Campylobacter (Campylobacter coli, Campylobacter jejuni and Campylobacter hepaticus). The three Campylobacter species produced a distinct curve profile and was differentiated using HRM curve analysis. The potential of the PCR-HRM curve analysis was shown in the genotyping of 37 Campylobacter isolates from clinical specimens from poultry farms. PCR-HRM curve analysis of DNA extracts from bile samples or cultures from bile samples, were identified as Campylobacter hepaticus and confirmed by DNA sequencing. The DNA sequence analysis of selected samples from each of the three HRM distinctive curves patterns showed that each DNA sequence was associated with a unique melt profile. The potential of the PCR-HRM curve analysis in genotyping of Campylobacter species was also evaluated using faecal specimens from 100 wild birds. The results presented in this study indicate that PCR followed by HRM curve analysis provides a rapid and robust technique for genotyping of Campylobacter species using either bacterial cultures or clinical specimens.

In the summer of 2019–2020, southern Australia experienced the largest fires on record, detrimentally impacting the habitat of native species, many of which were already threatened by past and current anthropogenic land use. A large-scale restoration effort to improve degraded species habitat would provide fire-affected species with the chance to recover and persist in burnt and unburnt habitat. To facilitate this, decision-makers require information on priority species needs for restoration intervention, the suite of potential restoration interventions, and the priority locations for applying these interventions. We prioritize actions in areas where restoration would most likely provide cost-effective benefits to priority species (defined by each species proportion of habitat burned, threat status, and vulnerability to fires), by integrating current and future species habitat suitability maps with spatially modelled costs of restoration interventions such as replanting, removing invasive species, and implementing ecologically appropriate fire management. We show that restoring the top ∼69% (112 million hectares) of the study region (current and future distributions of priority species) accounts for, on average, 95% of current and future habitat for every priority species and costs ∼AUD$73 billion yr ^−1 (AUD$650 hectare ^−1 yr ^−1 ) annualized over 30 years. This effort would include restoration actions over 6 million hectares of fire-impacted habitat, costing ∼AUD$8.8 billion/year. Large scale restoration efforts are often costly but can have significant societal co-benefits beyond biodiversity conservation. We also show that up to 291 MtCO2 (∼150 Mt DM) of carbon could be sequestered by restoration efforts, resulting in approximately AUD$253 million yr ^−1 in carbon market revenue if all carbon was remunerated. Our approach highlights the scale, costs, and benefits of targeted restoration activities both inside and outside of the immediate bushfire footprint over vast areas of different land tenures.

Abstract Background Intensive care unit (ICU) outcome prediction models, such as Acute Physiology And Chronic Health Evaluation (APACHE), were designed in general critical care populations and their use in obstetric populations is contentious. The aim of the CIPHER (Collaborative Integrated Pregnancy High-dependency Estimate of Risk) study was to develop and internally validate a multivariable prognostic model calibrated specifically for pregnant or recently delivered women admitted for critical care. Methods A retrospective observational cohort was created for this study from 13 tertiary facilities across five high-income and six low- or middle-income countries. Women admitted to an ICU for more than 24 h during pregnancy or less than 6 weeks post-partum from 2000 to 2012 were included in the cohort. A composite primary outcome was defined as maternal death or need for organ support for more than 7 days or acute life-saving intervention. Model development involved selection of candidate predictor variables based on prior evidence of effect, availability across study sites, and use of LASSO (Least Absolute Shrinkage and Selection Operator) model building after multiple imputation using chained equations to address missing data for variable selection. The final model was estimated using multivariable logistic regression. Internal validation was completed using bootstrapping to correct for optimism in model performance measures of discrimination and calibration. Results Overall, 127 out of 769 (16.5%) women experienced an adverse outcome. Predictors included in the final CIPHER model were maternal age, surgery in the preceding 24 h, systolic blood pressure, Glasgow Coma Scale score, serum sodium, serum potassium, activated partial thromboplastin time, arterial blood gas (ABG) pH, serum creatinine, and serum bilirubin. After internal validation, the model maintained excellent discrimination (area under the curve of the receiver operating characteristic (AUROC) 0.82, 95% confidence interval (CI) 0.81 to 0.84) and good calibration (slope of 0.92, 95% CI 0.91 to 0.92 and intercept of −0.11, 95% CI −0.13 to −0.08). Conclusions The CIPHER model has the potential to be a pragmatic risk prediction tool. CIPHER can identify critically ill pregnant women at highest risk for adverse outcomes, inform counseling of patients about risk, and facilitate bench-marking of outcomes between centers by adjusting for baseline risk.

Abstract Background In recent years, the incidence of several pathogens of public health importance (measles, mumps, pertussis and rubella) has increased in Europe, leading to outbreaks. This has included England, where GP practices implement the vaccination programme based on government guidance. However, there has been no study of how implementation takes place, which makes it difficult to identify organisational variation and thus limits the ability to recommend interventions to improve coverage. The aim of this study is to undertake a comparative process evaluation of the implementation of the routine vaccination programme at GP practices in England. Methods We recruited a sample of geographically and demographically diverse GP practices through a national research network and collected quantitative and qualitative data as part of a Time-Driven Activity-Based Costing analysis between May 2017 and February 2018. We conducted semi-structured interviews with practice staff involved in vaccination, who then completed an activity log for 2 weeks. Interviews were transcribed and coded using a framework method. Results Nine practices completed data collection from diverse geographic and socio-economic contexts, and 52 clinical and non-clinical staff participated in 26 interviews. Information relating to 372 vaccination appointments (233 childhood and 139 adult appointments) was captured using activity logs. We have defined a 14-stage care delivery value chain and detailed process map for vaccination. Areas of greatest variation include the method of reminder and recall activities, structure of vaccination appointments and task allocation between staff groups. For childhood vaccination, mean appointment length was 15.9 min (range 9.0–22.0 min) and 10.9 min for adults (range 6.8–14.1 min). Non-clinical administrative activities comprised 59.7% total activity (range 48.4–67.0%). Appointment length and total time were not related to coverage, whereas capacity in terms of appointments per eligible patient may improve coverage. Administrative tasks had lower fidelity of implementation. Conclusions There is variation in how GP practices in England implement the delivery of the routine vaccination programme. Further work is required to evaluate capacity factors in a wider range of practices, alongside other contextual factors, including the working culture within practices.

Background: Despite a growing number of prescriptions for antidepressants (over 70 million in 2018), there is uncertainty about when people with depression might benefit from antidepressant medication and concern that antidepressants are prescribed unnecessarily. Objectives: The main objective of the PANDA (What are the indications for Prescribing ANtiDepressAnts that will lead to a clinical benefit?) research programme was to provide more guidance about when antidepressants are likely to benefit people with depression. We aimed to estimate the minimal clinically important difference for commonly used self-administered scales for depression and anxiety, and to understand more about how patients respond to such assessments. We carried out an observational study of patients with depressive symptoms and a placebo-controlled randomised controlled trial of sertraline versus placebo to estimate the treatment effect in UK primary care. The hypothesis was that the severity and duration of symptoms were related to treatment response. Design: The programme consisted of three phases. The first phase relied on the secondary analysis of existing data extracted from published trials. The second phase was the PANDA cohort study of patients with depressive symptoms who presented to primary care and were followed up 2, 4 and 6 weeks after a baseline assessment. Both quantitative and qualitative methods were used in the analysis. The third phase was a multicentre randomised placebo-controlled double-blind trial of sertraline versus placebo in patients presenting to primary care with depressive symptoms. Setting: UK primary care in Bristol, London, Liverpool and York. Participants: Patients aged 18–74 years who were experiencing depressive symptoms in primary care. Eligibility for the PANDA randomised controlled trial included that there was uncertainty about the benefits about treatment with an antidepressant. Interventions: In the PANDA randomised controlled trial, patients were individually randomised to 100 mg daily of sertraline or an identical placebo. The PANDA cohort study was an observational study. Main outcome measures: Depressive symptoms measured using the Patient Health Questionnaire were the primary outcome for the randomised controlled trial. Other outcomes included anxiety symptoms using the Generalised Anxiety Disorder-7; depressive symptoms using the Beck Depression Inventory, version 2; health-related quality of life; self-reported improvement; and cost-effectiveness. Results: The secondary analysis of existing randomised controlled trials [GENetic and clinical Predictors Of treatment response in Depression (GenPod), TREAting Depression with physical activity (TREAD) and Clinical effectiveness and cost-effectiveness of cognitive Behavioural Therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care (CoBalT)] found evidence that the minimal clinically important difference increased as the initial severity of depressive symptoms rose. Our estimates of minimal clinically important difference were a 17% and 18% reduction in Beck Depression Inventory scores for GenPod and TREAD, respectively. In CoBalT, a 32% reduction corresponded to the minimal clinically important difference but the participants in this study had depression that had not responded to antidepressants. In the PANDA study cohort, and from our analyses in existing data, we found that the minimal clinically important difference varies considerably with the initial severity of depressive and anxiety symptoms. Expressing the minimal clinically important difference as a percentage reduction reduces this variation at higher scores, but at low scores the percentage reduction increased substantially. The results from the qualitative studies pointed out many limitations of the Patient Health Questionnaire-9 items in assessing change and recovery from depression. In the PANDA randomised controlled trial, there was no evidence that sertraline resulted in a reduction in depressive symptoms within 6 weeks of randomisation, but there was some evidence of a reduction by 12 weeks. However, sertraline led to a reduction in anxiety symptoms, an improvement of mental health-related quality of life and an increased likelihood of reporting improvement. The mean Patient Health Questionnaire-9 items score at 6 weeks was 7.98 (standard deviation 5.63) in the sertraline group and 8.76 (standard deviation 5.86) in the placebo group (5% relative reduction, 95% confidence interval –7% to 15%; p = 0.41). Of the secondary outcomes, there was strong evidence that sertraline reduced anxiety symptoms (Generalised Anxiety Disorder-7 score reduced by 17% (95% confidence interval 9% to 25%; p = 0.00005). Sertraline had a high probability (> 90%) of being cost-effective at 12 weeks. The PANDA randomised controlled trial found no evidence that treatment response or cost-effectiveness was related to severity or duration of depressive symptoms. The minimal clinically important difference estimates suggested that sertraline’s effect on anxiety, but not on depression, was likely to be clinically important. Limitations: The results from the randomised controlled trial and the estimates of minimal clinically important difference were not sufficiently precise to provide specific clinical guidance for individuals. We had low power in testing whether or not initial severity and duration of depressive symptoms are related to treatment response. Conclusions: The results of the trial support the use of sertraline and probably other selective serotonin reuptake inhibitors because of their action in reducing anxiety symptoms and the likelihood of longer-term benefit on depressive symptoms. Sertraline could be prescribed for anxiety symptoms that commonly occur with depression and many patients will experience a clinical benefit. The Patient Health Questionnaire-9 items and similar self-administered scales should not be used on their own to assess clinical outcome, but should be supplemented with further clinical assessment. Future work: We need to examine the longer-term effects of antidepressant treatment. We need more precise estimates of the treatment effects and minimal clinically important difference at different severities to provide more specific guidance for individuals. However, the methods we have developed provide an approach towards providing such detailed guidance. Trial registration: Current Controlled Trials ISRCTN84544741 and EudraCT number 2013-003440-22. Funding: This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 7, No. 10. See the NIHR Journals Library website for further project information.

Abstract Background Tumour cells have a high demand for arginine. However, a subset of glioblastomas has a defect in the arginine biosynthetic pathway due to epigenetic silencing of the rate limiting enzyme argininosuccinate synthetase (ASS1). These tumours are auxotrophic for arginine and susceptible to the arginine degrading enzyme, pegylated arginine deiminase (ADI-PEG20). Moreover, ASS1 deficient GBM have a worse prognosis compared to ASS1 positive tumours. Since altered tumour metabolism is one of the hallmarks of cancer we were interested to determine if these two subtypes exhibited different metabolic profiles that could allow for their non-invasive detection as well as unveil additional novel therapeutic opportunities. Methods We looked for basal metabolic differences using one and two-dimensional gas chromatography-time-of-flight mass spectrometry (1D/2D GC-TOFMS) followed by targeted analysis of 29 amino acids using liquid chromatography-time-of-flight mass spectrometry (LC-TOFMS). We also looked for differences upon arginine deprivation in a single ASS1 negative and positive cell line (SNB19 and U87 respectively). The acquired data was evaluated by chemometric based bioinformatic methods. Results Orthogonal partial least squares-discriminant analysis (OPLS-DA) of both the 1D and 2D GC-TOFMS data revealed significant systematic difference in metabolites between the two subgroups with ASS1 positive cells generally exhibiting an overall elevation of identified metabolites, including those involved in the arginine biosynthetic pathway. Pathway and network analysis of the metabolite profile show that ASS1 negative cells have altered arginine and citrulline metabolism as well as altered amino acid metabolism. As expected, we observed significant metabolite perturbations in ASS negative cells in response to ADI-PEG20 treatment. Conclusions This study has highlighted significant differences in the metabolome of ASS1 negative and positive GBM which warrants further study to determine their diagnostic and therapeutic potential for the treatment of this devastating disease.

The plastid-encoded RNA polymerase PEP is regulated according to plastid redox state. Here, the authors show that the redox-regulated PRIN2 protein is reduced to monomeric form in a thiol-dependent manner in response to light and that PRIN2 monomers are required for PEP activity and retrograde signaling.

Abstract Background Depressive symptoms are usually managed within primary care and antidepressant medication constitutes the first-line treatment. It remains unclear at present which people are more likely to benefit from antidepressant medication. This paper describes the protocol for a randomised controlled trial (PANDA) to investigate the severity and duration of depressive symptoms that are associated with a clinically significant response to sertraline compared to placebo, in people presenting to primary care with depression. Methods/design PANDA is a randomised, double blind, placebo controlled trial in which participants are individually randomised to sertraline or placebo. Eligible participants are those who are between the ages of 18 to 74; have presented to primary care with depression or low mood during the past 2 years; have not received antidepressant or anti-anxiety medication in the 8 weeks prior to enrolment in the trial and there is clinical equipoise about the benefits of selective serotonin reuptake inhibitor (SSRI) medication. Participants who consent to participate in the trial are randomised to receive either sertraline or matching placebo, starting at 50 mg daily for 1 week, increasing to 100 mg daily for up to 11 weeks (with the option of increasing to 150 mg if required). Participants, general practitioners (GPs) and the research team will be blind to treatment allocation. The primary outcome will be depressive symptoms measured by the Patient Health Questionnaire-9 (PHQ-9) at 6 weeks post randomisation, measured as a continuous outcome. Secondary outcomes include depressive symptoms measured with the PHQ-9 at 2 and 12 weeks as a continuous outcome and at 2, 6 and 12 weeks as a binary outcome; follow-up scores on depressive symptoms measured with the Beck Depression Inventory-II, anxiety symptoms measured by the Generalized Anxiety Disorder-7 and quality of life measured with the Euroqol-5D-5L and Short Form-12; emotional processing task scores measured at baseline, 2 and 6 weeks; and costs associated with healthcare use, time off work and personal costs. Discussion The PANDA trial uses a simple self-administered measure to establish the severity and duration of depressive symptoms associated with a clinically significant response to sertraline. The evidence from the trial will inform primary care prescribing practice by identifying which patients are more likely to benefit from antidepressants. Trial registration Controlled Trials ISRCTN Registry, ISRCTN84544741 . Registered on 20 March 2014. EudraCT Number: 2013-003440-22; Protocol Number: 13/0413 (version 6.1).

Abstract Background In 2014, over half (54%) of the world’s population lived in urban areas and this proportion will increase to 66% by 2050. This urbanizing trend has been accompanied by an increasing number of people living in urban poor communities and slums. Lower immunization coverage is found in poorer urban dwellers in many contexts. This study aims to identify factors associated with immunization coverage in poor urban areas and slums, and to identify interventions to improve coverage. Methods We conducted a systematic review, searching Medline, Embase, Global Health, CINAHL, Web of Science and The Cochrane Database with broad search terms for studies published between 2000 and 2016. Results Of 4872 unique articles, 327 abstracts were screened, leading to 63 included studies: 44 considering factors and 20 evaluating interventions (one in both categories) in 16 low or middle-income countries. A wide range of socio-economic characteristics were associated with coverage in different contexts. Recent rural-urban migration had a universally negative effect. Parents commonly reported lack of awareness of immunization importance and difficulty accessing services as reasons for under-immunization of their children. Physical distance to clinics and aspects of service quality also impacted uptake. We found evidence of effectiveness for interventions involving multiple components, especially if they have been designed with community involvement. Outreach programmes were effective where physical distance was identified as a barrier. Some evidence was found for the effective use of SMS (text) messaging services, community-based education programmes and financial incentives, which warrant further evaluation. No interventions were identified that provided services to migrants from rural areas. Conclusion Different factors affect immunization coverage in different urban poor and slum contexts. Immunization services should be designed in collaboration with slum-dwelling communities, considering the local context. Interventions should be designed and tested to increase immunization in migrants from rural areas.

This essay approaches the ideas of value and valuing though an exploration of the Maxwell Street market in Chicago, USA. The market was the largest open-air market in North America for much of the twentieth century. From the 1960s onwards it has been subjected to various forms of valuing and devaluing leading to its eventual demise in its historic location in 1994. The essay explores how the market and things in the market entered and left various regimes of value over time. The focus is on the role of hub-caps, home-made instruments called Stradizookys, and the process of tax-increment financing. The essay ends with some thought around order and regulation in the urban landscape.

In eukaryotic cells, ultimate specificity in activation and action—for example, by means of second messengers—of the myriad of signaling cascades is primordial. In fact, versatile and ubiquitous second messengers, such as calcium (Ca2+) and cyclic adenosine monophosphate (cAMP), regulate multiple—sometimes opposite—cellular functions in a specific spatiotemporal manner. Cells achieve this through segregation of the initiators and modulators to specific plasma membrane (PM) subdomains, such as lipid rafts and caveolae, as well as by dynamic close contacts between the endoplasmic reticulum (ER) membrane and other intracellular organelles, including the PM. Especially, these membrane contact sites (MCSs) are currently receiving a lot of attention as their large influence on cell signaling regulation and cell physiology is increasingly appreciated. Depletion of ER Ca2+ stores activates ER membrane STIM proteins, which activate PM-residing Orai and TRPC Ca2+ channels at ER–PM contact sites. Within the MCS, Ca2+ fluxes relay to cAMP signaling through highly interconnected networks. However, the precise mechanisms of MCS formation and the influence of their dynamic lipid environment on their functional maintenance are not completely understood. The current review aims to provide an overview of our current understanding and to identify open questions of the field.

Table of contents S1 Using computerized adaptive testing Tim Croudace S2 Well-being: what is it, how does it compare to health and what are the implications of using it to inform health policy John Brazier O1 “Am I going to get better?”—Using PROMs to inform patients about the likely benefit of surgery Nils Gutacker, Andrew Street O2 Identifying Patient Reported Outcome Measures for an electronic Personal Health Record Dan Robotham, Samantha Waterman, Diana Rose, Safarina Satkunanathan, Til Wykes O3 Examining the change process over time qualitatively: transformative learning and response shift Nasrin Nasr, Pamela Enderby O4 Developing a PROM to evaluate self-management in diabetes (HASMID): giving patients a voice Jill Carlton, Donna Rowen, Jackie Elliott, John Brazier, Katherine Stevens, Hasan Basarir, Alex Labeit O5 Development of the Primary Care Outcomes Questionnaire (PCOQ) Mairead Murphy, Sandra Hollinghurst, Chris Salisbury O6 Developing the PKEX score- a multimodal assessment tool for patients with shoulder problems Dominic Marley, James Wilson, Amy Barrat, Bibhas Roy O7 Applying multiple imputation to multi-item patient reported outcome measures: advantages and disadvantages of imputing at the item, sub-scale or score level Ines Rombach, Órlaith Burke, Crispin Jenkinson, Alastair Gray, Oliver Rivero-Arias O8 Integrating Patient Reported Outcome Measures (PROMs) into routine primary care for patients with multimorbidity: a feasibility study Ian Porter, Jaheeda Gangannagaripalli, Charlotte Bramwell, Jose M. Valderas O9 eRAPID: electronic self-report and management of adverse-events for pelvic radiotherapy (RT) patients Patricia Holch, Susan Davidson, Jacki Routledge, Ann Henry, Kevin Franks, Alex Gilbert, Kate Absolom & Galina Velikova O10 Patient reported outcomes (PROMs) based recommendation in clinical guidance for the management of chronic conditions in the United Kingdom Ian Porter, Jose M.Valderas O11 Cross-sectional and longitudinal parameter shifts in epidemiological data: measurement invariance and response shifts in cohort and survey data describing the UK’s Quality of Life Jan R. Boehnke O12 Patient-reported outcomes within health technology decision making: current status and implications for future policy Andrew Trigg, Ruth Howells O13 Can social care needs and well-being be explained by the EQ-5D? Analysis of Health Survey for England dataset Jeshika Singh, Subhash Pokhrel, Louise Longworth O14 Where patients and policy meet: exploring individual-level use of the Long-Term Conditions Questionnaire (LTCQ) Caroline Potter, Cheryl Hunter, Laura Kelly, Elizabeth Gibbons, Julian Forder, Angela Coulter, Ray Fitzpatrick, Michele Peters

Objectives: Developed countries are becoming more multi-ethnic, with consequent problems of maintaining invariance of health questionnaires. We aimed to explore commonalities in the structure of the Strengths and Difficulties Questionnaire (SDQ) completed for young children in a multi-ethnic English cohort while examining potential method effects and misfitting items. The secondary aim was to demonstrate the usefulness of bifactor modelling and exploratory structural equation modelling (ESEM) for kinanthropological research. Methods: We used SDQ data from 3,290 children enrolled in the Born in Bradford cohort, completed by parents (usually the mother) at child age 3 and 4 and teachers at age 5. The factor structure for 11 potential configurations was assessed in each age group using confirmatory factor analysis. ESEM was used to assess misfitting items under the best fitting configuration. Results: The best fitting configuration was a bifactor model of the 2 broader scales and a methods factor, using the 20 difficulties items. Generally, factor loadings increased between age 3 and age 5. Several items contributed to misfit. Conclusions: There was less support for the robustness and hypothesised structure of the SDQ in this sample. Bifactor scores that account for measurement error could be useful if carefully applied in epidemiological and kinanthropological studies in multi-ethnic and/or younger age samples.

Habitat selection is a central component of the ecology of individual animals as it affects body condition, survivorship, and reproductive output. We instrumented male and female moose (Alces alces) in north-central Alaska with GPS radio-collars to assess factors we hypothesized were important to their habitat selection. Using synoptic modeling techniques, we found that models with more covariates were better predictors of moose habitat selection than more simplistic models. As expected, moose selected for habitats with high canopy cover and/or that typically have abundant forage such as 11-30 year old burned areas. However, we detected differences in habitat selection between sexes, seasons (i.e., winter versus summer), during winters of varying severity, and females with differing maternal status. During winter males moved to lower elevation areas, presumably to avoid greater snow depths, whereas females remained at relatively similar elevations. Females selected burned habitat and areas that received higher amounts of solar radiation. We found that all moose selected for lower elevation habitats closer to rivers during moderate and severe winters, but elevation was not a strong influence during mild winters. We found that females with calves avoided riparian habitats and selected areas with more forested habitat than females without calves during both summer and winter. This suggests a trade-off between maximizing forage intake and reducing predation risk for their offspring. Our and similar data are useful to improve moose management strategies and provide a benchmark against which the impacts of climate change and industrial development are assessed in this rapidly-changing region.

The heat shock response (HSR) regulates induction of stress/heat shock proteins (HSPs) to preserve proteostasis during cellular stress. Earlier, our group established that the plasma membrane (PM) acts as a sensor and regulator of HSR through changes in its microdomain organization. PM microdomains such as lipid rafts, dynamic nanoscale assemblies enriched in cholesterol and sphingomyelin, and caveolae, cholesterol-rich PM invaginations, constitute clustering platforms for proteins functional in signaling cascades. Here, we aimed to compare the effect of cyclodextrin (MβCD)- and nystatin-induced cholesterol modulations on stress-activated expression of the representative HSPs, HSP70, and HSP25 in mouse B16-F10 melanoma cells. Depletion of cholesterol levels with MβCD impaired the heat-inducibility of both HSP70 and HSP25. Sequestration of cholesterol with nystatin impaired the heat-inducibility of HSP25 but not of HSP70. Imaging fluorescent correlation spectroscopy marked a modulated lateral diffusion constant of fluorescently labelled cholesterol in PM during cholesterol deprived conditions. Lipidomics analysis upon MβCD treatment revealed, next to cholesterol reductions, decreased lysophosphatidylcholine and phosphatidic acid levels. These data not only highlight the involvement of PM integrity in HSR but also suggest that altered dynamics of specific cholesterol pools could represent a mechanism to fine tune HSP expression.

Pulmonary hypertension (PH) is a progressive illness characterized by elevated pulmonary artery pressure; however, the main cause of mortality in PH patients is right ventricular (RV) failure. Historically, improving the hemodynamics of pulmonary circulation was the focus of treatment; however, it is now evident that cardiac response to a given level of pulmonary hemodynamic overload is variable but plays an important role in the subsequent prognosis. Non-invasive tests of RV function to determine prognosis and response to treatment in patients with PH is essential. Although the right ventricle is the focus of attention, it is clear that cardiac interaction can cause left ventricular dysfunction, thus biventricular assessment is paramount. There is also focus on the atrial chambers in their contribution to cardiac function in PH. Furthermore, there is evidence of regional dysfunction of the two ventricles in PH, so it would be useful to understand both global and regional components of dysfunction. In order to understand global and regional cardiac function in PH, the most obvious non-invasive imaging techniques are echocardiography and cardiac magnetic resonance imaging (CMRI). Both techniques have their advantages and disadvantages. Echocardiography is widely available, relatively inexpensive, provides information regarding RV function, and can be used to estimate RV pressures. CMRI, although expensive and less accessible, is the gold standard of biventricular functional measurements. The advent of 3D echocardiography and techniques including strain analysis and stress echocardiography have improved the usefulness of echocardiography while new CMRI technology allows the measurement of strain and measuring cardiac function during stress including exercise. In this review, we have analyzed the advantages and disadvantages of the two techniques and discuss pre-existing and novel forms of analysis where echocardiography and CMRI can be used to examine atrial, ventricular, and interventricular function in patients with PH at rest and under stress.

Sound drama production prior to the onset of the “Radio Age” underwent a pioneering development during the Great War. This was achieved by the making, publication and distribution of short audio dramas acted with sound effects and music in front of early microphones and released in the form of 78 rpm phonograph discs. Entertaining storytelling through dramatic performance was mobilized for the purposes of improving recruitment and disseminating patriotic endorsement recordings. This article focuses on the sound dramatization of the myth of “The Angels of Mons” released by Regal in 1915. The recording is examined as a text for its significance in terms of propaganda, style of audio-drama, and any cultural role it may have played in the media of the First World War. The Regal disc was an example of what was described at the time as “descriptive sketches.” This article explores why a sound phonograph was used to dramatize the myth that angels intervened to assist the British Expeditionary Force to resist the German Army invading France through Belgium in 1914. A number of historians have discussed the First World War as being a theatre for the first modern media war, in which the process of propaganda was modernized. To what extent does “The Angels of Mons” phonograph and the genre of descriptive sketches support this analysis? Does this short sound drama play have any relevance to the cultural phenomena of spiritualism, modernism and patriotic Christianity identified as being important during the Great War period?