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Objective: Few large cohort studies have reported data on maternal, fetal, perinatal and neonatal outcomes associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pregnancy. We report the outcome of infected pregnancies from a collaboration formed early during the pandemic between the investigators of two registries, the UK and Global Pregnancy and Neonatal outcomes in COVID-19 (PAN-COVID) study and the American Academy of Pediatrics (AAP) Section on Neonatal-Perinatal Medicine (SONPM) National Perinatal COVID-19 Registry.Methods: This was an analysis of data from the PAN-COVID registry (1 January to 25 July 2020), which includes pregnancies with suspected or confirmed maternal SARS-CoV-2 infection at any stage in pregnancy, and the AAP-SONPM National Perinatal COVID-19 registry (4 April to 8 August 2020), which includes pregnancies with positive maternal testing for SARS-CoV-2 from 14 days before delivery to 3 days after delivery. The registries collected data on maternal, fetal, perinatal and neonatal outcomes. The PAN-COVID results are presented overall for pregnancies with suspected or confirmed SARS-CoV-2 infection and separately in those with confirmed infection.Results: We report on 4005 pregnant women with suspected or confirmed SARS-CoV-2 infection (1606 from PAN-COVID and 2399 from AAP-SONPM). For obstetric outcomes, in PAN-COVID overall and in those with confirmed infection in PAN-COVID and AAP-SONPM, respectively, maternal death occurred in 0.5%, 0.5% and 0.2% of cases, early neonatal death in 0.2%, 0.3% and 0.3% of cases and stillbirth in 0.5%, 0.6% and 0.4% of cases. Delivery was preterm (< 37 weeks' gestation) in 12.0% of all women in PAN-COVID, in 16.1% of those women with confirmed infection in PAN-COVID and in 15.7% of women in AAP-SONPM. Extreme preterm delivery (< 27 weeks' gestation) occurred in 0.5% of cases in PAN-COVID and 0.3% in AAP-SONPM. Neonatal SARS-CoV-2 infection was reported in 0.9% of all deliveries in PAN-COVID overall, in 2.0% in those with confirmed infection in PAN-COVID and in 1.8% in AAP-SONPM; the proportions of neonates tested were 9.5%, 20.7% and 87.2%, respectively. The rates of a small-for-gestational-age (SGA) neonate were 8.2% in PAN-COVID overall, 9.7% in those with confirmed infection and 9.6% in AAP-SONPM. Mean gestational-age-adjusted birth-weight Z-scores were -0.03 in PAN-COVID and -0.18 in AAP-SONPM.Conclusions: The findings from the UK and USA registries of pregnancies with SARS-CoV-2 infection were remarkably concordant. Preterm delivery affected a higher proportion of women than expected based on historical and contemporaneous national data. The proportions of pregnancies affected by stillbirth, a SGA infant or early neonatal death were comparable to those in historical and contemporaneous UK and USA data. Although maternal death was uncommon, the rate was higher than expected based on UK and USA population data, which is likely explained by underascertainment of women affected by milder or asymptomatic infection in pregnancy in the PAN-COVID study, although not in the AAP-SONPM study. The data presented support strong guidance for enhanced precautions to prevent SARS-CoV-2 infection in pregnancy, particularly in the context of increased risks of preterm delivery and maternal mortality, and for priority vaccination of pregnant women and women planning pregnancy. Copyright © 2021 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Abstract Background Cognitive behaviour therapy (CBT) is the treatment of choice for common mental health problems, but this approach has only recently been adapted for people with learning disabilities, and there is a limited evidence base for the use of CBT with this client group. Anger treatment is the one area where there exists a reasonable number of small controlled trials. This study will evaluate the effectiveness of a manualized 12-week CBT intervention for anger. The intervention will be delivered by staff working in the day services that the participants attend, following training to act as 'lay therapists' by a Clinical Psychologist, who will also provide supervision. Methods/Design This is a multi-centre cluster randomized controlled trial of a group intervention versus a 'support as usual' waiting-list control group, with randomization at the level of the group. Outcomes will be assessed at the end of the intervention and again 6-months later. After completion of the 6-month follow-up assessments, the intervention will also be delivered to the waiting-list groups. The study will include a range of anger/aggression and mental health measures, some of which will be completed by service users and also by their day service key-workers and by home carers. Qualitative data will be collected to assess the impact of the intervention on participants, lay therapists, and services, and the study will also include a service-utilization cost and consequences analysis. Discussion This will be the first trial to investigate formally how effectively staff working in services providing day activities for people with learning disabilities are able to use a therapy manual to deliver a CBT based anger management intervention, following brief training by a Clinical Psychologist. The demonstration that service staff can successfully deliver anger management to people with learning disabilities, by widening the pool of potential therapists, would have very significant benefits in relation to the current policy of improving access to psychological therapies, in addition to addressing more effectively an important and often unmet need of this vulnerable client group. The economic analysis will identify the direct and indirect costs (and/or savings) of the intervention and consider these in relation to the range of observed effects. The qualitative analyses will enhance the interpretation of the quantitative data, and if the study shows positive results, will inform the roll-out of the intervention to the wider community. Trial registration ISRCTN: ISRCTN37509773

Abstract Background There is increased incidence of new cases of type 1 diabetes in children younger than 15 years. The debate concerning where best to manage newly diagnosed children continues. Some units routinely admit children to hospital whilst others routinely manage children at home. A Cochrane review identified the need for a large well-designed randomised controlled trial to investigate any significant differences in comprehensive short and long-term outcomes between the two approaches. The DECIDE study will address these knowledge gaps, providing high quality evidence to inform national and international policy and practice. Methods/Design This is a multi-centre randomised controlled trial across eight UK paediatric diabetes centres. The study aims to recruit 240 children newly diagnosed with type 1 diabetes and their parents/carers. Eligible patients (aged 0-17 years) will be remotely randomised to either 'hospital' or 'home' management. Parents/carers of patients will also be recruited. Nursing management of participants and data collection will be co-ordinated by a project nurse at each centre. Data will be collected for 24 months after diagnosis; at follow up appointments at 3, 12 and 24 months and every 3-4 months at routine clinic visits. The primary outcome measure is patients' glycosylated haemoglobin (HbA1c) at 24 months after diagnosis. Additional measurements of HbA1c will be made at diagnosis and 3 and 12 months later. HbA1c concentrations will be analysed at a central laboratory. Secondary outcome measures include length of stay at diagnosis, growth, adverse events, quality of life, anxiety, coping with diabetes, diabetes knowledge, home/clinic visits, self-care activity, satisfaction and time off school/work. Questionnaires will be sent to participants at 1, 12 and 24 months and will include a questionnaire, developed and validated to measure impact of the diagnosis on social activity and independence. Additional qualitative outcome measures include the experience of both approaches by a subgroup of participants (n = 30) and health professionals. Total health service costs will be evaluated. A cost effectiveness analysis will assess direct and indirect health service costs against the primary outcome (HbA1c). Discussion This will be the first randomised controlled trial to evaluate hospital and home management of children newly diagnosed with type 1 diabetes and the findings should provide important evidence to inform practice and national guidelines. Trial registration number ISRCTN: ISRCTN78114042

Background: Reconstruction of mandibular bone defects is a surgical challenge, and microvascular reconstruction is the current gold standard. The field of tissue bioengineering has been providing an increasing number of alternative strategies for bone reconstruction. Methods: In this preclinical study, the performance of two bioengineered scaffolds, a hydrogel made of polyethylene glycol-chitosan (HyCh) and a hybrid core-shell combination of poly (L-lactic acid)/poly ( ε -caprolactone) and HyCh (PLA-PCL-HyCh), seeded with different concentrations of human mesenchymal stromal cells (hMSCs), has been explored in non-critical size mandibular defects in a rabbit model. The bone regenerative properties of the bioengineered scaffolds were analyzed by in vivo radiological examinations and ex vivo radiological, histomorphological, and immunohistochemical analyses. Results: The relative density increase (RDI) was significantly more pronounced in defects where a scaffold was placed, particularly if seeded with hMSCs. The immunohistochemical profile showed significantly higher expression of both VEGF-A and osteopontin in defects reconstructed with scaffolds. Native microarchitectural characteristics were not demonstrated in any experimental group. Conclusion: Herein, we demonstrate that bone regeneration can be boosted by scaffold- and seeded scaffold-reconstruction, achieving, respectively, 50% and 70% restoration of presurgical bone density in 120 days, compared to 40% restoration seen in spontaneous regeneration. Although optimization of the regenerative performance is needed, these results will help to establish a baseline reference for future experiments., Competing Interests: Some of the following authors (LS, DR, SP, PN, MF, RG, and JI) declare the present patents, but declare no other financial or non-financial competing interests: LS, DR., SP, PN, MF, RG, JI “Integrated core-shell bioactive structure for the regeneration of bone and osteochondral tissues” licensed to PCT: WO2022009126 (2022); priority IT20200016579 (2020). LS, DR, PG, KD, Salmeron-Sanchez M., Borsani E. “Tridimensional bioactive porous body for bone tissue regeneration and process for its preparation “licensed to ”PCT: WO2022009125 (2022); priority: IT20200016576 (2020). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ferrari, Taboni, Chan, Townson, Gualtieri, Franz, Ruaro, Mathews, Daly, Douglas, Eu, Sahovaler, Muhanna, Ventura, Dey, Pandini, Pasini, Re, Bernardi, Bosio, Mattavelli, Doglietto, Joshi, Gilbert, Nicolai, Viswanathan, Sartore, Russo and Irish.)

Background: Children presenting to primary care with suspected type 1 diabetes should be referred immediately to secondary care to avoid life-threatening diabetic ketoacidosis. However, early recognition of children with type 1 diabetes is challenging. Children might not present with classic symptoms, or symptoms might be attributed to more common conditions. A quarter of children present with diabetic ketoacidosis, a proportion unchanged over 25 years. Our aim was to investigate whether a machine-learning algorithm could lead to earlier detection of type 1 diabetes in primary care., Methods: We developed the predictive algorithm using Welsh primary care electronic health records (EHRs) linked to the Brecon Dataset, a register of children newly diagnosed with type 1 diabetes. Children were included from their first primary care record within the study period of Jan 1, 2000, to Dec 31, 2016, until either type 1 diabetes diagnosis, they turned 15 years of age, or study end. We developed an ensemble learner (SuperLearner) using 26 potential predictors. Validation of the algorithm was done in English EHRs from the Clinical Practice Research Datalink (primary care) and Hospital Episode Statistics, focusing on the ability of the algorithm to identify children who went on to develop type 1 diabetes and the time by which diagnosis could be anticipated., Findings: The development dataset comprised 34 754 400 primary care contacts, relating to 952 402 children, and the validation dataset comprised 43 089 103 primary care contacts, relating to 1 493 328 children. Of these, 1829 (0·19%) children younger than 15 years in the development dataset, and 1516 (0·10%) in the validation dataset had a reliable date of type 1 diabetes diagnosis. If set to give an alert in 10% of contacts, an estimated 71·6% (95% CI 68·8-74·4) of the children with type 1 diabetes would receive an alert by the algorithm in the 90 days before diagnosis, with diagnosis anticipated, on average, by an estimated 9·34 days (95% CI 7·77-10·9)., Interpretation: If implemented into primary care settings, this predictive algorithm could substantially reduce the proportion of patients with new-onset type 1 diabetes presenting in diabetic ketoacidosis. Acceptability of alert thresholds should be explored in primary care., Funding: Diabetes UK., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background/aims: The value of using qualitative methods within clinical trials is widely recognised. How qualitative research is integrated within trials units to achieve this is less clear. This paper describes the process through which qualitative research has been integrated within Cardiff University's Centre for Trials Research (CTR) in Wales, UK. We highlight facilitators of, and challenges to, integration., Methods: We held group discussions on the work of the Qualitative Research Group (QRG) within CTR. The content of these discussions, materials for a presentation in CTR, and documents relating to the development of the QRG were interpreted at a workshop attended by group members. Normalisation Process Theory (NPT) was used to structure analysis. A writing group prepared a document for input from members of CTR, forming the basis of this paper., Results: Actions to integrate qualitative research comprised: its inclusion in Centre strategies; formation of a QRG with dedicated funding/roles; embedding of qualitative research within operating systems; capacity building/training; monitoring opportunities to include qualitative methods in studies; maximising the quality of qualitative research and developing methodological innovation. Facilitators of these actions included: the influence of the broader methodological landscape within trial/study design and its promotion of the value of qualitative research; and close physical proximity of CTR qualitative staff/students allowing sharing of methodological approaches. Introduction of innovative qualitative methods generated interest among other staff groups. Challenges included: pressure to under-resource qualitative components of research, preference for a statistical stance historically in some research areas and funding structures, and difficulties faced by qualitative researchers carving out individual academic profiles when working across trials/studies., Conclusions: Given that CTUs are pivotal to the design and conduct of RCTs and related study types across multiple disciplines, integrating qualitative research into trials units is crucial if its contribution is to be fully realised. We have made explicit one trials unit's experience of embedding qualitative research and present this to open dialogue on ways to operationalise and optimise qualitative research in trials. NPT provides a valuable framework with which to theorise these processes, including the importance of sense-making and legitimisation when introducing new practices within organisations., (© 2024. The Author(s).)

Developmental programming involves the accurate conversion of signalling levels and dynamics to transcriptional outputs. The transcriptional relay in the Notch pathway relies on nuclear complexes containing the co-activator Mastermind (Mam). By tracking these complexes in real time, we reveal that they promote the formation of a dynamic transcription hub in Notch ON nuclei which concentrates key factors including the Mediator CDK module. The composition of the hub is labile and persists after Notch withdrawal conferring a memory that enables rapid reformation. Surprisingly, only a third of Notch ON hubs progress to a state with nascent transcription, which correlates with polymerase II and core Mediator recruitment. This probability is increased by a second signal. The discovery that target-gene transcription is probabilistic has far-reaching implications because it implies that stochastic differences in Notch pathway output can arise downstream of receptor activation., Competing Interests: FD, CR, SB, JT, MG, SB No competing interests declared, (© 2023, DeHaro-Arbona et al.)

Introduction: Despite a growing body of research on the risks of SARS-CoV-2 infection during pregnancy, there is continued controversy given heterogeneity in the quality and design of published studies., Methods: We screened ongoing studies in our sequential, prospective meta-analysis. We pooled individual participant data to estimate the absolute and relative risk (RR) of adverse outcomes among pregnant women with SARS-CoV-2 infection, compared with confirmed negative pregnancies. We evaluated the risk of bias using a modified Newcastle-Ottawa Scale., Results: We screened 137 studies and included 12 studies in 12 countries involving 13 136 pregnant women.Pregnant women with SARS-CoV-2 infection-as compared with uninfected pregnant women-were at significantly increased risk of maternal mortality (10 studies; n=1490; RR 7.68, 95% CI 1.70 to 34.61); admission to intensive care unit (8 studies; n=6660; RR 3.81, 95% CI 2.03 to 7.17); receiving mechanical ventilation (7 studies; n=4887; RR 15.23, 95% CI 4.32 to 53.71); receiving any critical care (7 studies; n=4735; RR 5.48, 95% CI 2.57 to 11.72); and being diagnosed with pneumonia (6 studies; n=4573; RR 23.46, 95% CI 3.03 to 181.39) and thromboembolic disease (8 studies; n=5146; RR 5.50, 95% CI 1.12 to 27.12).Neonates born to women with SARS-CoV-2 infection were more likely to be admitted to a neonatal care unit after birth (7 studies; n=7637; RR 1.86, 95% CI 1.12 to 3.08); be born preterm (7 studies; n=6233; RR 1.71, 95% CI 1.28 to 2.29) or moderately preterm (7 studies; n=6071; RR 2.92, 95% CI 1.88 to 4.54); and to be born low birth weight (12 studies; n=11 930; RR 1.19, 95% CI 1.02 to 1.40). Infection was not linked to stillbirth. Studies were generally at low or moderate risk of bias., Conclusions: This analysis indicates that SARS-CoV-2 infection at any time during pregnancy increases the risk of maternal death, severe maternal morbidities and neonatal morbidity, but not stillbirth or intrauterine growth restriction. As more data become available, we will update these findings per the published protocol., Competing Interests: Competing interests: CW declares a relationship with Ferring Pharmaceuticals COVID-19 Investigational Grant and NHMRC Fellowship (salary support). AP declares the following research grants to her institution: ‘H2020-Grant—Consortium member of Innovative medicine initiative call 13 topic 9 «ConcePTION», Efficacy and safety studies on Medicines EMA/2017/09/PE/11, Lot 4, WP 2 lead, Safety monitoring of COVID-19 vaccines in the EU—Reopening of competition no. 20 under a framework contract following procurement procedure EMA/2017/09/PE (Lot 3) (Euro 110,000), Federal Office of Public Health (207,000 CHF)’. EM declares a relationship with the National Institute for Health Research (project grant for PAN COVID study). DM declares a relationship with the Canadian Institutes of Health Research (payments to institution only), Public Health Agency of Canada (payments to institution only), BC Women’s Foundation (payments to institution only) and is a member of the COVID-19 Immunity Task Force sponsored by the Canadian government. TDM declares a relationship with Pfizer (site principal investigator for SARS-CoV-2 vaccination in pregnancy study, money paid to institution and member of Medical Advisory Board for SARS-CoV-2 vaccination in pregnancy study, money paid to TDM), NICHD (subcommittee chair for the NICHD Maternal-Fetal Medicine Units Network Gestational Research Assessments of COVID-19 (GRAVID) study) and Society for Maternal-Fetal Medicine (board member). EL declares a relationship with the US NIH (paid institution) and is an employee of AbbVie, but was employed at the University of Washington at the time of the study. KK declares a relationship with the Bill & Melinda Gates Foundation. VJF declares a relationship with the Bill & Melinda Gates Foundation (payments to institution), Yellow Chair Foundation (payments to institution), Robert Woods Johnson Foundation (payments to institution), CDC Foundation, California Health Care Foundation (payments to institution), Tara Health Foundation (payments to institution), UCSF Women’s Health Center of Excellence (payments to institution) and California Department of Health Care Services (payments made to institution). JS-B declares a relationship with the Ferring Pharmaceuticals, which gave a grant ($10 000) for the expenses of RECOGEST trial and is a part of the Columbian Federation of Perinatology. YA declares a relationship with the Bill & Melinda Gates Foundation (payments made to institution), CDC Foundation (payments made to institution), Robert Woods Johnson Foundation (payments made to institution) and UCLA Dean’s Office COVID-19 research (payments made to institution). RC declares a relationship with the NIH HD36801 (MFMU Network DCC). MCN declares a relationship with the BMGF (project grant made to institution), EDCTP, Sanofi, AstraZeneca, Pfizer (research grants made to institution), Sanofi Pasteur (payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events) and Sanofi Pasteur and Pfizer (payment for expert testimony). ESM declares a relationship with Pfizer (site principal investigator for phase 2/3 RCT of COVID vaccine during pregnancy). OS declares a relationship with the NordForsk Funding (Nordic research funding grant number: 105545), the Swedish Medical Products Agency (funding for reports on COVID-19 vaccines and pregnancy) and Karolinska Institutet (funding for COVID research and pregnancy: 2020-01567). EG declares a relationship with the Stavros Niarchos Foundation, Santander Foundation and ‘La Caixa’ Foundation (payments made to institution). SAM declares a relationship with BMGF (funded study in South Africa)., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Rapid diagnostic centres (RDCs) are being implemented across the UK to accelerate the assessment of vague suspected cancer symptoms. Targeted behavioural interventions are needed to augment RDCs that serve socioeconomically deprived populations who are disproportionately affected by cancer, have lower cancer symptom awareness and are less likely to seek help for cancer symptoms. The aim of this study is to assess the feasibility and acceptability of delivering and evaluating a community-based vague cancer symptom awareness intervention in an area of high socioeconomic deprivation., Methods and Analysis: Intervention materials and messages were coproduced with local stakeholders in Cwm Taf Morgannwg, Wales. Cancer champions will be trained to deliver intervention messages and distribute intervention materials using broadcast media (eg, local radio), printed media (eg, branded pharmacy bags, posters, leaflets), social media (eg, Facebook) and attending local community events. A cross-sectional questionnaire will include self-reported patient interval (time between noticing symptoms to contacting the general practitioner), cancer symptom recognition, cancer beliefs and barriers to presentation, awareness of campaign messages, healthcare resource use, generic quality of life and individual and area-level deprivation indicators. Consent rates and proportion of missing data for patient questionnaires (n=189) attending RDCs will be measured. Qualitative interviews and focus groups will assess intervention acceptability and barriers/facilitators to delivery., Ethics and Dissemination: Ethical approval for this study was given by the London-West London & GTAC Research Ethics (21/LO/0402). This project will inform a potential future controlled study to assess intervention effectiveness in reducing the patient interval for vague cancer symptoms. The results will be critical to informing national policy and practice regarding behavioural interventions to support RDCs in highly deprived populations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: COVID-19 related lockdowns may have affected engagement in health behaviours among the UK adult population. This prospective observational study assessed socio-demographic patterning in attempts to change and maintain a range of health behaviours and changes between two time points during the pandemic., Methods: Adults aged 18 years and over (n = 4,978) were recruited using Dynata (an online market research platform) and the HealthWise Wales platform, supplemented through social media advertising. Online surveys were conducted in August/September 2020 when lockdown restrictions eased in the UK following the first major UK lockdown (survey phase 1) and in February/March 2021 during a further national lockdown (survey phase 2). Measures derived from the Cancer Awareness Measure included self-reported attempts to reduce alcohol consumption, increase fruit/vegetable consumption, increase physical activity, lose weight and reduce/stop smoking. Multivariable logistic regressions were used to assess individual health behaviour change attempts over time, adjusted for age, sex, ethnicity, employment and education., Results: Around half of participants in survey phase 1 reported trying to increase physical activity (n = 2607, 52.4%), increase fruit/vegetables (n = 2445, 49.1%) and lose weight (n = 2413, 48.5%), with 19.0% (n = 948) trying to reduce alcohol consumption among people who drink. Among the 738 participants who smoked, 51.5% (n = 380) were trying to reduce and 27.4% (n = 202) to stop smoking completely. Most behaviour change attempts were more common among women, younger adults and minority ethnic group participants. Efforts to reduce smoking (aOR: 0.98, 95% CI: 0.82-1.17) and stop smoking (aOR: 0.98, 95% CI: 0.80-1.20) did not differ significantly in phase 2 compared to phase 1. Similarly, changes over time in attempts to improve other health behaviours were not statistically significant: physical activity (aOR: 1.07; 95% CI: 0.99-1.16); weight loss (aOR: 0.95; 95% CI: 0.90-1.00); fruit/vegetable intake (aOR: 0.98, 95% CI: 0.91-1.06) and alcohol use (aOR: 1.32, 95% CI: 0.92-1.91)., Conclusion: A substantial proportion of participants reported attempts to change health behaviours in the initial survey phase. However, the lack of change observed over time indicated that overall motivation to engage in healthy behaviours was sustained among the UK adult population, from a period shortly after the first lockdown toward the end of the second prolonged lockdown., (© 2022. The Author(s).)

We urgently need answers to basic epidemiological questions regarding SARS-CoV-2 infection in pregnant and postpartum women and its effect on their newborns. While many national registries, health facilities, and research groups are collecting relevant data, we need a collaborative and methodologically rigorous approach to better combine these data and address knowledge gaps, especially those related to rare outcomes. We propose that using a sequential, prospective meta-analysis (PMA) is the best approach to generate data for policy- and practice-oriented guidelines. As the pandemic evolves, additional studies identified retrospectively by the steering committee or through living systematic reviews will be invited to participate in this PMA. Investigators can contribute to the PMA by either submitting individual patient data or running standardized code to generate aggregate data estimates. For the primary analysis, we will pool data using two-stage meta-analysis methods. The meta-analyses will be updated as additional data accrue in each contributing study and as additional studies meet study-specific time or data accrual thresholds for sharing. At the time of publication, investigators of 25 studies, including more than 76,000 pregnancies, in 41 countries had agreed to share data for this analysis. Among the included studies, 12 have a contemporaneous comparison group of pregnancies without COVID-19, and four studies include a comparison group of non-pregnant women of reproductive age with COVID-19. Protocols and updates will be maintained publicly. Results will be shared with key stakeholders, including the World Health Organization (WHO) Maternal, Newborn, Child, and Adolescent Health (MNCAH) Research Working Group. Data contributors will share results with local stakeholders. Scientific publications will be published in open-access journals on an ongoing basis., Competing Interests: Clare Whitehead declares a a relationship with the following entities, Ferring Pharmaceuticals COVID19 Investigational, Grant, NHMRC Fellowship (salary support). Edward Mullins declares a relationship with the following entities National Institute for Health Research (Project grant for PAN COVID study). Deborah Money declares a relationship with the following entities, Canadian Institutes of Health Research (payments to my institution only), Public Health Agency of Canada (payments to institution only), BC Women’s Foundation (payments to institution only) and is a Member of the COVID-19 Immunity Task Force sponsored by the Canadian government. Torri D. Metz declares a relationship with the following entities, Pfizer (site Principal Investigator for SARS-CoV-2 vaccination in pregnancy study, money paid to institution and member of Medical Advisory Board for SARS-CoV-2 vaccination in pregnancy study, money paid to me), NICHD (subcommittee Chair for the NICHD Maternal-Fetal Medicine Units Network Gestational Research Assessments of COVID-19 (GRAVID) study), and Society for Maternal-Fetal Medicine (board member). Erica Lokken declares a relationship with the following entity, US NIH (paid institution). Karen L. Kotloff declares a relationship with the following entity, Bill and Melinda Gates Foundation. Siran He declares a relationship with the following entity, Bill and Melinda Gates Foundtion (payments made to institution). Valerie Flaherman declares a relationship with the following entities, Bill and Melinda Gates Foundation (payments to institution), Yellow Chair Foundation (payments to institution), Robert Woods Johnson Foundation (payments to institution), CDC Foundation, California Health Care Foundation (payments to institution), Tara Health Foundation (payments to institution), UCSF Women’s Health Center of Excellence (payments to institution) and California Department of Health Care Services (payments made to institution). Jose Sanin-Blair declares a relationship with the following entity, Ferring Pharmaceuticals which gave a grant ($10,000) for the expenses of RECOGEST trial and is a part of the Columbian Federation of Perinatology. Yalda Afshar declares a relationship with the following entities, Bill and Melinda Gates Foundation (payments made to institution), CDC Foundation (payments made to my institution), Robert Woods Johnson Foundation (payments made to institution), and UCLA Dean’s Office COVID-19 research (payments made to institution). Rebecca Clifton declares a relationship with the following entity, NIH HD36801 (MFMU Network DCC). Alice Panchaud declared a relationship with the European Medicines Agency (research grant to institution) and the Federal Office of Public Health Switzerland (research grant to institution).

A great promise for tissue engineering is represented by scaffolds that host stem cells during proliferation and differentiation and simultaneously replace damaged tissue while maintaining the main vital functions. In this paper, a novel process was adopted to develop composite scaffolds with a core-shell structure for bone tissue regeneration, in which the core has the main function of temporary mechanical support, and the shell enhances biocompatibility and provides bioactive properties. An interconnected porous core was safely obtained, avoiding solvents or other chemical issues, by blending poly(lactic acid), poly(ε-caprolactone) and leachable superabsorbent polymer particles. After particle leaching in water, the core was grafted with a gelatin/chitosan hydrogel shell to create a cell-friendly bioactive environment within its pores. The physicochemical, morphological, and mechanical characterization of the hybrid structure and of its component materials was carried out by means of infrared spectroscopy, thermogravimetric analysis, scanning electron microscopy, and mechanical testing under different loading conditions. These hybrid polymer devices were found to closely mimic both the morphology and the stiffness of bones. In addition, in vitro studies showed that the core-shell scaffolds are efficiently seeded by human mesenchymal stromal cells, which remain viable, proliferate, and are capable of differentiating towards the osteogenic phenotype if adequately stimulated.

Introduction: Following the detection of fetal growth restriction, there is no consensus about the criteria that should trigger delivery in the late preterm period. The consequences of inappropriate early or late delivery are potentially important yet practice varies widely around the world, with abnormal findings from fetal heart rate monitoring invariably leading to delivery. Indices derived from fetal cerebral Doppler examination may guide such decisions although there are few studies in this area. We propose a randomised, controlled trial to establish the optimum method of timing delivery between 32 weeks and 36 weeks 6 days of gestation. We hypothesise that delivery on evidence of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity, with no worsening of neurodevelopmental outcome at 2 years., Methods and Analysis: Women with non-anomalous singleton pregnancies 32+0 to 36+6 weeks of gestation in whom the estimated fetal weight or abdominal circumference is <10th percentile or has decreased by 50 percentiles since 18-32 weeks will be included for observational data collection. Participants will be randomised if cerebral blood flow redistribution is identified, based on umbilical to middle cerebral artery pulsatility index ratio values. Computerised cardiotocography (cCTG) must show normal fetal heart rate short term variation (≥4.5 msec) and absence of decelerations at randomisation. Randomisation will be 1:1 to immediate delivery or delayed delivery (based on cCTG abnormalities or other worsening fetal condition). The primary outcome is poor condition at birth and/or fetal or neonatal death and/or major neonatal morbidity, the secondary non-inferiority outcome is 2-year infant general health and neurodevelopmental outcome based on the Parent Report of Children's Abilities-Revised questionnaire., Ethics and Dissemination: The Study Coordination Centre has obtained approval from London-Riverside Research Ethics Committee (REC) and Health Regulatory Authority (HRA). Publication will be in line with NIHR Open Access policy., Trial Registration Number: Main sponsor: Imperial College London, Reference: 19QC5491. Funders: NIHR HTA, Reference: 127 976. Study coordination centre: Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS with Centre for Trials Research, College of Biomedical & Life Sciences, Cardiff University. IRAS Project ID: 266 400. REC reference: 20/LO/0031. ISRCTN registry: 76 016 200., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coidisclosure.pdfanddeclare: no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Reducing bullying is a public health priority. KiVa, a school-based anti-bullying programme, is effective in reducing bullying in Finland and requires rigorous testing in other countries, including the UK. This trial aims to test the effectiveness and cost-effectiveness of KiVa in reducing child reported bullying in UK schools compared to usual practice. The trial is currently on-going. Recruitment commenced in October 2019, however due to COVID-19 pandemic and resulting school closures was re-started in October 2020., Methods: Design: Two-arm pragmatic multicentre cluster randomised controlled trial with an embedded process and cost-effectiveness evaluation., Participants: 116 primary schools from four areas; North Wales, West Midlands, South East and South West England. Outcomes will be assessed at student level (ages 7-11 years; n = approximately 13,000 students)., Intervention: KiVa is a whole school programme with universal actions that places a strong emphasis on changing bystander behaviour alongside indicated actions that provide consistent strategies for dealing with incidents of bullying. KiVa will be implemented over one academic year., Comparator: Usual practice., Primary Outcome: Student-level bullying-victimisation assessed through self-report using the extensively used and validated Olweus Bully/Victim questionnaire at baseline and 12-month follow-up., Secondary Outcomes: student-level bullying-perpetration; student mental health and emotional well-being; student level of, and roles in, bullying; school related well-being; school attendance and academic attainment; and teachers' self-efficacy in dealing with bullying, mental well-being, and burnout., Sample Size: 116 schools (58 per arm) with an assumed ICC of 0.02 will provide 90% power to identify a relative reduction of 22% with a 5% significance level., Randomisation: recruited schools will be randomised on 1:1 basis stratified by Key-Stage 2 size and free school meal status. Process evaluation: assess implementation fidelity, identify influences on KiVa implementation, and examine intervention mechanisms. Economic evaluation: Self-reported victimisation, Child Health Utility 9D, Client Service Receipt Inventory, frequency of services used, and intervention costs. The health economic analysis will be conducted from a schools and societal perspective., Discussion: This two-arm pragmatic multicentre cluster randomised controlled trial will evaluate the KiVa anti-bullying intervention to generate evidence of the effectiveness, cost-effectiveness and scalability of the programme in the UK. Our integrated process evaluation will assess implementation fidelity, identify influences on KiVa implementation across England and Wales and examine intervention mechanisms. The integrated health economic analysis will be conducted from a schools and societal perspective. Our trial will also provide evidence regarding the programme impact on inequalities by testing whether KiVa is effective across the socio-economic gradient., Trial Registration: Trials ISRCTN 12300853 Date assigned 11/02/2020., (© 2022. The Author(s).)

Background: The use of administrative data in health and social science research continues to expand, with increased availability of data and interest from funders. Researchers, however, continue to experience delays in access, storage and sharing of administrative data. Training opportunities are limited and typically specific to individual data providers or focussed on the analytical aspects of working with administrative data. The CENTRIC study was funded by the Information Commissioners Office, with the aim of developing a broader training curriculum for researchers working with administrative data in the UK., Methods: A mixed-methods design informed curriculum content, including surveys with researchers, focus group discussions with data providers and workshops with members of the public. Researchers were identified from relevant administrative data networks and invited to participate in an online survey identifying training needs. Data providers were approached with a request to input to a face-to-face or online meeting with two members of the research team about their experiences of working with researchers. Data were analysed within the broad framework of the interview schedule, free text responses in the survey were analysed thematically., Results: 107 researchers responded to the online survey and four data providers participated in the focus groups. We identified five main themes, relating to research training needs for UK researchers working with administrative data: communication; timelines; changes & amendments; future-proofing applications; and, the availability of training and support. Data providers either provided additional evidence on these learning needs or ways to address identified challenges. Six modules were developed addressing these training needs. Quotes from the survey and focus groups are used anonymously in the online training modules., Conclusion: The CENTRIC online training curriculum was launched in September 2020 and is available, free of charge for UK researchers. CENTRIC specifically addresses commonly identified training needs of researchers working with administrative data., Competing Interests: Statement on conflicts of interest: The authors declare that they have no competing interests.

Background: Cancer outcomes are poor in socioeconomically deprived communities, with low symptom awareness contributing to prolonged help-seeking and advanced disease. Targeted cancer awareness interventions require evaluation., Methods: This is a randomised controlled trial involving adults aged 40+ years recruited in community and healthcare settings in deprived areas of South Yorkshire and South-East Wales., Intervention: personalised behavioural advice facilitated by a trained lay advisor., Control: usual care. Follow-up at two weeks and six months post-randomisation., Primary Outcome: total cancer symptom recognition score two weeks post-randomisation., Results: Two hundred and thirty-four participants were randomised. The difference in total symptom recognition at two weeks [adjusted mean difference (AMD) 0.6, 95% CI: -0.03, 1.17, p = 0.06] was not statistically significant. Intervention participants reported increased symptom recognition (AMD 0.8, 95% CI: 0.18, 1.37, p = 0.01) and earlier intended presentation (AMD -2.0, 95% CI: -3.02, -0.91, p < 0.001) at six months. "Lesser known" symptom recognition was higher in the intervention arm (2 weeks AMD 0.5, 95% CI: 0.03, 0.97 and six months AMD 0.7, 95% CI: 0.16, 1.17). Implementation cost per participant was £91.34, with no significant between-group differences in healthcare resource use post-intervention., Conclusions: Improved symptom recognition and earlier anticipated presentation occurred at longer-term follow-up. The ABACus Health Check is a viable low-cost intervention to increase cancer awareness in socioeconomically deprived communities., Clinical Trial Registration: ISRCTN16872545., (© 2021. The Author(s).)

Objectives: To understand self-reported potential cancer symptom help-seeking behaviours and attitudes during the first 6 months (March-August 2020) of the UK COVID-19 pandemic., Design: UK population-based survey conducted during August and September 2020. Correlates of help-seeking behaviour were modelled using logistic regression in participants reporting potential cancer symptoms during the previous 6 months. Qualitative telephone interviews with a purposeful subsample of participants, analysed thematically., Setting: Online UK wide survey., Participants: 7543 adults recruited via Cancer Research UK online panel provider (Dynata) and HealthWise Wales (a national register of 'research ready' participants) supplemented with social media (Facebook and Twitter) recruitment. 30 participants were also interviewed., Main Outcome Measures: Survey measures included experiences of 15 potential cancer symptoms, help-seeking behaviour, barriers and prompts to help-seeking., Results: Of 3025 (40.1%) participants who experienced a potential cancer symptom, 44.8% (1355/3025) had not contacted their general practitioner (GP). Odds of help-seeking were higher among participants with disability (adjusted OR (aOR)=1.38, 95% CI 1.11 to 1.71) and who experienced more symptoms (aOR=1.68, 95% CI 1.56 to 1.82), and lower among those who perceived COVID-19 as the cause of symptom(s) (aOR=0.36, 95% CI 0.25 to 0.52). Barriers included worries about wasting the doctor's time (1158/7543, 15.4%), putting strain on healthcare services (945, 12.6%) and not wanting to make a fuss (907, 12.0%). Interviewees reported reluctance to contact the GP due to concerns about COVID-19 and fear of attending hospitals, and described putting their health concerns on hold., Conclusions: Many people avoided healthcare services despite experiencing potential cancer symptoms during the COVID-19 pandemic. Alongside current help-seeking campaigns, well-timed and appropriate nationally coordinated campaigns should signal that services are open safely for those with unusual or persistent symptoms., Trial Registration Number: ISRCTN17782018., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Importance  Skull base surgery requires precise preoperative assessment and intraoperative management of the patient. Surgical navigation is routinely used for complex skull base cases; however, the image guidance is commonly based on preoperative scans alone. Objective  The primary objective of this study was to assess the image quality of intraoperative cone-beam computed tomography (CBCT) within anatomical landmarks used in sinus and skull base surgery. The secondary objective was to assess the registration error of a surgical navigation system based on intraoperative CBCT. Design  Present study is a retrospective case series of image quality after intraoperative cone beam CT. Setting  The study was conducted at Toronto General Hospital and Princess Margaret Cancer Centre, University Health Network, Toronto. Participants  A total of 46 intraoperative scans (34 patients, 21 skull base, 13 head and neck) were studied. Main Outcome and Measures  Thirty anatomical landmarks (vascular, soft tissue, and bony) within the sinuses and anterior skull base were evaluated for general image quality characteristics: (1) bony detail visualization; (2) soft-tissue visualization; (3) vascular visualization; and (4) freedom from artifacts (e.g., metal). Levels of intravenous (IV) contrast enhancement were quantified in Hounsfield's units (HU). Standard paired-point registration between imaging and tracker coordinates was performed using 6 to 8 skin fiducial markers and the corresponding fiducial registration error (FRE) was measured. Results  Median score for bony detail on CBCT was 5, remaining at 5 after administration of IV contrast. Median soft-tissue score was 2 for both pre- and postcontrast. Median vascular score was 1 precontrast and 3 postcontrast. Median score for artifacts on CBCT were 2 for both pre-and postcontrast, and metal objects were noted to be the most significant source of artifact. Intraoperative CBCT allowed preresection images and immediate postresection images to be available to the skull base surgeon. There was a significant improvement in mean (standard deviation [SD]) CT intensity in the left carotid artery postcontrast 334 HU (67 HU) ( p  < 10 -10 ). The mean FRE was 1.8 mm (0.45 mm). Conclusion  Intraoperative CBCT in complex skull base procedures provides high-resolution bony detail allowing immediate assessment of complex resections. The use of IV contrast with CBCT improves the visualization of vasculature. Image-guidance based on CBCT yields registration errors consistent with standard techniques., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Objective: The aim of this economic evaluation was to assess whether home management could represent a cost-effective strategy in the patient pathway of type 1 diabetes (T1D). This is based on the Delivering Early Care In Diabetes Evaluation trial (ISRCTN78114042), which compared home versus hospital management from diagnosis in childhood diabetes and found no statistically significant difference in glycaemic control at 24 months., Design: Cost-effectiveness analysis alongside a randomised controlled trial., Setting: Eight paediatric diabetes centres in England, Wales and Northern Ireland., Participants: 203 clinically well children aged under 17 years, with newly diagnosed T1D and their carers., Outcome Measures: The base-case analysis adopted n National Health Service (NHS) perspective. A scenario analysis assessed costs from a broader societal perspective. The incremental cost-effectiveness ratio (ICER), expressed as cost per mmol/mol reduction in glycated haemoglobin (HbA1c), was based on the mean difference in costs between the home and hospital groups, divided by mean differences in effectiveness (HbA1c). Uncertainty was considered in terms of the probability of cost-effectiveness., Results: At 24 months postintervention, the base-case analysis showed a difference in costs between home and hospital, in favour of home management (mean difference -£2,217; 95% CI -£2825 to -£1,609; p<0.001). Home care dominated, with an ICER of £7434 (saved) per mmol/mol reduction of HbA1c. The results of the scenario analysis also favoured home management. The greatest driver of cost differences was hospitalisation during the initiation period., Conclusions: Home management from diagnosis of children with T1D who are medically stable represents a less costly approach for the NHS in the UK, without impacting clinical effectiveness., Trial Registration Number: ISRCTN78114042., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Previous novel COVID-19 pandemics, SARS and middle east respiratory syndrome observed an association of infection in pregnancy with preterm delivery, stillbirth and increased maternal mortality. COVID-19, caused by SARS-CoV-2 infection, is the largest pandemic in living memory.Rapid accrual of robust case data on women in pregnancy and their babies affected by suspected COVID-19 or confirmed SARS-CoV-2 infection will inform clinical management and preventative strategies in the current pandemic and future outbreaks., Methods and Analysis: The pregnancy and neonatal outcomes in COVID-19 (PAN-COVID) registry are an observational study collecting focused data on outcomes of pregnant mothers who have had suspected COVID-19 in pregnancy or confirmed SARS-CoV-2 infection and their neonates via a web-portal. Among the women recruited to the PAN-COVID registry, the study will evaluate the incidence of: (1) miscarriage and pregnancy loss, (2) fetal growth restriction and stillbirth, (3) preterm delivery, (4) vertical transmission (suspected or confirmed) and early onset neonatal SARS-CoV-2 infection.Data will be centre based and collected on individual women and their babies. Verbal consent will be obtained, to reduce face-to-face contact in the pandemic while allowing identifiable data collection for linkage. Statistical analysis of the data will be carried out on a pseudonymised data set by the study statistician. Regular reports will be distributed to collaborators on the study research questions., Ethics and Dissemination: This study has received research ethics approval in the UK. For international centres, evidence of appropriate local approval will be required to participate, prior to entry of data to the database. The reports will be published regularly. The outputs of the study will be regularly disseminated to participants and collaborators on the study website (https://pan-covid.org) and social media channels as well as dissemination to scientific meetings and journals., Study Registration Number: ISRCTN68026880., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Recruitment of research participants poses challenges in socioeconomically deprived areas. The Awareness and Beliefs About Cancer (ABACus) phase 3 Randomised Control Trial recruited adult participants from socioeconomically deprived areas using a combined healthcare/community engagement model. We report the strategies used to successfully recruit and retain our trial participant sample., Methods: Community and healthcare settings in areas of high socioeconomic deprivation were identified by lay advisors who recruited participants opportunistically or by appointment. Follow-up was done by telephone or post at 2-weeks and 6-months after recruitment, and all participants were offered financial incentives. Qualitative interviews were conducted with lay advisors regarding their experience and reflections., Results: The lay advisors identified and contacted 107 potential recruitment venues across South and West Yorkshire and South East Wales of which 41.1% (n = 42) were opened for recruitment. A total of 234 participants were recruited, with 91% (n = 212) retention at 2-weeks and 85% (n = 199) at 6-months. Community settings yielded 75% (n = 176) of participants. Participants had a mean age of 61.3 years and 63.3% (n = 148) were female, with 66% (n = 154) resident in the most deprived geographical areas. Lay advisors described recruitment as intensive, although engaging participants was easier in community settings., Conclusions: The ABACus3 trial achieved recruitment and high retention with a population that is often "hard to reach" or entirely missed in health research. Strategies were specifically tailored to engage the venues and adult residents of highly deprived areas. Future studies recruiting adults living in the most deprived areas might benefit from community recruitment and from collaborating with local gatekeepers who are key to engagement. This study adheres to CONSORT guidelines., Trial Registration: Retrospectively registered with ISRCTN ( http://www.isrctn.com/ISRCTN16872545 ) on 12.01.2018.

Introduction: Worldwide large cohort studies have invested in community engagement to promote studies and aid recruitment. HealthWise Wales, a national population study, aims to create a register of 'research ready' participants and provide long-term follow up data on health behaviours, outcomes and wider social and environmental determinants. Public involvement and engagement was key to the development of HealthWise Wales. We describe how a model for promoting HealthWise Wales was co-produced with members of the public., Methods: Members of the public were invited to take part in a workshop, either in North or South Wales, to discuss public involvement in long-term cohort studies. Information on community engagement, projects that had used the concept of "citizen scientists" to promote involvement, and other large longitudinal studies was provided to 15 members of the public prior to the meeting. Eight of these attended the workshops, to explore the concept of citizen scientist and how it may relate to HealthWise Wales., Results: Data from two workshops was used to draft a protocol for involvement that was reviewed and refined by members of the public. The protocol describes two levels of public involvement, HealthWise Wales Champion or Supporter. The Champion is a more formal role that requires promoting the project at public events, whereas Supporters pledge to promote the study to friends and family. Training was provided to 17 of the 26 members of the public who had expressed interest in becoming HWW Champions. Twelve trained Champions attended 41 events to promote the study and collect 'consent to contact' forms from members of the public., Conclusions: It is possible to develop a model of community engagement with members of the public to promote and raise awareness of a national population study in Wales. It is essential that adequate resource is provided to support the concept.

Objective: To determine whether, in children with newly diagnosed type 1 diabetes who were not acutely unwell, management at home for initiation of insulin treatment and education of the child and family, would result in improved clinical and psychological outcomes at 2 years postdiagnosis., Design: A multicentre randomised controlled trial (January 2008/October 2013)., Setting: Eight paediatric diabetes centres in England, Wales and Northern Ireland., Participants: 203 clinically well children aged under 17 years, with newly diagnosed type 1 diabetes and their carers., Intervention: Management of the initiation period from diagnosis at home, for a minimum of 3 days, to include at least six supervised injections and delivery of pragmatic educational care., Main Outcome Measures: Primary outcome was glycosylated haemoglobin (HbA1c) concentration at 24 months postdiagnosis. Secondary outcomes included coping, anxiety, quality of life and use of NHS resources., Results: 203 children, newly diagnosed, were randomised to commence management at home (n=101) or in hospital (n=102). At the 24 month primary end point, there was one withdrawal and a follow-up rate of 194/202 (96%). Mean HbA1c in the home treatment arm was 72.1 mmol/mol and in the hospital treated arm 72.6 mmol/mol. There was a negligible difference between the mean HbA1c levels in the two arms adjusted for baseline (1.01, 95% CI 0.93 to 1.09). There were mostly no differences in secondary outcomes at 24 months, apart from better child self-esteem in the home-arm. No home-arm children were admitted to hospital during initiation and there were no adverse events at that time. The number of investigations was higher in hospital patients during the follow-up period. There were no differences in insulin regimens between the two arms., Conclusions: There is no evidence of a difference between home-based and hospital-based initiation of care in children newly diagnosed with type 1 diabetes across relevant outcomes., Trial Registration Number: ISRCTN78114042., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Recruitment and follow-up in epidemiological studies are time-consuming and expensive. Combining online data collection with a register of individuals who agree to be contacted about research opportunities provides an efficient, cost-effective platform for population-based research. HealthWise Wales (HWW) aims to facilitate research by recruiting a cohort of individuals who have consented to be informed about research projects, advertising studies to participants, supporting data collection on specific topics and providing access to linked healthcare data for secondary analyses. In this paper, we describe the design of the project, ongoing data collection, methods of data linkage to routine healthcare records, baseline characteristics of participants, the strengths and limitations of the register, and the ways in which the project can support researchers., Participants: Adults (aged 16 years and above) living or receiving their healthcare in Wales are eligible for inclusion. Participants consent to be contacted for follow-up data collection and for their details to be used to access their routinely collected National Health Service records for research purposes. Data are collected using a web-based application, with new questionnaires added every 6 months. Data collection on sociodemographic and lifestyle factors is repeated at intervals of 2-3 years. Recruitment is ongoing, with 21 779 participants alive and currently registered., Findings to Date: 99% of participants have complete information on age and sex, and 64% have completed questionnaires on sociodemographic and lifestyle factors. These data can be linked with national health databases within the Secure Anonymised Information Linkage (SAIL) databank, with 93% of participants matching a record in SAIL. HWW has facilitated the recruitment of 43 826 participants to 15 different studies., Future Plans: The medium-term goal for the project is to enrol at least 50 000 adults. Recruitment strategies are being devised to achieve a study sample that closely models the population of Wales. Potential biosampling methods are also currently being explored., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cancer survival is lower in socioeconomically deprived communities, partly due to low awareness of symptoms, negative beliefs and delayed help-seeking. We developed an interactive health check questionnaire facilitated by trained lay advisors. It entails 29 questions about background, lifestyle and health with tailored behaviour change advice. Personalised results are printed using a traffic light (red/amber/green) system, highlighting areas where action should be taken. This is an individually randomised control trial to test effectiveness of the health check on symptom recognition., Methods: A total 246 participants aged 40+ years will be recruited from community and healthcare settings in socioeconomically deprived areas of Yorkshire and South Wales. Participants will be randomised to receive the health check or standard care (1:1 ratio). Outcome measures include: adapted Awareness and Beliefs about Cancer (primary outcome), brief State Trait Anxiety Inventory, intentions and motivation to adopt recommended health behaviours (early symptom presentation, cancer screening and lifestyle behaviours), adapted Client Service Receipt Inventory, brief medical history/screening and demographic questionnaire at: baseline; 2-weeks; and 6-months post-randomisation. A purposive sample of intervention sessions will be audio-recorded (n = 24) and half will additionally be observed (n = 12). Semi-structured interviews will take place at 2-weeks (n = 30) and 6-months (n = 15-20) post-randomisation. The primary analysis will compare cancer symptom recognition scores between arms at 2-weeks. Secondary analysis will assess cancer beliefs, barriers/time to presentation, screening and lifestyle behaviours, anxiety and costs. A process evaluation will assess intervention fidelity, dose and contamination. The London-Surrey NHS Research Ethics Committee (Ref: 17/LO/1507) approved this trial., Discussion: This is a trial of a theoretically underpinned complex intervention which has undergone phase 1 and 2 development work. The findings will evaluate evidence about the effect of the health check on symptom awareness. Although there are few exclusion criteria there are limitations regarding the population we are able to reach, who may have even higher risks of late diagnosis and poor cancer prognosis. However, the health check has the potential to improve cancer symptom awareness and encourage early help-seeking behaviour in deprived populations, thereby reducing inequalities in longer term cancer outcomes., Trial Registration: Retrospectively registered with ISRCTN (Ref: ISRCTN16872545 ) on 12.01.2018.

Background: Cancer survival rates in the UK are lower in comparison with similar countries in Europe and this may be linked to socioeconomic inequalities in stage of cancer diagnosis and survival. Targeted cancer awareness interventions have the potential to improve earlier symptomatic diagnosis and reduce socioeconomic inequalities in cancer outcomes. The health check is an innovative, theory-based intervention designed to increase awareness of cancer symptoms and risk factors, and encourage timely help seeking among adults living in deprived communities., Methods: A prospective, non-randomised evaluation was undertaken to test the feasibility and acceptability of the health check for adults aged 40 years and over living in deprived areas of Wales. Primary outcomes included recruitment and retention of approximately 100 adults, reach to participants in the lowest deprivation quartile, and intervention acceptability. Secondary outcomes included self-reported cancer symptom recognition, help-seeking behaviours and state anxiety pre/post intervention., Results: Of 185 individuals approached, 98 (53%) completed the intervention. Sixty-six of 98 participants were recruited from community settings (67%) and 32 from healthcare settings (33%), with 56 (57%) from the lowest deprivation quartile. Eighty-three (85%) participants completed follow-up assessment. Participants recognised on average one extra cancer symptom post intervention, with improved recognition of and anticipated presentation for non-specific symptoms. State anxiety scores remained stable. Qualitative interviews (n = 25) demonstrated that the intervention was well received and motivated change., Conclusions: Recruitment was feasible in community and healthcare settings, with good reach to adults from low socioeconomic groups. The health check intervention was acceptable and demonstrated potential for improved cancer awareness and symptom presentation, especially for non-specific symptoms, in communities most affected by cancer.

Nanoparticles have shown great promise in improving cancer treatment efficacy while reducing toxicity and treatment side effects. Predicting the treatment outcome for nanoparticle systems by measuring nanoparticle biodistribution has been challenging due to the commonly unmatched, heterogeneous distribution of nanoparticles relative to free drug distribution. We here present a proof-of-concept study that uses mathematical modeling together with experimentation to address this challenge. Individual mice with 4T1 breast cancer were treated with either nanoparticle-delivered or free doxorubicin, with results demonstrating improved cancer kill efficacy of doxorubicin loaded nanoparticles in comparison to free doxorubicin. We then developed a mathematical theory to render model predictions from measured nanoparticle biodistribution, as determined using graphite furnace atomic absorption. Model analysis finds that treatment efficacy increased exponentially with increased nanoparticle accumulation within the tumor, emphasizing the significance of developing new ways to optimize the delivery efficiency of nanoparticles to the tumor microenvironment.

Aims: The aim of this study was to explore from the perspectives of key stakeholders involved in the pathway to diagnosis, the barriers and facilitators to a timely diagnosis of type 1 diabetes in childhood., Methods: Qualitative interviews and free-text analyses were undertaken in 21 parents with a child diagnosed with type 1 diabetes, 60 parents without a child diagnosed with type 1 diabetes, 9 primary healthcare professionals, 9 teachers and 3 community diabetes liaison nurses . Data were analysed thematically and 30% double coded., Results: Two key themes were identified, namely the importance of widespread awareness and knowledge and seeking healthcare professional help . Parents with a child diagnosed with type 1 diabetes described seeking opinions from a number of individuals prior to seeking health professional help. Healthcare professionals recognized the rarity of the condition and the need for it to be kept on their "radar", to ensure they considered it when examining an unwell child. The process of obtaining a primary healthcare appointment was identified as potentially playing a crucial role in the diagnostic process. However, most parents with a child diagnosed with type 1 diabetes described receiving an appointment on the day they sought it., Conclusions: Knowledge and awareness of type 1 diabetes in childhood remain limited in the general population and misconceptions persist relating to how children present with this serious condition. An effective community-based intervention to raise awareness amongst key stakeholders is required to ensure children receive a timely diagnosis once symptomatic.

Background: Self-management and self-efficacy for physical activity is not routinely considered in neurologic rehabilitation., Objective: This study assessed feasibility and outcomes of a 14-week physical activity self-management and coaching intervention compared with social contact in Huntington disease (HD) to inform the design of a future full-scale trial., Design: Assessor blind, multisite, randomized pilot feasibility trial., Setting: Participants were recruited and assessed at baseline, 16 weeks following randomization, and then again at 26 weeks in HD specialist clinics with intervention delivery by trained coaches in the participants' homes., Patients and Intervention: People with HD were allocated to the ENGAGE-HD physical activity coaching intervention or a social interaction intervention., Measurements: Eligibility, recruitment, retention, and intervention participation were determined at 16 weeks. Other outcomes of interest included measures of mobility, self-efficacy, physical activity, and disease-specific measures of motor and cognition. Fidelity and costs for both the physical activity and social comparator interventions were established., Results: Forty percent ( n = 46) of eligible patients were enrolled; 22 were randomized to the physical intervention and 24 to social intervention. Retention rates in the physical intervention and social intervention were 77% and 92%, respectively. Minimum participation criteria were achieved by 82% of participants in the physical intervention and 100% in the social intervention. There was no indication of between-group treatment effects on function; however, increases in self-efficacy for exercise and self-reported levels of physical activity in the physical intervention lend support to our predefined intervention logic model., Limitations: The use of self-report measures may have introduced bias., Conclusions: An HD physical activity self-management and coaching intervention is feasible and worthy of further investigation., (© 2017 American Physical Therapy Association)

Background: Fissure sealant (FS) and fluoride varnish (FV) have been shown to be effective in preventing dental caries when tested against a no-treatment control. However, the relative clinical effectiveness and cost-effectiveness of these interventions is unknown., Objective: To compare the clinical effectiveness and cost-effectiveness of FS and FV in preventing dental caries in first permanent molars (FPMs) in 6- and 7-year-olds and to determine their acceptability., Design: A randomised controlled allocation-blinded clinical trial with two parallel arms., Setting: A targeted population programme using mobile dental clinics (MDCs) in schools located in areas of high social and economic deprivation in South Wales., Participants: In total, 1016 children were randomised, but one parent subsequently withdrew permission and so the analysis was based on 1015 children. The randomisation of participants was stratified by school and balanced for sex and primary dentition baseline caries levels using minimisation in a 1 : 1 ratio for treatments. A random component was added to the minimisation algorithm, such that it was not completely deterministic. Of the participants, 514 were randomised to receive FS and 502 were randomised to receive FV., Interventions: Resin-based FS was applied to caries-free FPMs and maintained at 6-monthly intervals. FV was applied at baseline and at 6-month intervals over the course of 3 years., Main Outcome Measures: The proportion of children developing caries into dentine (decayed, missing, filled teeth in permanent dentition, i.e. D 4-6 MFT) on any one of up to four treated FPMs after 36 months. The assessors were blinded to treatment allocation; however, the presence or absence of FS at assessment would obviously indicate the probable treatment received. Economic measures established the costs and budget impact of FS and FV and the relative cost-effectiveness of these technologies. Qualitative interviews determined the acceptability of the interventions., Results: At 36 months, 835 (82%) children remained in the trial: 417 in the FS arm and 418 in the FV arm. The proportion of children who developed caries into dentine on a least one FPM was lower in the FV arm (73; 17.5%) than in the FS arm (82, 19.6%) [odds ratio (OR) 0.84, 95% confidence interval (CI) 0.59 to 1.21; p  = 0.35] but the difference was not statistically significant. The results were similar when the numbers of newly decayed teeth (OR 0.86, 95% CI 0.60 to 1.22) and tooth surfaces (OR 0.85, 95% CI 0.59 to 1.21) were examined. Trial fidelity was high: 95% of participants received five or six of the six scheduled treatments. Between 74% and 93% of sealants (upper and lower teeth) were intact at 36 months. The costs of the two technologies showed a small but statistically significant difference; the mean cost to the NHS (including intervention costs) per child was £500 for FS, compared with £432 for FV, a difference of £68.13 (95% CI £5.63 to £130.63; p  = 0.033) in favour of FV. The budget impact analysis suggests that there is a cost saving of £68.13 (95% CI £5.63 to £130.63; p  = 0.033) per child treated if using FV compared with the application of FS over this time period. An acceptability score completed by the children immediately after treatment and subsequent interviews demonstrated that both interventions were acceptable to the children. No adverse effects were reported., Limitations: There are no important limitations to this study., Conclusions: In a community oral health programme utilising MDCs and targeted at children with high caries risk, the twice-yearly application of FV resulted in caries prevention that is not significantly different from that obtained by applying and maintaining FSs after 36 months. FV proved less expensive., Future Work: The clinical effectiveness and cost-effectiveness of FS and FV following the cessation of active intervention merits investigation., Trial Registration: EudraCT number 2010-023476-23, Current Controlled Trials ISRCTN17029222 and UKCRN reference 9273., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 21, No. 21. See the NIHR Journals Library website for further project information.

Background: Trials of complex interventions are associated with high costs and burdens in terms of paperwork, management, data collection, validation, and intervention fidelity assessment occurring across multiple sites. Traditional data collection methods rely on paper-based forms, where processing can be time-consuming and error rates high. Electronic source data collection can potentially address many of these inefficiencies, but has not routinely been used in complex intervention trials. Here we present the use of an on-line system for managing all aspects of data handling and for the monitoring of trial processes in a multicentre trial of a complex intervention. We custom built a web-accessible software application for the delivery of ENGAGE-HD, a multicentre trial of a complex physical therapy intervention. The software incorporated functionality for participant randomisation, data collection and assessment of intervention fidelity. It was accessible to multiple users with differing levels of access depending on required usage or to maintain blinding. Each site was supplied with a 4G-enabled iPad for accessing the system. The impact of this system was quantified through review of data quality and collation of feedback from site coordinators and assessors through structured process interviews., Results: The custom-built system was an efficient tool for collecting data and managing trial processes. Although the set-up time required was significant, using the system resulted in an overall data completion rate of 98.5% with a data query rate of 0.1%, the majority of which were resolved in under a week. Feedback from research staff indicated that the system was highly acceptable for use in a research environment. This was a reflection of the portability and accessibility of the system when using the iPad and its usefulness in aiding accurate data collection, intervention fidelity and general administration., Conclusions: A combination of commercially available hardware and a bespoke online database designed to support data collection, intervention fidelity and trial progress provides a viable option for streamlining trial processes in a multicentre complex intervention trial. There is scope to further extend the system to cater for larger trials and add further functionality such as automatic reporting facilities and participant management support., Trial Registration: ISRCTN65378754 , registered on 13 March 2014.

Background and Purpose: We studied the development and delivery of a 14-week complex physical activity intervention for people with Huntington disease, where detailed information about the intervention was fully embedded in the trial design process., Methods: Intervention Development: The intervention was developed through a series of focus groups. The findings from the focus groups informed the development of a logic model for the physical activity intervention that was broadly consistent with the framework of self-determination theory. Intervention Delivery: Key components underpinning the delivery of the intervention were implemented including a defined coach training program and intervention fidelity assessment methods. Training of coaches (physical therapists, occupational therapists, research nurses, and exercise trainers) was delivered via group and 1:1 training sessions using a detailed coach's manual, and with ongoing support via video calls, and e-mail communication as needed. Detailed documentation was provided to determine costs of intervention development and coach training., Results: Intervention delivery coaches at 8 sites across the United Kingdom participated in the face-to-face training. Self-report checklists completed by each of the coaches indicated that all components of the intervention were delivered in accordance with the protocol. Mean (standard deviation) intervention fidelity scores (n = 15), as measured using a purpose-developed rating scale, was 11 (2.4) (out of 16 possible points). Coaches' perceptions of intervention fidelity were similarly high. The total cost of developing the intervention and providing training was £30,773 ($47,042 USD)., Discussion and Conclusions: An important consideration in promoting translation of clinical research into practice is the ability to convey the detailed components of how the intervention was delivered to facilitate replication if the results are favorable. This report presents an illustrative example of a physical activity intervention, including the development and the training required to deliver it. This approach has the potential to facilitate reproducibility, evidence synthesis, and implementation in clinical practice.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A122).

Background: Obesity has significant health and NHS cost implications. Relatively small reductions in weight have clinically important benefits, but long-term weight loss maintenance (WLM) is challenging. Behaviour change interventions have been identified as key for WLM. Motivation is crucial to supporting behaviour change, and motivational interviewing (MI) has been identified as a successful approach to changing health behaviours. The study was designed as an adequately powered, pragmatic randomised controlled trial (RCT); however, owing to recruitment issues, the study became a feasibility trial., Objectives: To assess recruitment, retention, feasibility, acceptability, compliance and delivery of a 12-month intervention to support WLM. Secondary objectives were to assess the impact of the intervention on body mass index (BMI) and other secondary outcomes., Design: Three-arm individually randomised controlled trial comprising an intensive arm, a less intensive arm and a control arm., Setting: Community setting in South Wales and the East Midlands., Participants: Individuals aged 18-70 years with a current or previous BMI of ≥ 30 kg/m(2) who could provide evidence of at least 5% weight loss during the previous 12 months., Intervention: Participants received individually tailored MI, which included planning and self-monitoring. The intensive arm received six face-to-face sessions followed by nine telephone sessions. The less intensive arm received two face-to-face sessions followed by two telephone sessions. The control arm received a leaflet advising them on healthy lifestyle., Main Outcome Measures: Feasibility outcomes included numbers recruited, retention and adherence. The primary effectiveness outcome was BMI at 12 months post randomisation. Secondary outcomes included waist circumference, waist-to-hip ratio, physical activity, proportion maintaining weight loss, diet, quality of life, health service resource usage, binge eating and well-being. A process evaluation assessed intervention delivery, adherence, and participants' and practitioners' views. Economic analysis aimed to assess cost-effectiveness in terms of quality-adjusted life-years (QALYs)., Results: A total of 170 participants were randomised. Retention was good (84%) and adherence was excellent (intensive, 83%; less intensive, 91%). The between-group difference in mean BMI indicated the intensive arm had BMIs 1.0 kg/m(2) lower than the controls [95% confidence interval (CI) -2.2 kg/m(2) to 0.2 kg/m(2)]. Similarly, a potential difference was found in weight (average difference of 2.8 kg, 95% CI -6.1 kg to 0.5 kg). The intensive arm had odds of maintaining on average 43% [odds ratio(OR) 1.4, 95% CI 0.6 to 3.5] higher than controls. None of these findings were statistically significant. Further analyses controlling for level of adherence indicated that average BMI was 1.2 kg/m(2) lower in the intensive arm than the control arm (95% CI -2.5 kg/m(2) to 0.0 kg/m(2)). The intensive intervention led to a statistically significant difference in weight (mean -3.7 kg, 95% CI -7.1 kg to -0.3 kg). The other secondary outcomes showed limited evidence of differences between groups. The intervention was delivered as planned, and both practitioners and participants were positive about the intervention and its impact. Although not powered to assess cost-effectiveness, results of this feasibility study suggest that neither intervention as currently delivered is likely to be cost-effective in routine practice., Conclusion: This is the first trial of an intervention for WLM in the UK, the intervention is feasible and acceptable, and retention and adherence were high. The main effectiveness outcome showed a promising mean difference in the intensive arm. Owing to the small sample size, we are limited in the conclusions we can draw. However, findings suggest that the intensive intervention may facilitate long-term weight maintenance and, therefore, further testing in an effectiveness trial may be indicated. Research examining WLM is in its infancy, further research is needed to develop our understanding of WLM and to expand theory to inform the development of interventions to be tested in rigorously designed RCTs with cost-effectiveness assessed., Trial Registration: Current Controlled Trials ISRCTN35774128., Funding: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 50. See the NIHR Journals Library website for further project information.

Background: Postpartum haemorrhage (PPH) is a major cause of maternal morbidity. Bleeding is caused by a combination of physical causes, such as failure of the uterus to contract or operations, and is made worse by impairment of the blood clotting system. A number of studies have shown that low levels of the blood clotting factor fibrinogen are associated with progression of bleeding, the need for invasive interventions and transfusions of red blood cells and fresh frozen plasma (FFP). This trial will investigate whether early infusion of fibrinogen concentrate during a major PPH, with the aim of correcting a low fibrinogen to a level that is normal for delivery, based on the Fibtem test, reduces the total number of allogeneic blood products (red blood cells, FFP, cryoprecipitate and platelets) transfused after study medication until discharge, compared to placebo., Methods/design: This is a prospective, randomised, double-blind placebo controlled trial. Women will enter an observational phase and if their Fibtem levels fall they will be randomised in the interventional phase. A total of 60 women will be randomised and women are eligible for the trial if they meet all of the following inclusion criteria: age 18 years or over, gestation ≥24 + 0 weeks, haemorrhage of about 1500 ml and on-going bleeding without another complication or haemorrhage of about 1000 ml and caesarean section/uterine atony/placental abruption/placenta praevia/cardiovascular instability or microvascular oozing. Participants with a Fibtem A5 < 16 mm will be randomly allocated to receive either a bolus infusion of fibrinogen concentrate or placebo (isotonic saline). The dose of fibrinogen concentrate or placebo will be calculated based on the woman's ideal body weight for height and the measured Fibtem A5 with the aim of increasing the Fibtem A5 to 23 mm., Discussion: The trial aims to provide evidence on the efficacy and safety of fibrinogen concentrate during acute bleeding in an obstetric setting., Trial Registration: ISRCTN ref: ISRCTN46295339 (01.07.2013); EudraCT: 2012-005511-11 (28.11.2012), UKCRN ref: 13940.

Background: Huntington's disease (HD) is a complex, single-gene inherited neurodegenerative condition resulting in symptoms that occur across a wide range of neurological domains, including cognitive, behavioral and motor. The benefits of regular physical activity for people with HD are widely recognized. However, a number of factors can prohibit sustained exercise and activity. The purpose of this trial is to explore the feasibility, acceptability and effectiveness of a physical activity intervention program targeted for people with early- to mid-stage HD., Methods/design: The proposed trial is a single blind, multisite, exploratory, randomized controlled feasibility trial of a physical activity intervention. A total of 62 participants with genetically confirmed HD will be recruited. Each participant will be involved in the trial for 26 weeks. Participants will be randomized immediately following the baseline assessment into either a physical activity intervention or a social contact control intervention. The physical activity intervention is framed around self-determination theory placed within a broader behaviour change wheel framework. An HD-specific workbook and individual goal setting will be utilized over six 1:1 sessions, with interim telephone calls. All participants will be reassessed at 16 weeks following the baseline assessment, and then again at a final follow-up assessment 26 weeks later. At the end of the study, all participants will be offered a brief version of the alternative intervention, with one home visit and one follow-up telephone call., Discussion: Engaging and supporting people with HD in a regular physical activity program raises a number of challenges. The physical activity intervention and the comparator social interaction intervention have been developed following consultation with people with HD and their families. Each are individually tailored and determined on individual needs and goals. The results from this trial will provide guidance for the development of definitive trials., Trial Registration: The trial was registered with ISRCTN ( http://www.isrctn.com/ISRCTN65378754) on 13 March 2014.

Background: Task-specific training may be a suitable intervention to address mobility limitations in people with Huntington disease (HD)., Objective: The aim of this study was to assess the feasibility and safety of goal-directed, task-specific mobility training for individuals with mid-stage HD., Design: This study was a randomized, blinded, feasibility trial; participants were randomly assigned to control (usual care) and intervention groups., Setting: This multisite study was conducted in 6 sites in the United Kingdom., Patients: Thirty individuals with mid-stage HD (13 men, 17 women; mean age=57.0 years, SD=10.1) were enrolled and randomly assigned to study groups., Intervention: Task-specific training was conducted by physical therapists in participants' homes, focusing on walking, sit-to-stand transfers, and standing, twice a week for 8 weeks. Goal attainment scaling was used to individualize the intervention and monitor achievement of personal goals., Measurements: Adherence and adverse events were recorded. Adjusted between-group comparisons on standardized outcome measures were conducted at 8 and 16 weeks to determine effect sizes., Results: Loss to follow-up was minimal (n=2); adherence in the intervention group was excellent (96.9%). Ninety-two percent of goals were achieved at the end of the intervention; 46% of the participants achieved much better than expected outcomes. Effect sizes on all measures were small., Limitations: Measurements of walking endurance were lacking., Conclusions: The safety of and excellent adherence to a home-based, task-specific training program, in which most participants exceeded goal expectations, are encouraging given the range of motivational, behavioral, and mobility issues in people with HD. The design of the intervention in terms of frequency (dose), intensity (aerobic versus anaerobic), and specificity (focused training on individual tasks) may not have been sufficient to elicit any systematic effects. Thus, a larger-scale trial of this specific intervention does not seem warranted., (© 2014 American Physical Therapy Association.)

Background: Many people with intellectual disabilities find it hard to control their anger and this often leads to aggression which can have serious consequences, such as exclusion from mainstream services and the need for potentially more expensive emergency placements., Aims: To evaluate the effectiveness of a cognitive-behavioural therapy (CBT) intervention for anger management in people with intellectual disabilities., Method: A cluster-randomised trial of group-based 12-week CBT, which took place in day services for people with intellectual disabilities and was delivered by care staff using a treatment manual. Participants were 179 service users identified as having problems with anger control randomly assigned to either anger management or treatment as usual. Assessments were conducted before the intervention, and at 16 weeks and 10 months after randomisation (trial registration: ISRCTN37509773)., Results: The intervention had only a small, and non-significant, effect on participants' reports of anger on the Provocation Index, the primary outcome measure (mean difference 2.8, 95% CI -1.7 to 7.4 at 10 months). However, keyworker Provocation Index ratings were significantly lower in both follow-up assessments, as were service-user ratings on another self-report anger measure based on personally salient triggers. Both service users and their keyworkers reported greater usage of anger coping skills at both follow-up assessments and keyworkers and home carers reported lower levels of challenging behaviour., Conclusions: The intervention was effective in improving anger control by people with intellectual disabilities. It provides evidence of the effectiveness of a CBT intervention for this client group and demonstrates that the staff who work with them can be trained and supervised to deliver such an intervention with reasonable fidelity.

Background: Anger is a frequent problem for many people with intellectual disabilities, and is often expressed as verbal and/or physical aggression. Cognitive-behaviour therapy (CBT) is the treatment of choice for common mental health problems, but CBT has only recently been adapted for people with intellectual disabilities. Anger is the main psychological presentation in which controlled trials have been used to evaluate CBT interventions for people with intellectual disabilities but these do not include rigorous randomised studies., Objectives: To evaluate (1) the impact of a staff-delivered manualised CBT anger management intervention on (a) reported anger among people with mild to moderate intellectual disabilities, and (b) anger coping skills, aggression, mental health, quality of life and costs of health and social care; (2) factors that influence outcome; and (3) the experience of service users, lay therapists and service managers., Design: A cluster randomised controlled trial based on 30 day centres (15 intervention and 15 control). Intention-to-treat comparisons of outcomes used a two-level linear regression model to allow for clustering within centres with baseline outcome levels as a covariate. Comparison of cost data used non-parametric bootstrapping. Qualitative analysis used interpretative phenomenological analysis and thematic analysis., Setting: Recruited day centres had four-plus service users with problem anger who were prepared to participate, two-plus staff willing to be lay therapists, a supportive manager and facilities for group work, and no current anger interventions., Participants: A total of 212 service users with problem anger were recruited. Thirty-three were deemed ineligible (30 could not complete assessments and three withdrew before randomisation). Retention at follow-up was 81%, with 17 withdrawals in each arm. Two to four staff per centre were recruited as lay therapists. Eleven service users, nine lay therapists and eight managers were interviewed., Interventions: The manualised intervention comprised 12 weekly 2-hour group sessions supplemented by 'homework'. Lay therapists received training and ongoing supervision from a clinical psychologist. Treatment fidelity, group attendance and resources used in intervention delivery were monitored., Main Outcome Measures: The primary outcome was the service user-rated Provocation Index (PI), a measure of response to hypothetical situations that may provoke anger. Secondary trial outcomes were the key worker-rated PI; the service user- and key worker-rated Profile of Anger Coping Skills (PACS); the service user-rated PACS imaginal provocation test (PACS-IPT), a measure of response to actual situations known to provoke anger; aggression; mental health; self-esteem; quality of life; and health and social care resource use. Assessments were administered before randomisation and at 16 weeks and 10 months after randomisation., Results: Fourteen treatment groups were delivered, each with 12 sessions lasting an average of 114 minutes, with a mean of 4.9 service users and 2.0 lay therapists. The mean hourly cost per service user was £ 25.26. The mean hourly excess cost over treatment as usual was £ 12.34. There was no effect of intervention on the primary outcome - self-rated PI. There was a significant impact on the following secondary outcomes at the 10-month follow-up: key worker-rated PI, self-rated PACS-IPT and self- and key worker-rated PACS. Key workers and home carers reported significantly lower aggression at 16 weeks, but not at 10 months. There was no impact on mental health, self-esteem, quality of life or total cost of health and social care. Service users, key workers and service managers were uniformly positive., Conclusions: The intervention was effective at changing anger coping skills and staff-rated anger. Impact on self-rated anger was equivocal. With hindsight there are reasons, from an analysis of factors influencing outcomes, to think that self-rated PI was not a well-chosen primary outcome. Widespread implementation of manualised lay therapist-led but psychologist-supervised anger management CBT for people with mild to moderate intellectual disabilities is recommended.

To enter its target cells, human immunodeficiency virus (HIV) must interact with CD4 and one of a family of chemokine receptors. CCR5 is widely used by the virus in this context, and its ligands can prevent HIV entry. Amino-terminal modified chemokine variants, in particular AOP-RANTES (aminooxypentane-linked regulated on activation normal T cell expressed and secreted), exhibit enhanced HIV entry inhibition. We have previously demonstrated that a non-allelic isoform of macrophage inflammatory protein (MIP)-1alpha, termed MIP-1alphaP, is the most active naturally occurring inhibitor of HIV entry known. Here we report the properties of a variant of MIP-1alphaP with an AOP group on the amino terminus. We show that, like RANTES, the addition of AOP to MIP-1alphaP enhances its interactions with CCR1 and CCR5, allows more effective internalization of CCR5, and increases the ligand's potency as an inhibitor of HIV entry through CCR5. Importantly, AOP-MIP-1alphaP is about 10-fold more active than AOP-RANTES at inhibiting HIV entry, making it the most effective chemokine-based inhibitor of HIV entry through CCR5 described to date. Surprisingly, the enhanced receptor interactions of AOP-MIP-1alphaP do not translate into increased chemotaxis or coupling to calcium ion fluxes, suggesting that this protein should be viewed as a partial, rather than a full, agonist for CCR1 and CCR5.