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Abstract Background Autism spectrum disorder (hereafter referred to as autism) is characterised by difficulties with (i) social communication, social interaction, and (ii) restricted and repetitive interests and behaviours. Estimates of autism prevalence within the criminal justice system (CJS) vary considerably, but there is evidence to suggest that the condition can be missed or misidentified within this population. Autism has implications for an individual’s journey through the CJS, from police questioning and engagement in court proceedings through to risk assessment, formulation, therapeutic approaches, engagement with support services, and long-term social and legal outcomes. Methods This consensus based on professional opinion with input from lived experience aims to provide general principles for consideration by United Kingdom (UK) CJS personnel when working with autistic individuals, focusing on autistic offenders and those suspected of offences. Principles may be transferable to countries beyond the UK. Multidisciplinary professionals and two service users were approached for their input to address the effective identification and support strategies for autistic individuals within the CJS. Results The authors provide a consensus statement including recommendations on the general principles of effective identification, and support strategies for autistic individuals across different levels of the CJS. Conclusion Greater attention needs to be given to this population as they navigate the CJS.

Background There is evidence to support COVID-19 rehabilitation programmes improving persistent COVID-19 symptoms; however, there is concern that therapies that include an exercise component may increase fatigue and post-exertional symptom exacerbation (PESE). The objectives of the present study were to determine the effect of a 6-week COVID-19 rehabilitation programme on fatigue and PESE in individuals with ongoing COVID-19 symptoms. Methods After a routine medical assessment, individuals with persistent COVID-19 symptoms were enrolled on a 6-week COVID-19 specific rehabilitation programme. The programme included symptom-titrated exercise, education and self-management advice. Fatigue was assessed pre- and post-programme using the Functional Assessment Chronic Illness Therapy Fatigue questionnaire (FACIT). Exercise capacity (Incremental and Endurance Shuttle Walking Test (ISWT and ESWT)) and PESE (DePaul Symptom Questionnaire (DSQ)) were also assessed pre- and post-programme. Composite scores were calculated for the frequency and severity domains of the DSQ. Results 148 patients (median (IQR) age 59 (49–72) years, 82 (55%) female, 81 (54%) hospitalised) completed the COVID-19 rehabilitation programme. FACIT score was reduced pre- to post-programme by a mean (CI) change of −5 (−7– −4); p

Abstract Driven by the need to make high temperature thermoplastic polymers more processable and expand the range of applications, this study reports on the properties of a novel PAEK material developed by Victrex (Thornton Cleveleys, UK) which is capable of undergoing crosslinking or crystallisation, two competing processes that can be adapted via specific processing temperature and time conditions. The uniqueness of this PAEK material resides in its manufacturing approach, where the crosslinkers are incorporated during the polymerisation process, and its distinct properties, including a controllable viscosity that can be tuned from low to high to allow its application in complex manufacturing processes, such as thermoplastic carbon fibre manufacturing.

Objectives To undertake further psychometric testing of the Multimorbidity Treatment Burden Questionnaire (MTBQ) and examine whether reversing the scale reduced floor effects.Design Survey.Setting UK primary care.Participants Adults (≥18 years) with three or more long-term conditions randomly selected from four general practices and invited by post.Measures Baseline survey: sociodemographics, MTBQ (original or version with scale reversed), Treatment Burden Questionnaire (TBQ), four questions (from QQ-10) on ease of completing the questionnaires. Follow-up survey (1–4 weeks after baseline): MTBQ, TBQ and QQ-10. Anonymous data collected from electronic GP records: consultations (preceding 12 months) and long-term conditions. The proportion of missing data and distribution of responses were examined for the original and reversed versions of the MTBQ and the TBQ. Intraclass correlation coefficient (ICC) and Spearman’s rank correlation (Rs) assessed test–retest reliability and construct validity, respectively. Ease of completing the MTBQ and TBQ was compared. Interpretability was assessed by grouping global MTBQ scores into 0 and tertiles (>0).Results 244 adults completed the baseline survey (consent rate 31%, mean age 70 years) and 225 completed the follow-up survey. Reversing the scale did not reduce floor effects or data skewness. The global MTBQ scores had good test–retest reliability (ICC for agreement at baseline and follow-up 0.765, 95% CI 0.702 to 0.816). Global MTBQ score was correlated with global TBQ score (Rs 0.77, p

Abstract Background Cross-sectionally, older age and obesity are associated with increased coronavirus disease-2019 (COVID-19) risk. We assessed the longitudinal associations of baseline and changes in adiposity parameters with COVID-19 incidence in older adults at high cardiovascular risk. Methods This analysis included 6874 men and women (aged 55–75 years) with overweight/obesity and metabolic syndrome in the PREDIMED-Plus lifestyle intervention trial for cardiovascular risk reduction. Body weight, body-mass-index (BMI), waist circumference, waist-to-height ratio (WHtR), and a body shape index (ABSI) were measured at baseline and annual follow-up visits. COVID-19 was ascertained by an independent Event Committee until 31 December 2021. Cox regression models were fitted to evaluate the risk of COVID-19 incidence based on baseline adiposity parameters measured 5–6 years before the pandemic and their changes at the visit prior to censoring. Results At the time of censoring, 653 incident COVID-19 cases occurred. Higher baseline body weight, BMI, waist circumference, and WHtR were associated with increased COVID-19 risk. During the follow-up, every unit increase in body weight (HRadj (95%CI): 1.01 (1.00, 1.03)) and BMI (HRadj: 1.04 (1.003, 1.08)) was associated with increased COVID-19 risk. Conclusions In older adults with overweight/obesity, clinically significant weight loss may protect against COVID-19. Trial registration This study is registered at the International Standard Randomized Controlled Trial (ISRCT; http://www.isrctn.com/ISRCTN89898870 ).

Abstract Background Putting patients’ needs and priorities at the forefront of healthcare initiatives and medical product development is critical to achieve outcomes that matter most to patients. This relies on the integration of early, meaningful patient engagement (PE) to learn what is important to patients, and collection of representative patient experience data (PXD). The increased number of PE/PXD efforts across global regulatory, health technology assessment, and healthcare systems is an important step forward to deliver improved health outcomes for patients. However, these initiatives are fragmented and lack integration, which is necessary to maximize efforts and reduce burden on patients. To overcome these challenges, the Global Patient Experience Data Navigator has been co-created by Patient Focused Medicines Development to provide practical resources that can facilitate and optimize PXD generation, collection, analysis, and dissemination for patient benefit and aims to be applicable across all therapeutic areas for all stakeholders. Methods Co-creation of the Navigator took place through an iterative process of validation and formalization driven by a diverse, multi-stakeholder working group with individuals who have varying knowledge/experience in PE/PXD. Results A series of workshops took place to conduct a gap analysis, develop a taxonomy model, and integrate existing frameworks. The collective insights led to the development of the Navigator consisting of four specific tools in the form of downloadable templates, which can be used to: (1) prioritize outcomes that matter most to patients and their caregivers; (2) select appropriate measurement methods for these outcomes; (3) identify when and why PXD is used throughout the product development cycle for each stakeholder; (4) identify when and why PXD is used throughout the healthcare process for each stakeholder. A public consultation was carried out to collect user feedback before the Navigator was made publicly available in December 2022. Conclusion To our knowledge, the Global Patient Experience Data Navigator is the only publicly available toolkit developed with a multi-stakeholder and disease-agnostic approach providing taxonomically grouped resources to optimize the collection and collation of PXD for patient benefit. Future work will aim to further engage patients by adding a PE dimension to the Navigator.

Patients with diabetic foot ulcers have poor adherence to treatment recommendations. However, the most effective way to support adherence in this population is unknown. This study aimed to assess the preliminary effectiveness of a motivation communication training programme for healthcare professionals working with these patients, using theory and evidence-based strategies.A proof-of-concept study using a non-randomised, controlled before-and-after design. Six podiatrists took part in the motivation communication training programme. Pre-training, observation was undertaken to examine the communication style currently used by podiatrists in routine consultations. Patients' (n = 25) perceptions of podiatrist autonomy support, self-determination for limiting weight-bearing activity and average daily step count were also assessed. Post training, observations and patient measures were repeated with a different group of patients (n = 24). Observations indicated that podiatrists exhibited a more need-supportive communication style (e.g., taking time to understand patients' perspectives) after undergoing the training programme. Patients in the post-training group reported higher levels of autonomy support, while self-determination to limit weight-bearing activity remained unchanged. Although the post-training group had a lower average daily step count, the difference was not statistically significant. This is the first study to investigate implementation of motivation communication strategies in routine consultations with patients with diabetic foot ulcers. Results suggest that training can enhance healthcare professionals' motivation communication skills with potential for addressing adherence issues, however, a larger cluster randomised controlled trial is necessary to confirm this.

Abstract The induction of antiviral innate immunity by systemic immunization with live virus can be employed to positively impact the response to therapeutic vaccination. We previously demonstrated that systemic immunization with a non-replicating MVA encoding CD40 ligand (CD40L) enhances innate immune cell activation and function, and triggers potent antitumor CD8+ T cell responses in different murine tumor models. Antitumor efficacy was increased when combined with tumor targeting antibodies. Here we report the development of TAEK-VAC-HerBy (TVH), a first-in-class human tumor antibody enhanced killing (TAEK) vaccine based on the non-replicating MVA-BN viral vector. It encodes the membrane bound form of human CD40L, HER2 and the transcription factor Brachyury. TVH is designed for therapeutic use in HER2- or Brachyury-expressing cancer patients in combination with tumor targeting antibodies. To preclude possible oncogenic activities in infected cells and to prevent binding of vaccine-encoded HER2 by monoclonal antibodies trastuzumab and pertuzumab, genetic modifications of HER2 were introduced in the vaccine. Brachyury was genetically modified to prevent nuclear localization of the protein thereby inhibiting its transcriptional activity. CD40L encoded in TVH enhanced human leukocyte activation and cytokine secretion in vitro. Lastly, TVH intravenous administration to non-human primates was proven immunogenic and safe in a repeat-dose toxicity study. Nonclinical data presented here highlight TVH as a first-in-class immunotherapeutic vaccine platform currently under clinical investigation.

BackgroundMigrants are disproportionately affected by HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV). Clinicians, at times, fail to offer rapid diagnostic testing (RDT) for these viruses when a language barrier exists in the patient-clinician relationship, therefore creating missed testing opportunities. Although their effectiveness has been demonstrated elsewhere, conventional, in-person interpreters are costly and underused in practice. Furthermore, clinicians often call upon ad hoc interpreters, which introduces complexities in the clinical relationship. Digital solutions exist to diminish the burden of language barriers; however, the challenges of developing a multilingual and multicultural app have yet to be documented with respect to RDT in the nonfrancophone migrant population in France. ObjectiveOur goal was to design a multilingual app to overcome language barriers, health literacy barriers, and fears related to being tested to promote RDT of HIV, HBV, and HCV in the nonfrancophone migrant population in France. MethodsA combination of qualitative methods, agile development, and user-centered design was used. We conducted 2 focus groups (FGs) with 12 participants, including physicians, nurses, and social workers conducting RDT, as well as 1 modified Delphi survey with 68 participants including physicians and nurses. FGs explored the content (risk factors and medical history), functions (cultural adaptation and instant translation), and interface ergonomics (graphics and font) needed in the app. The Delphi presented 95 content items that the researchers sought to include in the app. ResultsUsing FGs to inform the Delphi survey, we scientifically determined the app’s content consisting of 95 items using expert consensus, developed a mock-up, and conducted initial user testing. We created an app that contains both migrant and clinician interfaces and includes a sociodemographic, risk assessment, health literacy, and testing barrier questionnaires available in 11 languages. Educational content is related to HIV, HBV, and HCV, along with the ability to understand whether the migrant agrees to be tested. ConclusionsThis study allowed us to conceptualize a multilingual app that aims to increase the acceptance of RDT for HIV, HBV, and HCV. The specific features of the Assistant intelligent au dépistage des allophones app were designed to overcome the testing barriers in the nonfrancophone migrant population. The next phase will be an implementation study, as we intend to validate our app.

BackgroundChronic or persistent pain affects one’s ability to work or be productive at work, generating high societal and economic burden. However, the provision of work-related advice and support for people with chronic pain is variable or lacking. The Pain-at-Work (PAW) Toolkit was cocreated with people who live with pain, health care professionals, and employers. It aims to increase knowledge about employee rights and how to access support for managing a painful chronic condition in the workplace and provides advice on lifestyle behaviors that facilitate the management of chronic pain. ObjectiveWe aimed to establish the feasibility of conducting a definitive cluster randomized controlled trial comparing access to the PAW Toolkit and telephone support calls from an occupational therapist (PAW) with treatment as usual (ie, standard support from their employer). Our primary outcomes are establishing parameters of feasibility, acceptability, usability, and safety of this digital workplace health intervention. We will assess the candidate primary and secondary outcomes’ feasibility and test research processes for a definitive trial. MethodsThis is an open-label, parallel 2-arm pragmatic feasibility cluster randomized controlled trial with exploratory health economics analysis and a nested qualitative interview study. We aim to recruit 120 participants from at least 8 workplace clusters (any type, >10 employees) in England. The recruitment of workplaces occurs via personal approach, and the recruitment of individual participants is web based. Eligible participants are vocationally active adults aged ≥18 years with internet access and self-reporting chronic pain interfering with their ability to undertake or enjoy productive work. A restricted 1:1 cluster-level randomization is used to allocate employment settings to PAW or treatment as usual; participants are unblinded to group allocation. Following site- and individual-level consent, participants complete a web-based baseline survey (time 0), including measures of work capacity, health and well-being, and health care resource use. Follow-up is performed at 3 months (time 1) and 6 months (time 2). Feasibility outcomes relate to recruitment; intervention fidelity (eg, delivery, reach, uptake, and engagement); retention; and follow-up. Qualitative evaluation (time 2) is mapped to the Capability, Opportunity, Motivation–Behavior model and will explore intervention acceptability to employees and employers, along with individual and contextual factors influencing the delivery and uptake of the intervention. ResultsEthics approval was obtained in March 2023. Trial recruitment began in June 2023. ConclusionsThe PAW Toolkit is the first evidence-based digital health intervention aimed at supporting the self-management of chronic or persistent pain at work. This study will inform the design of a definitive trial, including sample size estimation, approaches to cluster site identification, primary and secondary outcomes’ selection, and the final health economic model. Findings will inform approaches for the future delivery of this digital health intervention. Trial RegistrationClinicalTrials.gov NCT05838677; https://clinicaltrials.gov/study/NCT05838677 International Registered Report Identifier (IRRID)DERR1-10.2196/51474

BackgroundThe use of social media assists in the distribution of information about COVID-19 to the general public and health professionals. Alternative-level metrics (ie, Altmetrics) is an alternative method to traditional bibliometrics that assess the extent of dissemination of a scientific article on social media platforms. ObjectiveOur study objective was to characterize and compare traditional bibliometrics (citation count) with newer metrics (Altmetric Attention Score [AAS]) of the top 100 Altmetric-scored articles on COVID-19. MethodsThe top 100 articles with the highest AAS were identified using the Altmetric explorer in May 2020. AAS, journal name, and mentions from various social media platforms (Twitter, Facebook, Wikipedia, Reddit, Mendeley, and Dimension) were collected for each article. Citation counts were collected from the Scopus database. ResultsThe median AAS and citation count were 4922.50 and 24.00, respectively. TheNew England Journal of Medicine published the most articles (18/100, 18%). Twitter was the most frequently used social media platform with 985,429 of 1,022,975 (96.3%) mentions. Positive correlations were observed between AAS and citation count (r2=0.0973; P=.002). ConclusionsOur research characterized the top 100 COVID-19–related articles by AAS in the Altmetric database. Altmetrics could complement traditional citation count when assessing the dissemination of an article regarding COVID-19. International Registered Report Identifier (IRRID)RR2-10.2196/21408

(1) Background: VR is based on a virtual world that creates sounds effects and videos that replace the real environment. Arising literature shows VR efficacy in the field of neurological rehabilitation (NR) and that its use is also taking a place in musculoskeletal rehabilitation (MSR), as a treatment of various disorders that cause disability and chronic pain. (2) Aim: We discuss the role of VR in MSR, presenting its use and development on acute and chronic musculoskeletal disorders, based on the most recent literature. (3) Design and Methods: Literature searches were conducted in the databases Pubmed and Medline up to 30 September 2023. The PRISMA-Scr Checklist was followed. (4) Results: A total of 51 records were included. The analysed studies were conducted within a variety of populations, musculoskeletal disorders, settings, and VR technologies. Only a few studies could statistically affirm the efficacy of VR in MSR, as mentioned for the rehabilitation of the upper limb. Nevertheless, the observed trend is an improvement of the global perceived effect compared to traditional rehabilitation. (5) Conclusion: VR allows for the personalisation of treatment with an adaptable treatment platform, which may improve the participation of the patient and increase acceptability and adherence to long-term rehabilitation programs. We provide recommendations and suggestions for future research and use of VR in musculoskeletal rehabilitation.

Objectives To evaluate the impact and feasibility of multisource feedback compared with traditional feedback for trauma team captains (TTCs).Design A mixed-methods, non-randomised prospective study.Setting A level one trauma centre in Ontario, Canada.Participants Postgraduate medical residents in emergency medicine and general surgery participating as TTCs. Selection was based on a convenience sampling method.Intervention Postgraduate medical residents participating as TTCs received either multisource feedback or standard feedback following trauma cases.Main outcome measures TTCs completed questionnaires designed to measure the self-reported intention to change practice (catalytic effect), immediately following a trauma case and 3 weeks later. Secondary outcomes included measures of perceived benefit, acceptability, and feasibility from TTCs and other trauma team members.Results Data were collected following 24 trauma team activations: TTCs from 12 activations received multisource feedback and 12 received standard feedback. The self-reported intention for practice change was not significantly different between groups initially (4.0 vs 4.0, p=0.57) and at 3 weeks (4.0 vs 3.0, p=0.25). Multisource feedback was perceived to be helpful and superior to the existing feedback process. Feasibility was identified as a challenge.Conclusions The self-reported intention for practice change was no different for TTCs who received multisource feedback and those who received standard feedback. Multisource feedback was favourably received by trauma team members, and TTCs perceived multisource feedback as useful for their development.

Abstract Background After repair of esophageal atresia (EA), childhood survivors commonly present with digestive and respiratory morbidity, and around 55% have associated anomalies. Although it is known that these problems can reduce health-related quality of life in children with EA, less is understood about the impact on the family. We aimed to identify factors related to family impact in children with EA. Methods One parent each of a child with EA (2–18 years) in 180 families from Sweden and Germany answered the PedsQL™ Family Impact Module as the dependent variable. The independent variables were the child’s parent-reported health-related quality of life as measured by PedsQL™ 4.0, current symptoms, school situation, and parent/family characteristics together with child clinical data from the medical records. Results Stepwise multivariable regression analysis showed a multifactorial model of the total family impact scores (R 2 = 0.60), with independent factors being the child’s overall generic health-related quality of life, school-absence ≥ 1/month, severe tracheomalacia, a family receiving carer’s allowance, and a parent with no university/college education, p

BackgroundAt the start of the COVID-19 pandemic, unprecedented pressure was placed on health care services globally. An opportunity to alleviate this pressure was to introduce a digital health platform that provided COVID-19–related advice and helped individuals understand and manage their COVID-19 symptoms. Therefore, in July 2020, the Your COVID Recovery website was launched by the National Health Service of England with the aim of creating a practical tool that provides advice and support to individuals recovering from COVID-19. The website includes information on many of the key COVID-19 symptoms. To date, public use of the Your COVID Recovery website and user behavior remain unknown. However, this information is likely to afford insight into the impact of the website and most commonly experienced COVID-19 symptoms. ObjectiveThis study aimed to evaluate public use of the Your COVID Recovery website, a digital health platform that provides support to individuals recovering from COVID-19, and determine user behavior during its first year of operation. MethodsGoogle Analytics software that was integrated into the Your COVID Recovery website was used to assess website use and user behavior between July 31, 2020, and July 31, 2021. Variables that were tracked included the number of users, user country of residence, traffic source, number of page views, number of session views, and mean session duration. User data were compared to COVID-19 case data downloaded from the UK government’s website. ResultsDuring the study period, 2,062,394 users accessed the Your COVID Recovery website. The majority of users were located in the United Kingdom (1,265,061/2,062,394, 61.30%) and accessed the website via a search engine (1,443,057/2,062,394, 69.97%). The number of daily website users (n=15,298) peaked on January 18, 2021, during the second wave of COVID-19 in the United Kingdom. The most frequently visited pages after the home page were for the following COVID-19 symptoms: Cough (n=550,190, 12.17%), Fatigue (n=432,421, 9.56%), Musculoskeletal pain (n=406,859, 9.00%), Taste and smell (n=270,599, 5.98%), and Breathlessness (n=203,136, 4.49%). The average session duration was 1 minute 13 seconds. ConclusionsA large cohort of individuals actively sought help with their COVID-19 recovery from the website, championing the potential of this tool to target an unmet health care need. User behavior demonstrated that individuals were primarily seeking advice on how to relieve and manage COVID-19 symptoms, especially symptoms of cough, fatigue, and musculoskeletal pain. COVID-19 rehabilitation programs should use the results of this study to ensure that the program content meets the needs of the post–COVID-19 population.

Objective: This study aimed to synthesise current evidence about the optimal hours of use of CPAP for OSA to offer an evidence-based approach to using this therapy.Method: A systematic integrative literature review was conducted with quality assessment criteria applied.Results: 10 of 4693 studies met inclusion criteria. Thematic analysis identified three themes: 1) more is better, but anything is better than nothing; 2) six hours is optimal; 3) the percentage of total sleep time/individualised optimal hours are the best way to determine ‘compliance’ and efficacy. Hours per night in the context of total sleep time may offer a more individualised indicator of compliance than four hours per night for every user.Conclusion: Overall, this review identified limited evidence about optimal hours of CPAP use for OSA. The previously employed four hours of use as the threshold for determining compliance warrants review in the context of total sleep time per night. Additionally, patients can be encouraged that any CPAP is better than none and increasing use should yield clinical improvement. We argue that optimal hours of use are an individualised definition and that previous ideas around universally applicable optimal hours be discarded in favour of a focus on improving clinical indicators and CPAP use as a percentage of total sleep time.

Abstract Background The aim was to compare parent and child-reported health-related quality of life (HRQOL) of children born with esophageal atresia (EA) and determine factors that affect the level of parent–child agreement. Methods We included 63 parent–child dyads of children born with EA aged 8–18 from Germany and Sweden. The generic PedsQL 4.0™ questionnaire and the condition-specific EA QOL questionnaire were used to assess children’s HRQOL from parents' and children’s perspectives. The PedsQL™ Family Impact Module was used to assess parental HRQOL and Family Functioning. Results On an individual level, intra-class correlation coefficients indicated strong levels of parent–child agreement (.61–.97). At the group level, the analyses showed no significant differences between the responses of parents and children. When a disagreement occurred, parents were more likely to rate generic HRQOL lower than the children (19–35%) and condition-specific HRQOL higher than the children (17–33%). Findings of the binary logistic regression analyzes showed that the child’s age, gender, and country (Germany vs. Sweden) were significant predictors of parent–child agreement in condition-specific HRQOL. We did not identify any significant variables that explain agreement for the generic HRQOL. Conclusion The parent–child agreement is mostly good, suggesting that parent-reports are a reliable source of information. However, discrepancies may occur and can be explained by the child's age, gender, and country (Sweden vs. Germany). Both perspectives are essential sources for treating EA patients and should not be considered right or wrong. Instead, this information broadens the perspective on pediatric EA patients.

Abstract This article describes my reflections of speaking with three patients and their families living with mastocytosis, who I was introduced to through the UK Mastocytosis Support Group. I discuss the various ways in which the condition affects their day-to-day lives and how this has changed during the Covid-19 pandemic. I have tried to give an insight into the particular difficulties that this patient group faces, both during and before the pandemic, whilst also considering how these challenges may resonate more widely with other patient groups in the rare disease community. Pseudonyms are used throughout to protect patient anonymity.

Abstract A case report highlighting the importance of cautious interpretation of thyroglobulin washouts in fine needle aspirates when deciding on management of differentiated thyroid cancer, so as to avoid unnecessary surgery.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

AbstractBackground:In order to conduct translational science, scientists must combine domain-specific expertise with knowledge on how to identify and cross translational hurdles, and insights on positioning discoveries for the next translational stage. Expert educators from the Clinical and Translational Science Awards (CTSA) Consortium identified 97 knowledge, skills, and abilities (KSAs) important to include in training programs for translational scientists. To assist educators and trainees to use these KSAs, a conceptual model called “Personalized Pathways” was developed that prioritizes KSAs based on trainee background, research area, or phenotype, and expertise on the research team.Purpose:To understand how CTSA educators prioritize specific KSAs when developing personalized training plans for different translational phenotypes and to identify areas of similarity and difference across phenotypes.Methods:A web-based, cross-sectional survey of CTSA educators was done. For a selected phenotype, respondents recommended one of four levels of mastery for each of the 97 KSAs. Results were tabulated by frequency, weighted by importance, and divided into tertiles representing high, middle, and lower priority KSAs. Agreement across phenotypes was compared using Krippendorff’s alpha.Results:Ten KSAs were high training priority for Preclinical, Clinical, and Community-Engaged phenotypes. These address research methods, responsible conduct of research, team building, and communicating research results. Nine KSAs were in the next tertile for priority reflecting KSAs in biostatistics, bioinformatics, regulatory precepts, and translating implications of research findings.Conclusion:A smaller set of KSAs can be prioritized for training Preclinical-, Clinical-, and Community-Engaged researchers. Future work should explore this approach for other phenotypes.

Objectives To describe the early data from the Your COVID Recovery® digital programme and to explore the data collected from two embedded outcome measures.Design Observational.Setting Primary and secondary care (England—Online).Participants 110 individuals completed the programme (68.1% female, 88.1% White British, age: 46.3 (10.8) years, weight: 86.5 (21.1) kg, height: 169.3 (10.0) cm). 47.2% of patients reported comorbidities.Intervention Following an assessment by a healthcare professional, individuals with long COVID were offered access to the Your COVID Recovery® digital programme. The programme comprises of four stages for the participants to progress through. Participants are encouraged to record severity of their symptoms and amount of activity they are doing on a symptom and an activity tracker. Resources and interactive material on managing symptoms of long COVID are available throughout each stage.Primary outcome measures Questionnaire (EuroQ0l 5-Dimension 5-Level (EQ-5D-5L) and the chronic obstructive pulmonary disease assessment test (CAT)) data were extracted from the site from 11 March 2021 until 9 November 2021.Results Participants were on the programme for 8.6 (4.3) weeks. There was a statistically significant increase in EQ-5D-5L visual analogue scale (VAS) score (pre=48.8 (19.5); post=59.9 (22.1); p

Introduction This study protocol outlines the evaluation of the pictorial support in person-centred care for children (PicPecc). PicPecc is a digital tool used by children aged 5–17 years to self-report symptoms of acute lymphoblastic leukaemia, who undergo high-dose methotrexate treatments. The design of the digital platform follows the principles of universal design using pictorial support to provide accessibility for all children regardless of communication or language challenges and thus facilitating international comparison.Methods and analysis Both effect and process evaluations will be conducted. A crossover design will be used to measure the effect/outcome, and a mixed-methods design will be used to measure the process/implementation. The primary outcome in the effect evaluation will be self-reported distress. Secondary outcomes will be stress levels monitored via neuropeptides, neurosteroids and peripheral steroids indicated in plasma blood samples; frequency of in-app estimation of high levels of distress by the children; children's use of analgesic medicine and person centeredness evaluated via the questionnaire Visual CARE Measure. For the process evaluation, qualitative interviews will be carried out with children with cancer, their legal guardians and case-related healthcare professionals. These interviews will address experiences with PicPecc in terms of feasibility and frequency of use from the child’s perspective and value to the caseworker. Interview transcripts will be analysed using an interpretive description methodology.Ethics and dissemination Ethical approval was obtained from the Swedish Ethical Review Authority (reference 2019-02392; 2020-02601; 2020-06226). Children, legal guardians, healthcare professionals, policymaking and research stakeholders will be involved in all stages of the research process according to Medical Research Council’s guidelines. Research findings will be presented at international cancer and paediatric conferences and published in scientific journals.Trial registration ClinicalTrials.gov; NCT04433650.

Introduction The coronavirus disease 2019 (COVID-19) pandemic has seen many cardiopulmonary rehabilitation services delivering programmes remotely. One area of concern is how to assess exercise capacity when a supervised exercise test is not possible. The aim of this review was to examine the relationship between functional exercise tests and recommended exercise tests for cardiopulmonary rehabilitation. Methods A rapid narrative review was carried out. Searches were conducted by two of the study authors. The study had the following features. Participants: adults, all with long-term conditions; intervention: any/none; outcome: Duke activity status index (DASI), sit to stand (STS, 30 s, 1 min and 5 repetitions), short physical performance battery (SPPB), 4-metre gait speed (4MGS) or step test (Chester/others) AND directly compared to one of the recommended exercise tests for cardiopulmonary rehabilitation: 6-min walk test (6MWT), incremental shuttle walk test (ISWT) or cardiopulmonary exercise test (CPET) in terms of reporting agreement/correlation; Study design: primary research only, controlled trials or observational studies. Results Sixteen articles out of 249 screened were included (n=2271 patients). Overall, there were weak–strong correlations for the included tests with a recommended exercise test (r=0.38–0.85). There were few reported issues with feasibility or safety of the tests. However, all tests were supervised in a clinical setting. The test that had the highest correlation with the field walking test was the 4MGS with the ISWT (r=0.78) and with the 6MWT (r=0.85). Discussion The 4MGS has the highest correlation with routine measures of exercise tolerance. However, it may be difficult to standardise in a remote assessment or to prescribe exercise from. Clinicians should strive for face-to-face standardised exercise tests where possible to be able to guide exercise prescription.

Objectives Informing research participants of the results of studies in which they took part is viewed as an ethical imperative. However, there is little guidance in the literature about how to do this. The Fluoxetine Or Control Under Supervision trial randomised 3127 patients with a recent acute stroke to 6 months of fluoxetine or placebo and was published in the Lancet on 5 December 2018. The trial team decided to inform the participants of the results at exactly the same time as the Lancet publication, and also whether they had been allocated fluoxetine or placebo. In this report, we describe how we informed participants of the results.Design In the 6-month and 12-month follow-up questionnaires, we invited participants to provide an email address if they wished to be informed of the results of the trial. We re-opened our trial telephone helpline between 5 December 2018 and 31 March 2019.Setting UK stroke services.Participants 3127 participants were randomised. 2847 returned 6-month follow-up forms and 2703 returned 12-month follow-up forms; the remaining participants had died (380), withdrawn consent or did not respond.Results Of those returning follow-up questionnaires, a total of 1845 email addresses were provided and a further 50 people requested results to be sent by post. Results were sent to all email and postal addresses provided; 309 emails were returned unrecognised. Seventeen people replied, of whom three called the helpline and the rest responded by email.Conclusion It is feasible to disseminate results of large trials to research participants, though only around 60% of those randomised wanted to receive the results. The system we developed was efficient and required very little resource, and could be replicated by trialists in the future.Trial registration number ISRCTN83290762; Post-results.

Objectives To determine any change in referral patterns and outcomes in children (0–18) referred for child protection medical examination (CPME) during the COVID-19 pandemic compared with previous years.Design Retrospective observational study, analysing routinely collected clinical data from CPME reports in a rapid response to the pandemic lockdown.Setting Birmingham Community Healthcare NHS Trust, which provides all routine CPME for Birmingham, England, population 1.1 million including 288 000 children.Participants Children aged under 18 years attending CPME during an 18-week period from late February to late June during the years 2018–2020.Main outcome measures Numbers of referrals, source of disclosure and outcomes from CPME.Results There were 78 CPME referrals in 2018, 75 in 2019 and 47 in 2020, this was a 39.7% (95% CI 12.4% to 59.0%) reduction in referrals from 2018 to 2020, and a 37.3% (95% CI 8.6% to 57.4%) reduction from 2019 to 2020. There were fewer CPME referrals initiated by school staff in 2020, 12 (26%) compared with 36 (47%) and 38 (52%) in 2018 and 2019, respectively. In all years 75.9% of children were known to social care prior to CPME, and 94% of CPME concluded that there were significant safeguarding concerns.Conclusions School closure due to COVID-19 may have harmed children as child abuse has remained hidden. There needs to be either mandatory attendance at schools in future or viable alternatives found. There may be a significant increase in safeguarding referrals when schools fully reopen as children disclose the abuse they have experienced at home.

BackgroundLarge sample sizes are often required to detect statistically significant associations between pharmacogenetic markers and treatment response. Meta-analysis may be performed to synthesize data from several studies, increasing sample size and, consequently, power to detect significant genetic effects. However, performing robust synthesis of data from pharmacogenetic studies is often challenging because of poor reporting of key data in study reports. There is currently no guideline for the reporting of pharmacogenetic studies that has been developed using a widely accepted robust methodology. The objective of this project was to develop the STrengthening the Reporting Of Pharmacogenetic Studies (STROPS) guideline.Methods and findingsWe established a preliminary checklist of reporting items to be considered for inclusion in the guideline. We invited representatives of key stakeholder groups to participate in a 2-round Delphi survey. A total of 52 individuals participated in both rounds of the survey, scoring items with regards to their importance for inclusion in the STROPS guideline. We then held a consensus meeting, at which 8 individuals considered the results of the Delphi survey and voted on whether each item ought to be included in the final guideline. The STROPS guideline consists of 54 items and is accompanied by an explanation and elaboration document. The guideline contains items that are particularly important in the field of pharmacogenetics, such as the drug regimen of interest and whether adherence to treatment was accounted for in the conducted analyses. The guideline also requires that outcomes be clearly defined and justified, because in pharmacogenetic studies, there may be a greater number of possible outcomes than in other types of study (for example, disease-gene association studies). A limitation of this project is that our consensus meeting involved a small number of individuals, the majority of whom are based in the United Kingdom.ConclusionsOur aim is for the STROPS guideline to improve the transparency of reporting of pharmacogenetic studies and also to facilitate the conduct of high-quality systematic reviews and meta-analyses. We encourage authors to adhere to the STROPS guideline when publishing pharmacogenetic studies.

Serious concerns about the way research is organized collectively are increasingly being raised. They include the escalating costs of research and lower research productivity, low public trust in researchers to report the truth, lack of diversity, poor community engagement, ethical concerns over research practices, and irreproducibility. Open science (OS) collaborations comprise of a subset of open practices including open access publication, open data sharing and the absence of restrictive intellectual property rights with which institutions, firms, governments and communities are experimenting in order to overcome these concerns. We gathered two groups of international representatives from a large variety of stakeholders to construct a toolkit to guide and facilitate data collection about OS and non-OS collaborations. Ultimately, the toolkit will be used to assess and study the impact of OS collaborations on research and innovation. The toolkit contains the following four elements: 1) an annual report form of quantitative data to be completed by OS partnership administrators; 2) a series of semi-structured interview guides of stakeholders; 3) a survey form of participants in OS collaborations; and 4) a set of other quantitative measures best collected by other organizations, such as research foundations and governmental or intergovernmental agencies. We opened our toolkit to community comment and input. We present the resulting toolkit for use by government and philanthropic grantors, institutions, researchers and community organizations with the aim of measuring the implementation and impact of OS partnership across these organizations. We invite these and other stakeholders to not only measure, but to share the resulting data so that social scientists and policy makers can analyse the data across projects.

Abstract Prostate cancer is the most common cancer among western men, with a significant mortality and morbidity reported for advanced metastatic disease. Current understanding of metastatic disease is limited due to difficulty of sampling as prostate cancer mainly metastasizes to bone. By analysing prostate cancer bone metastases using high density microarrays, we found a common genomic copy number loss at 6q16.1–16.2, containing the FBXL4 gene, which was confirmed in larger series of bone metastases by fluorescence in situ hybridisation (FISH). Loss of FBXL4 was also detected in primary tumours and it was highly associated with prognostic factors including high Gleason score, clinical stage, prostate-specific antigen (PSA) and extent of disease, as well as poor patient survival, suggesting that FBXL4 loss contributes to prostate cancer progression. We also demonstrated that FBXL4 deletion is detectable in circulating tumour cells (CTCs), making it a potential prognostic biomarker by ‘liquid biopsy’. In vitro analysis showed that FBXL4 plays a role in regulating the migration and invasion of prostate cancer cells. FBXL4 potentially controls cancer metastasis through regulation of ERLEC1 levels. Therefore, FBXL4 could be a potential novel prostate cancer suppressor gene, which may prevent cancer progression and metastasis through controlling cell invasion.

Background: Patients with chronic diseases such as Type 2 diabetes mellitus (DM) usually have a relatively poor quality of life (QoL), because the cost of care (living expenses and health) or diet restrictions are heavily felt by these patients, and this is of a public health concern. However, limited data on DM QoL exist in Ghana and Nigeria. This makes it imperative for data to be collated in that regard. Materials and Methods: We adopted the Strengthening The reporting of observational studies in epidemiology (STROBE) consensus checklist to survey the patients with DM seen at the diabetic clinic at the Department of Medicine of the Korle-Bu Teaching Hospital and University College Hospital, Ibadan, Nigeria. Patients with Type 2 DM aged 40 years and older were recruited by using systematic random sampling method. The World Health Organization Quality of Life-BREF, diabetes empowerment scale, and DM knowledge scale were used to assess QoL, patient empowerment, and knowledge of DM, respectively. The predictors of QoL were determined using multiple linear regression analyses. Results: A total of 198 patients in Ghana and 203 patients in Nigeria completed the survey, with female-to-male ratio being 3:1 and 2:1, respectively. The overall QoL in both countries was relatively low: 56.19 ± 8.23 in Ghana and 64.34 ± 7.34 in Nigeria. In Ghana, significant correlates of higher scores on the QoL scale were medication adherence (P = 0.02) and employment status (P = 0.02). Among patients in Nigeria, employment status (P = 0.02) and DM empowerment (0.03) were significant predictors of QoL in patients with DM. Conclusion: Our study revealed an association between a number of psychosocial factors and QoL among patients with DM in Ghana and Nigeria.

BackgroundPhysical and cognitive impairments are important risk factors for falls in older people. However, no studies have been adequately powered to examine whether cognitive or cognitive-motor training can prevent falls in older people. This is despite good evidence of improvements in fall-related cognitive and physical functions following both intervention types. This manuscript describes the study protocol for a three-arm randomised controlled trial to evaluate the effectiveness of home-based cognitive and cognitive-motor training interventions, compared to a minimal-intervention control group, in preventing falls in older people. This trial was prospectively registered with the Australia New Zealand Clinical Trial Registry, number ACTRN12616001325493.Methods and analysisCommunity-dwelling adults aged 65 years and over, residing in Sydney Australia, will be recruited. Participants (n=750) will be randomly allocated to (1) cognitive-only training, (2) cognitive-motor training or (3) control groups. Both training interventions involve the use of the smart±step home-based computerised game playing system for a recommended 120 min/week for 12 months. Cognitive training group participants will use a desktop electronic touch pad to play games with the smart±step system while seated and using both hands. The cognitive-motor training group participants will use a wireless electronic floor step mat that requires accurate stepping using both legs for playing the same smart±step games, hence incorporating balance exercises. All groups will receive an education booklet on fall prevention. The primary outcome will be rate of falls, reported by monthly diaries during the 12-month duration of the study and analysis will be by intention-to-treat. Secondary outcomes include the proportion of fallers, physical and cognitive performance in 300 participants, and brain structure and function in 105 participants who will undertake MRI scans at baseline and 6 months. Cost-effectiveness will be determined using intervention and health service costs.Ethics and disseminationEthical approval was obtained from UNSW Ethics Committee in September 2015 (ref number HC15203). Outcomes will be disseminated through publication in peer-reviewed journals and presentations at international conferences.Trial registration numberACTRN12616001325493

BACKGROUND:Poor access to care and physician shortage are major barriers to hypertension control in sub-Saharan Africa. Implementation of evidence-based systems-level strategies targeted at these barriers are lacking. We conducted a study to evaluate the comparative effectiveness of provision of health insurance coverage (HIC) alone versus a nurse-led task shifting strategy for hypertension control (TASSH) plus HIC on systolic blood pressure (SBP) reduction among patients with uncontrolled hypertension in Ghana. METHODS AND FINDINGS:Using a pragmatic cluster randomized trial, 32 community health centers within Ghana's public healthcare system were randomly assigned to either HIC alone or TASSH + HIC. A total of 757 patients with uncontrolled hypertension were recruited between November 28, 2012, and June 11, 2014, and followed up to October 7, 2016. Both intervention groups received health insurance coverage plus scheduled nurse visits, while TASSH + HIC comprised cardiovascular risk assessment, lifestyle counseling, and initiation/titration of antihypertensive medications for 12 months, delivered by trained nurses within the healthcare system. The primary outcome was change in SBP from baseline to 12 months. Secondary outcomes included lifestyle behaviors and blood pressure control at 12 months and sustainability of SBP reduction at 24 months. Of the 757 patients (389 in the HIC group and 368 in the TASSH + HIC group), 85% had 12-month data available (60% women, mean BP 155.9/89.6 mm Hg). In intention-to-treat analyses adjusted for clustering, the TASSH + HIC group had a greater SBP reduction (-20.4 mm Hg; 95% CI -25.2 to -15.6) than the HIC group (-16.8 mm Hg; 95% CI -19.2 to -15.6), with a statistically significant between-group difference of -3.6 mm Hg (95% CI -6.1 to -0.5; p = 0.021). Blood pressure control improved significantly in both groups (55.2%, 95% CI 50.0% to 60.3%, for the TASSH + HIC group versus 49.9%, 95% CI 44.9% to 54.9%, for the HIC group), with a non-significant between-group difference of 5.2% (95% CI -1.8% to 12.4%; p = 0.29). Lifestyle behaviors did not change appreciably in either group. Twenty-one adverse events were reported (9 and 12 in the TASSH + HIC and HIC groups, respectively). The main study limitation is the lack of cost-effectiveness analysis to determine the additional costs and benefits, if any, of the TASSH + HIC group. CONCLUSIONS:Provision of health insurance coverage plus a nurse-led task shifting strategy was associated with a greater reduction in SBP than provision of health insurance coverage alone, among patients with uncontrolled hypertension in Ghana. Future scale-up of these systems-level strategies for hypertension control in sub-Saharan Africa requires a cost-benefit analysis. TRIAL REGISTRATION:ClinicalTrials.gov NCT01802372.

Globally, epilepsy is a common serious brain disorder. In addition to seizure activity, epilepsy is associated with cognitive impairments including static cognitive impairments present at onset, progressive seizure-induced impairments and co-morbid dementia. Epilepsy occurs naturally in domestic dogs but its impact on canine cognition has yet to be studied, despite canine cognitive dysfunction (CCD) recognised as a spontaneous model of dementia. Here we use data from a psychometrically validated tool, the canine cognitive dysfunction rating (CCDR) scale, to compare cognitive dysfunction in dogs diagnosed with idiopathic epilepsy (IE) with controls while accounting for age. An online cross-sectional study resulted in a sample of 4051 dogs, of which n = 286 had been diagnosed with IE. Four factors were significantly associated with a diagnosis of CCD (above the diagnostic cut-off of CCDR ≥50): (i) epilepsy diagnosis: dogs with epilepsy were at higher risk; (ii) age: older dogs were at higher risk; (iii) weight: lighter dogs (kg) were at higher risk; (iv) training history: dogs with more exposure to training activities were at lower risk. Impairments in memory were most common in dogs with IE, but progression of impairments was not observed compared to controls. A significant interaction between epilepsy and age was identified, with IE dogs exhibiting a higher risk of CCD at a young age, while control dogs followed the expected pattern of low-risk throughout middle age, with risk increasing exponentially in geriatric years. Within the IE sub-population, dogs with a history of cluster seizures and high seizure frequency had higher CCDR scores. The age of onset, nature and progression of cognitive impairment in the current IE dogs appear divergent from those classically seen in CCD. Longitudinal monitoring of cognitive function from seizure onset is required to further characterise these impairments.

BACKGROUND:ATCC HIV-1 drug resistance test kit was designed to detect HIV-1 drug resistance (HIVDR) mutations in the protease and reverse transcriptase genes for all HIV-1 group M subtypes and circulating recombinant forms. The test has been validated for both plasma and dried blood spot specimen types with viral load (VL) of ≥1000 copies/ml. We performed an in-country assessment on the kit to determine the genotyping sensitivity and its accuracy in detecting HIVDR mutations using plasma samples stored under suboptimal conditions. METHODS:Among 572 samples with VL ≥1000 copies/ml that had been genotyped by ViroSeq assay, 183 were randomly selected, including 85 successful genotyped and 98 unsuccessful genotyped samples. They were tested with ATCC kits following the manufacturer's instructions. Sequence identity and HIVDR patterns were analysed with Stanford University HIV Drug Resistance HIVdb program. RESULTS:Of the 183 samples, 127 (69.4%) were successfully genotyped by either method. While ViroSeq system genotyped 85/183 (46.5%) with median VL of 32,971 (IQR: 11,150-96,506) copies/ml, ATCC genotyped 115/183 (62.8%) samples with median VL of 23,068 (IQR: 7,397-86,086) copies/ml. Of the 98 unsuccessful genotyped samples with ViroSeq assay, 42 (42.9%) samples with lower median VL of 13,906 (IQR: 6,122-72,329) copies/ml were successfully genotyped using ATCC. Sequence identity analysis revealed that the sequences generated by both methods were >98% identical and yielded similar HIVDR profiles at individual patient level. CONCLUSION:This study confirms that ATCC kit showed greater sensitivity in genotyping plasma samples stored in suboptimal conditions experiencing frequent and prolonged power outage. Thus, it is more sensitive particularly for subtypes A and A/G HIV-1 in resource-limited settings.

Modified Vaccinia Ankara (MVA) is a live, viral vaccine under advanced development as a non-replicating smallpox vaccine. A randomised, double-blind, placebo-controlled phase III clinical trial was conducted to demonstrate the humoral immunogenic equivalence of three consecutively manufactured MVA production lots, and to confirm the safety and tolerability of MVA focusing on cardiac readouts.The trial was conducted at 34 sites in the US. Vaccinia-naïve adults aged 18-40 years were randomly allocated to one of four groups using a 1:1:1:1 randomization scheme. Subjects received either two MVA injections from three consecutive lots (Groups 1-3), or two placebo injections (Group 4), four weeks apart. Everyone except personnel involved in vaccine handling and administration was blinded to treatment. Safety assessment focused on cardiac monitoring throughout the trial. Vaccinia-specific antibody titers were measured using a Plaque Reduction Neutralization Test (PRNT) and an Enzyme-Linked Immunosorbent Assay (ELISA). The primary immunogenicity endpoint was Geometric Mean Titers (GMTs) after two MVA vaccinations measured by PRNT at trial visit 4. This trial is registered with ClinicalTrials.gov, number NCT01144637.Between March 2013 and May 2014, 4005 subjects were enrolled and received at least one injection of MVA (n = 3003) or placebo (n = 1002). The three MVA lots induced equivalent antibody titers two weeks after the second vaccination, with seroconversion rates of 99·8% (PRNT) and 99·7% (ELISA). Overall, 180 (6·0%) subjects receiving MVA and 29 (2·9%) subjects in the placebo group reported at least one unsolicited Adverse Event (AE) that was considered trial-related. Vaccination was well tolerated without significant safety concerns, particularly regarding cardiac assessment.The neutralizing and total antibody titers induced by each of the three lots were equivalent. No significant safety concerns emerged in this healthy trial population, especially regarding cardiac safety, thus confirming the excellent safety and tolerability profile of MVA.ClinicalTrials.gov NCT01144637.

An altered intestinal microbiota composition has been implicated in the pathogenesis of metabolic disease including obesity and type 2 diabetes mellitus (T2DM). Low grade inflammation, potentially initiated by the intestinal microbiota, has been suggested to be a driving force in the development of insulin resistance in obesity. Here, we report that bacterial DNA is present in mesenteric adipose tissue of obese but otherwise healthy human subjects. Pyrosequencing of bacterial 16S rRNA genes revealed that DNA from the Gram-negative species Ralstonia was most prevalent. Interestingly, fecal abundance of Ralstonia pickettii was increased in obese subjects with pre-diabetes and T2DM. To assess if R. pickettii was causally involved in development of obesity and T2DM, we performed a proof-of-concept study in diet-induced obese (DIO) mice. Compared to vehicle-treated control mice, R. pickettii-treated DIO mice had reduced glucose tolerance. In addition, circulating levels of endotoxin were increased in R. pickettii-treated mice. In conclusion, this study suggests that intestinal Ralstonia is increased in obese human subjects with T2DM and reciprocally worsens glucose tolerance in DIO mice.

Background: Two classes of amine oxidases are found in mammals: those with a flavin adenine dinucleotide as a cofactor, such as monoamine oxidases (MAO) and lysine-specific demethylases (LSD), and those with copper as a cofactor, including copper-containing amine oxidases (AOC) and lysyl oxidases (LOX). All are expressed in adipose tissue, including a semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1) strongly present on the adipocyte surface. Methods: Previously, irreversible MAO inhibitors have been reported to limit food intake and/or fat extension in rodents; however, their use for the treatment of depressed patients has not revealed a clear anti-obesity action. Semicarbazide and other molecules inhibiting SSAO/VAP-1 also reduce adiposity in obese rodents. Results: Recently, a LOX inhibitor and a subtype-selective MAO inhibitor have been shown to limit fattening in high-fat diet-fed rats. Phenelzine, which inhibits MAO and AOC, limits adipogenesis in cultured preadipocytes and impairs lipogenesis in mature adipocytes. When tested in rats or mice, phenelzine reduces food intake and/or fat accumulation without cardiac adverse effects. Novel amine oxidase inhibitors have been recently characterized in a quest for promising anti-inflammatory or anti-cancer approaches; however, their capacity to mitigate obesity has not been studied so far. Conclusions: The present review of the diverse effects of amine oxidase inhibitors impairing adipocyte differentiation or limiting excessive fat accumulation indicates that further studies are needed to reveal their potential anti-obesity properties.

2013 marks a milestone year for plasmid DNA vaccine development as a first-in-class cytomegalovirus (CMV) DNA vaccine enters pivotal phase 3 testing. This vaccine consists of two plasmids expressing CMV antigens glycoprotein B (gB) and phosphoprotein 65 (pp65) formulated with a CRL1005 poloxamer and benzalkonium chloride (BAK) delivery system designed to enhance plasmid expression. The vaccine’s planned initial indication under investigation is for prevention of CMV reactivation in CMV-seropositive (CMV+) recipients of an allogeneic hematopoietic stem cell transplant (HCT). A randomized, double-blind placebo-controlled phase 2 proof-of-concept study provided initial evidence of the safety of this product in CMV+ HCT recipients who underwent immune ablation conditioning regimens. This study revealed a significant reduction in viral load endpoints and increased frequencies of pp65-specific interferon-γ-producing T cells in vaccine recipients compared to placebo recipients. The results of this endpoint-defining trial provided the basis for defining the primary and secondary endpoints of a global phase 3 trial in HCT recipients. A case study is presented here describing the development history of this vaccine from product concept to initiation of the phase 3 trial.

Sustainability is a key challenge for humanity in the 21st century. Ecosystem services—the benefits that people derive from nature and natural capital—is a concept often used to help explain human reliance on nature and frame the decisions we make in terms of the ongoing value of nature to human wellbeing. Yet ecosystem service science has not always lived up to the promise of its potential. Despite advances in the scientific literature, ecosystem service science has not yet answered some of the most critical questions posed by decision-makers in the realm of sustainability. Here, we explore the history of ecosystem service science, discuss advances in conceptualization and measurement, and point toward further work needed to improve the use of ecosystem service in decisions about sustainable development.

Objectives To audit patient hospital records to evaluate the performance of acute general and mental health services in delivering inpatient care to people with learning disability and explore the influence of organisational factors on the quality of care they deliver.Setting Nine acute general hospital Trusts and six mental health services.Participants Adults with learning disability who received inpatient hospital care between May 2013 and April 2014.Primary and secondary outcome measures Data on seven key indicators of high-quality care were collected from 176 patients. These covered physical health/monitoring, communication and meeting needs, capacity and decision-making, discharge planning and carer involvement. The impact of services having an electronic system for flagging patients with learning disability and employing a learning disability liaison nurse was assessed.Results Indicators of physical healthcare (body mass index, swallowing assessment, epilepsy risk assessment) were poorly recorded in acute general and mental health inpatient settings. Overall, only 34 (19.3%) patients received any assessment of swallowing and 12 of the 57 with epilepsy (21.1%) had an epilepsy risk assessment. For most quality indicators, there was a non-statistically significant trend for improved performance in services with a learning disability liaison nurse. The presence of an electronic flagging system showed less evidence of benefit.Conclusions Inpatient care for people with learning disability needs to be improved. The work gives tentative support to the role of a learning disability liaison nurse in acute general and mental health services, but further work is needed to confirm these benefits and to trial other interventions that might improve the quality and safety of care for this high-need group.

Introduction An increasing number of people are living with multimorbidity. The evidence base for how best to manage these patients is weak. Current clinical guidelines generally focus on single conditions, which may not reflect the needs of patients with multimorbidity. The aim of the 3D study is to develop, implement and evaluate an intervention to improve the management of patients with multimorbidity in general practice.Methods and analysis This is a pragmatic two-arm cluster randomised controlled trial. 32 general practices around Bristol, Greater Manchester and Glasgow will be randomised to receive either the ‘3D intervention’ or usual care. 3D is a complex intervention including components affecting practice organisation, the conduct of patient reviews, integration with secondary care and measures to promote change in practice organisation. Changes include improving continuity of care and replacing reviews of each disease with patient-centred reviews with a focus on patients' quality of life, mental health and polypharmacy. We aim to recruit 1383 patients who have 3 or more chronic conditions. This provides 90% power at 5% significance level to detect an effect size of 0.27 SDs in the primary outcome, which is health-related quality of life at 15 months using the EQ-5D-5L. Secondary outcome measures assess patient centredness, illness burden and treatment burden. The primary analysis will be a multilevel regression model adjusted for baseline, stratification/minimisation, clustering and important co-variables. Nested process evaluation will assess implementation, mechanisms of effectiveness and interaction of the intervention with local context. Economic analysis of cost-consequences and cost-effectiveness will be based on quality-adjusted life years.Ethics and dissemination This study has approval from South-West (Frenchay) National Health Service (NHS) Research Ethics Committee (14/SW/0011). Findings will be disseminated via final report, peer-reviewed publications and guidance to healthcare professionals, commissioners and policymakers.Trial registration number ISRCTN06180958; Pre-results.

Since plant mating choices are flexible and responsive to the environment, rates of spontaneous hybridization may vary across ecological clines. Developing a robust and predictive framework for rates of plant gene flow requires assessing the role of environmental sensitivity on plant reproductive traits, relative abundance, and pollen vectors. Therefore, across a soil moisture gradient, we quantified pollinator movement, life-history trait variation, and unidirectional hybridization rates from crop (Raphanus sativus) to wild (Raphanus raphanistrum) radish populations. Both radish species were grown together in relatively dry (no rain), relatively wet (double rain), or control soil moisture conditions in Ohio, USA. We measured wild and crop radish life-history, phenology and pollinator visitation patterns. To quantify hybridization rates from crop-to-wild species, we used a simply inherited morphological marker to detect F1 hybrid progeny. Although crop-to-wild hybridization did not respond to watering treatments, the abundance of hybrid offspring was higher in fruits produced late in the period of phenological overlap, when both species had roughly equal numbers of open flowers. Therefore, the timing of fruit production and its relationship to flowering overlap may be more important to hybrid zone formation in Raphanus spp. than soil moisture or pollen vector movements.

BACKGROUND:Modified Vaccinia Ankara MVA-BN® is a live, highly attenuated, viral vaccine under advanced development as a non-replicating smallpox vaccine. In this Phase II trial, the safety and immunogenicity of Modified Vaccinia Ankara MVA-BN® (MVA) was assessed in a 56-80 years old population. METHODS:MVA with a virus titer of 1 x 108 TCID50/dose was administered via subcutaneous injection to 56-80 year old vaccinia-experienced subjects (N = 120). Subjects received either two injections of MVA (MM group) or one injection of Placebo and one injection of MVA (PM group) four weeks apart. Safety was evaluated by assessment of adverse events (AE), focused physical exams, electrocardiogram recordings and safety laboratories. Solicited AEs consisted of a set of pre-defined expected local reactions (erythema, swelling, pain, pruritus, and induration) and systemic symptoms (body temperature, headache, myalgia, nausea and fatigue) and were recorded on a memory aid for an 8-day period following each injection. The immunogenicity of the vaccine was evaluated in terms of humoral immune responses measured with a vaccinia-specific enzyme-linked immunosorbent assay (ELISA) and a plaque reduction neutralization test (PRNT) before and at different time points after vaccination. RESULTS:Vaccinations were well tolerated by all subjects. No serious adverse event related to MVA and no case of myopericarditis was reported. The overall incidence of unsolicited AEs was similar in both groups. For both groups immunogenicity responses two weeks after the final vaccination (i.e. Visit 4) were as follows: Seroconversion (SC) rates (doubling of titers from baseline) in vaccine specific antibody titers measured by ELISA were 83.3% in Group MM and 82.8% in Group PM (difference 0.6% with 95% exact CI [-13.8%, 15.0%]), and 90.0% for Group MM and 77.6% for Group PM measured by PRNT (difference 12.4% with 95% CI of [-1.1%, 27.0%]). Geometric mean titers (GMT) measured by ELISA two weeks after the final vaccination for Group MM were 804.1 and 605.8 for Group PM (with ratio of GMTs of 1.33 with 95% CI of [0.96, 1.84]). Similarly, GMTs measured by PRNT were 210.3 for Group MM and 126.7 for Group PM (with ratio 1.66 and 95% CI [0.95, 2.90]). CONCLUSIONS:One or two doses of MVA were safe and immunogenic in a 56-80 years old vaccinia-experienced population. No cases of myopericarditis were observed following vaccinations with MVA. The safety, reactogenicity and immunogenicity were similar to that seen in younger (18-55 year old) healthy populations as investigated in other MVA trials. The results suggest that a single dose of MVA in a 56-80 years old population was well tolerated and sufficient to rapidly boost the long-term B cell memory response induced by a prior vaccination with a traditional smallpox vaccine. TRIAL REGISTRATION:ClinicalTrials.gov NCT00857493.

To investigate the possibility of oral transmission of atypical scrapie in sheep and determine the distribution of infectivity in the animals’ peripheral tissues, we challenged neonatal lambs orally with atypical scrapie; they were then killed at 12 or 24 months. Screening test results were negative for disease-specific prion protein in all but 2 recipients; they had positive results for examination of brain, but negative for peripheral tissues. Infectivity of brain, distal ileum, and spleen from all animals was assessed in mouse bioassays; positive results were obtained from tissues that had negative results on screening. These findings demonstrate that atypical scrapie can be transmitted orally and indicate that it has the potential for natural transmission and iatrogenic spread through animal feed. Detection of infectivity in tissues negative by current surveillance methods indicates that diagnostic sensitivity is suboptimal for atypical scrapie, and potentially infectious material may be able to pass into the human food chain.

The interactions of host and infecting strain in ovine transmissible spongiform encephalopathies are known to be complex, and have a profound effect on the resulting phenotype of disease. In contrast to classical scrapie, the pathology in naturally-occurring cases of atypical scrapie appears more consistent, regardless of genotype, and is preserved on transmission within sheep homologous for the prion protein (PRNP) gene. However, the stability of transmissible spongiform encephalopathy phenotypes on passage across and within species is not absolute, and there are reports in the literature where experimental transmissions of particular isolates have resulted in a phenotype consistent with a different strain. In this study, intracerebral inoculation of atypical scrapie between two genotypes both associated with susceptibility to atypical forms of disease resulted in one sheep displaying an altered phenotype with clinical, pathological, biochemical and murine bioassay characteristics all consistent with the classical scrapie strain CH1641, and distinct from the atypical scrapie donor, while the second sheep did not succumb to challenge. One of two sheep orally challenged with the same inoculum developed atypical scrapie indistinguishable from the donor. This study adds to the range of transmissible spongiform encephalopathy phenotype changes that have been reported following various different experimental donor-recipient combinations. While these circumstances may not arise through natural exposure to disease in the field, there is the potential for iatrogenic exposure should current disease surveillance and feed controls be relaxed. Future sheep to sheep transmission of atypical scrapie might lead to instances of disease with an alternative phenotype and onward transmission potential which may have adverse implications for both public health and animal disease control policies.

The gastrointestinal tract constitutes a physiological interface integrating nutrient and microbiota-host metabolism. Conjugated linoleic acids (CLA) have been reported to contribute to decreased body weight and fat accretion. The modulation by dietary CLA of stomach proteins related to energy homeostasis or microbiota may be involved, although this has not been previously analysed. This is examined in the present study, which aims to underline the potential mechanisms of CLA which contribute to body weight regulation. Adult mice were fed either a normal fat (NF, 12% kJ content as fat) or a high-fat (HF, 43% kJ content as fat) diet. In the latter case, half of the animals received daily oral supplementation of CLA. Expression and content of stomach proteins and specific bacterial populations from caecum were analysed. CLA supplementation was associated with an increase in stomach protein expression, and exerted a prebiotic action on both Bacteroidetes/Prevotella and Akkermansia muciniphila. However, CLA supplementation was not able to override the negative effects of HF diet on Bifidobacterium spp., which was decreased in both HF and HF+CLA groups. Our data show that CLA are able to modulate stomach protein expression and exert a prebiotic effect on specific gut bacterial species.

Replicating smallpox vaccines can cause severe complications in individuals with atopic dermatitis (AD). Prior studies evaluating Modified Vaccinia Ankara virus (MVA), a non-replicating vaccine in humans, showed a favorable safety and immunogenicity profile in healthy volunteers.This Phase II study compared the safety and immunogenicity of MVA enrolling groups of 350 subjects with AD (SCORAD ≤ 30) and 282 healthy subjects.Subjects were vaccinated twice with MVA, each dose given subcutaneously 4 weeks apart. Adverse events, cardiac parameters, and the development of vaccinia virus humoral immune responses were monitored.The overall safety of the vaccine was similar in both groups. Adverse events affecting skin were experienced significantly more often in subjects with AD, but the majority of these events were mild to moderate in intensity. Seroconversion rates and geometric mean titers for total and neutralizing vaccinia-specific antibodies in the AD group were non-inferior compared to the healthy subjects.The size of the study population limited the detection of serious adverse events occurring at a frequency less than 1%.MVA has a favorable safety profile and the ability to elicit vaccinia-specific immune responses in subjects with AD.ClinicalTrials.gov NCT00316602.