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Objectives: Functional defecation disorders (FDDs) are common among children worldwide. The prevalence of these disorders has not been clearly described in Europe. This study performed a systematic review and meta-analysis on the prevalence of FDD in European children and assessed geographical, age, and sex distribution and associated factors., Methods: PubMed, Embase, Psycinfo, Cochrane Library, and Cinahl were searched from 1999 to July 2023. Included studies were (1) prospective or cross-sectional studies of European population-based samples; (2) reporting the prevalence of infant dyschezia (ID) according to Rome II, III, or IV criteria or functional constipation (FC) or functional non-retentive fecal incontinence (FNRFI) according to Rome III or IV criteria; (3) aged 0-18 years; and (4) published in English, Dutch or Spanish. PRISMA guidelines for extracting data and assessing data quality were followed., Results: Twenty-eight studies were included. Pooled prevalence was 6.9% (95% confidence interval [CI]: 3.1%-11.9%) for ID in infants 0-12 months (9 studies, n = 5611), 8.17% (95% CI: 6.33%-10.22%) for FC in children <4 years (25 studies, n = 35,189), 11.39% (95% CI: 9.34%-14.11%) for FC in children 4-18 years, and 0.24% (95% CI: 0.07%-0.49%) for FNRFI in children 4-18 years (7 studies, n = 16,873). No sex predominance was found for FC. FC prevalence did not differ significantly when diagnosed according to Rome III versus IV. FC prevalence differed between countries, with greatest rates in Italy, Germany, and Spain. No meta-analysis could be performed on other factors associated with FDD., Conclusions: FDD is common in European children. Future longitudinal studies are needed to provide better insight into associated factors in pathogenesis., (© 2025 The Author(s). Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Addressing loneliness, which is associated with poor mental and physical health, implicates the need for connectivity to a broad set of situated relationships and activities in the contexts of people's everyday lives. Social engagement has been identified as a relevant psychosocial mechanism mediating health and wellness and is central to addressing loneliness. The aim here is to explore the way in which people identified as lonely conceptualise their experiences of loneliness and social engagement for the purposes of incorporating these into the design and workings of an intervention that allows people to map their social networks and connect them to community-based valued activities., Methods: Semi-structured qualitative interviews were undertaken with 20 participants, aged 21-82 years old (mean age 59.7) nested within a pragmatic, community-based randomised controlled trial in the north and south of England. Participants had wide-ranging social network sizes (from 1 to 10 individuals) and reported variable impact of loneliness on their lives., Results: Loneliness consisted as an absence of intimacy in the face of being surrounded by others, a sense of entrapment and boredom, lacking access to meaningful activities and difficulties in relating to others. The analysis highlighted the role that important relationships have in mediating loneliness. Individual readiness, skills and confidence in forming new connections and engaging with new activities are important barriers that exist in overcoming loneliness. For many, wider socio-political factors, such as transport provision, availability of resources and costs associated with social engagement are also important barriers which are difficult to overcome., Implications: Exploring the link between feelings, experiences and meaning of loneliness and the way in which a network intervention can be incorporated offers a focus for mediating the richness and opportunities that arise from locality-based connections and collective activities in the broader social environment. However, any intervention seeking to address loneliness requires a further focus on both individual and relational factors which might contribute to addressing loneliness and increasing a sense of wellness., Patient or Public Contribution: The study team worked closely with community partner organisations in all aspects of this research, including, the submission of the funding proposal, development of the study protocol and procedures, recruitment, intervention deployment and assessment of implementation. PPI representatives provided advice on participant materials and interview schedules, and project management throughout and contributed to management and steering committee meetings., (© 2024 The Author(s). Health Expectations published by John Wiley & Sons Ltd.)

Background: Acrylate polymers and cross-polymers (ACPs) are frequently used cosmetic ingredients. The British Society for Cutaneous Allergy (BSCA) and the UK Cosmetic, Toiletry and Perfumery Association (CTPA) collaborated to investigate the allergenic potential of three commonly-used ACPs., Objectives: The objective of this study is to determine the prevalence of allergic contact dermatitis (ACD) to three ACPs: glyceryl acrylate/acrylic acid co-polymer, sodium polyacrylate, and acrylates/C10-30 alkyl acrylate cross-polymer (Carbopol®)., Materials and Methods: The BSCA prospectively audited data collected from 20 centres in the UK and Ireland between 1st September 2021 and 1st September 2022. Patients with suspected ACD to (meth)acrylates, with facial dermatitis, or consecutive patients, were patch tested to glyceryl acrylate/acrylic acid co-polymer 10% aqueous (aq.) sodium polyacrylate 2% aq., and to acrylates/C10-30 alkyl acrylate cross-polymer 2% aq. (Carbopol®). The frequencies of positive, irritant, and doubtful reactions were recorded., Results: In total, 1302 patients were patch tested. To glyceryl acrylate/acrylic acid co-polymer, there was one doubtful reaction in a patient allergic to multiple (meth)acrylates, and one irritant. To sodium polyacrylate, there were four irritant reactions, one doubtful, and one positive reaction; in all cases, relevance was unknown and there was no demonstrable (meth)acrylate allergy. There were no reactions to Carbopol®., Conclusions: Sensitisation to these concentrations of the three tested ACPs is rare. Elicitation of dermatitis in (meth)acrylate-sensitised patients by exposure to these three ACPs appears unlikely., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aims: The randomized, double-blind, placebo-controlled HOPE-HF trial assessed the benefit of atrio-ventricular (AV) delay optimization delivered using His bundle pacing. It recruited patients with left ventricular ejection fraction ≤40%, PR interval ≥200 ms, and baseline QRS ≤140 ms or right bundle branch block. Overall, there was no significant increase in peak oxygen uptake (VO 2 max) but there was significant improvement in heart failure specific quality of life. In this pre-specified secondary analysis, we evaluated the impact of baseline PR interval, echocardiographic E-A fusion, and the magnitude of acute high-precision haemodynamic response to pacing, on outcomes., Methods and Results: All 167 randomized participants underwent measurement of PR interval, acute haemodynamic response at optimized AV delay, and assessment of presence of E-A fusion. We tested the impact of these baseline parameters using a Bayesian ordinal model on VO 2 max, quality of life and activity measures. There was strong evidence of a beneficial interaction between the baseline acute haemodynamic response and the blinded benefit of pacing for VO 2 (Pr 99.9%), Minnesota Living With Heart Failure (MLWHF) (Pr 99.8%), MLWHF physical limitation score (Pr 98.9%), EQ-5D visual analogue scale (Pr 99.6%), and exercise time (Pr 99.4%). The baseline PR interval and the presence of baseline E-A fusion did not have this reliable ability to predict the clinical benefit of pacing over placebo across multiple endpoints., Conclusions: In the HOPE-HF trial, the acute haemodynamic response to pacing reliably identified patients who obtained clinical benefit. Patients with a long PR interval (≥200 ms) and left ventricular impairment who obtained acute haemodynamic improvement with AV-optimized His bundle pacing were likely to obtain clinical benefit, consistent across multiple endpoints. Importantly, this gradation can be reliably tested for before randomization, but does require high-precision AV-optimized haemodynamic assessment to be performed., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background and Purpose: Sudden unexpected death in epilepsy (SUDEP) is a leading cause of epilepsy mortality. All international guidance strongly advocates for clinicians working with people with epilepsy (PWE) to discuss SUDEP. Clinician views working with PWE in the UK and Norway on SUDEP counselling are compared., Methods: A cross-sectional online mixed methodology survey of 17 Likert and free-text response questions using validated themes was circulated via International League against Epilepsy/Epilepsy Specialist Nurses Association in the UK and International League against Epilepsy/Epilepsinet in Norway using a non-discriminatory exponential snowballing technique leading to non-probability sampling. Quantitative data were analysed using descriptive statistics and Mann-Whitney, Kruskal-Wallis, chi-squared and Fisher's exact tests. Significance was accepted at p < 0.05. Thematic analysis was conducted on free-text responses., Results: Of 309 (UK 197, Norway 112) responses, UK clinicians were more likely to have experienced an SUDEP (p < 0.001), put greater importance on SUDEP communication (p < 0.001), discuss SUDEP with all PWE particularly new patients (p < 0.001), have access and refer to bereavement support (p < 0.001) and were less likely to never discuss SUDEP (p < 0.001). Significant differences existed between both countries' neurologists and nurses in SUDEP counselling with UK clinicians generally being more supportive. UK responders were more likely to be able to identify bereavement support (p < 0.001). Thematic analysis highlighted four shared themes and two specific to Norwegians., Discussion: Despite all international guidelines stating the need/importance to discuss SUDEP with all PWE there remain hesitation, avoidance and subjectivity in clinicians having SUDEP-related conversations, more so in Norway than the UK. Training and education are required to improve communication, engagement and decision making., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Neurotrophic receptor tyrosine kinase (NTRK)-rearranged spindle cell neoplasms are a recently described group of soft tissue tumors. They commonly present as a painless mass on the extremities of children and young adults. They are characterized microscopically by a heterogeneous spectrum of infiltrative spindle cell proliferations, which can morphologically mimic several other spindle cell neoplasms. Their identification is vital, as they may be amenable to treatment with tyrosine kinase-targeted therapy. This case report describes a rare NTRK3-rearranged spindle cell neoplasm in the groin of a 29-year-old female and provides further clinical and morphological features of this entity., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: Expanding and sustaining student nurse placements outside of the acute sector is a universal challenge. This paper aims to evaluate the Care Home Education Facilitator Role introduced in one area of Wales, United Kingdom, and to report on the outcomes achieved from this novel role., Methods: Semi-structured interviews were undertaken with key stakeholders including the Care Home Education Facilitator postholder leading the pilot, care home managers, higher education institutions' placement managers/coordinators, student nurses and national health service staff., Results: Five key areas were identified, which included timing of introducing the post and establishing a clear rationale and understanding of the intention of the role. The benefits, challenges and suggested improvements to the Care Home Education Facilitator initiative are provided., Conclusion: Introducing the role of the Care Home Education Facilitator to work closely with key stakeholders resulted in increased placements for student nurses, but investing time in developing relationships with these stakeholders was critical to the success of the role., (© 2024 The Authors. International Journal of Nursing Practice published by John Wiley & Sons Australia, Ltd.)

Background and Purpose: Treatment persistence is the continuation of therapy over time. It reflects a combination of treatment efficacy and tolerability. We aimed to describe real-world rates of persistence on disease-modifying therapies (DMTs) for people with multiple sclerosis (pwMS) and reasons for DMT discontinuation., Methods: Treatment data on 4366 consecutive people with relapse-onset multiple sclerosis (MS) were pooled from 13 UK specialist centres during 2021. Inclusion criteria were exposure to at least one MS DMT and a complete history of DMT prescribing. PwMS in blinded clinical trials were excluded. Data collected included sex, age at MS onset, age at DMT initiation, DMT treatment dates, and reasons for stopping or switching DMT. For pwMS who had received immune reconstituting therapies (cladribine/alemtuzumab), discontinuation date was defined as starting an alternative DMT. Kaplan-Meier survival analyses were used to express DMT persistence., Results: In 6997 treatment events (1.6 per person with MS), median time spent on any single maintenance DMT was 4.3 years (95% confidence interval = 4.1-4.5 years). The commonest overall reasons for DMT discontinuation were adverse events (35.0%) and lack of efficacy (30.3%). After 10 years, 20% of people treated with alemtuzumab had received another subsequent DMT, compared to 82% of people treated with interferon or glatiramer acetate., Conclusions: Immune reconstituting DMTs may have the highest potential to offer a single treatment for relapsing MS. Comparative data on DMT persistence and reasons for discontinuation are valuable to inform treatment decisions and in personalizing treatment in MS., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Healthcare and support workers play a pivotal role in delivering quality services and support to people seeking sanctuary who have experienced poor physical and mental health linked to previous trauma, relocation and loss of freedoms. However, they often encounter various challenges in their daily work, ranging from communication barriers to resource constraints. This qualitative study seeks to delve into the perspectives of healthcare and support workers' experience of workarounds, employed to overcome barriers to providing care., Aim: This study aims to describe healthcare providers', practitioners' and health and third sector support workers' views on barriers and workarounds to providing care for people seeking sanctuary, to inform policy and practice., Design: A qualitative study was carried out using semi-structured telephone interviews., Setting: This study focused on primary, secondary, community and specialist National Health Service (NHS) support services for people seeking sanctuary in Wales, United Kingdom (2018)., Method: We interviewed 32 healthcare providers, practitioners and support workers employed by primary care and third sector organisations. Our approach involved obtaining verbal informed consent before digitally recording and transcribing all interviews. To analyse the data, we used the Four Levels of Change for Improving Quality model as a guiding framework for interpretation., Results: Our study findings reveal that certain respondents expressed challenges in meeting the needs of people seeking sanctuary; notably, their experience of delivering care differed by care settings. Specifically, those involved in providing specialist NHS care believed that there was room for improvement. Mainstream primary, secondary and community health practitioners faced limitations due to resource constraints and lacked tailored information to address the unique circumstances and needs of sanctuary seekers. To address these gaps, workarounds emerged at both individual and local levels (team/departmental and organisational level). These included establishing informal communication channels between providers, fostering cross service collaboration to fill gaps and adapting existing services to enhance accessibility., Conclusion: Understanding healthcare providers', practitioners' and support workers' perspectives offers invaluable insights into ways to enhance healthcare delivery to sanctuary seekers. Acknowledging challenges and harnessing innovative workarounds can foster a more effective and compassionate service for this vulnerable population., Patient or Public Contribution: The HEAR study actively involved public contributors in the design, delivery and dissemination of the research. Two public contributors (S. M. and G. R.) who had personal experience of seeking asylum served as study co-applicants. They played pivotal roles in shaping the research by participating in its development and securing funding. Alongside other co-applicants, S. M. and G. R. formed the Research Management Group, overseeing study delivery. Their contributions extended to strategic decision-making and specific feedback at critical junctures, including participant recruitment, data collection, analysis and reporting. Additionally, S. M. and G. R. were instrumental in recruiting and supporting a team of peer researchers, enhancing respondent participation among people seeking sanctuary. To facilitate effective public involvement, we provided named contacts for support (A. K. and R. F.), research training, honoraria, reimbursement of expenses and accessible information in line with best practice., (© 2024 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Past research suggests that reactions to research on sex differences are often less positive when the findings put men in a better light than women, especially when the lead researcher is a man. The factors underlying this effect, however, are not yet fully understood. The present study aimed to provide the first experimental test of the hypothesis that the key variable is perceived harm to women. Participants (214 men and 219 women) evaluated a bogus popular-science article reporting fictional research finding either a female- or a male-favouring sex difference in intelligence, attributed to either a female or a male lead researcher. To examine the effects of perceived harm, the introduction to the task highlighted either the potential benefits or potential drawbacks of sex-differences research in general. Consistent with past research, participants reacted less positively to the male-favouring difference, especially for male-led research. Consistent with the harm hypothesis, the effect was stronger after highlighting the potential drawbacks of sex-differences research than after highlighting the potential benefits. Our findings suggest that perceptions of harm to women underpin the aversion to male-favouring findings., (© 2024 International Union of Psychological Science.)

Voltage-clamp experiments are commonly utilised to characterise cellular ion channel kinetics. In these experiments, cells are stimulated using a known time-varying voltage, referred to as the voltage protocol, and the resulting cellular response, typically in the form of current, is measured. Parameters of models that describe ion channel kinetics are then estimated by solving an inverse problem which aims to minimise the discrepancy between the predicted response of the model and the actual measured cell response. In this paper, a novel framework to evaluate the information content of voltage-clamp protocols in relation to ion channel model parameters is presented. Additional quantitative information metrics that allow for comparisons among various voltage protocols are proposed. These metrics offer a foundation for future optimal design frameworks to devise novel, information-rich protocols. The efficacy of the proposed framework is evidenced through the analysis of seven voltage protocols from the literature. By comparing known numerical results for inverse problems using these protocols with the information-theoretic metrics, the proposed approach is validated. The essential steps of the framework are: (i) generate random samples of the parameters from chosen prior distributions; (ii) run the model to generate model output (current) for all samples; (iii) construct reduced-dimensional representations of the time-varying current output using proper orthogonal decomposition (POD); (iv) estimate information-theoretic metrics such as mutual information, entropy equivalent variance, and conditional mutual information using non-parametric methods; (v) interpret the metrics; for example, a higher mutual information between a parameter and the current output suggests the protocol yields greater information about that parameter, resulting in improved identifiability; and (vi) integrate the information-theoretic metrics into a single quantitative criterion, encapsulating the protocol's efficacy in estimating model parameters., (© 2024 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd.)

Background: This study aimed to evaluate medium to long-term outcomes following treatment of lameness associated with cranial cruciate ligament insufficiency using the tibial tuberosity advancement (TTA)-Rapid technique and to investigate risk factors associated with outcome, including tibial plateau angle (TPA)., Methods: Patient records for cases treated over an 80-month period were examined retrospectively. An owner postal questionnaire using a clinical metrology instrument (Liverpool Osteoarthritis in Dogs) evaluated the outcome at least 6 months after surgery., Results: A total of 149 procedures were carried out in 120 dogs. Questionnaires were received for 64 dogs (53.3%), with a median follow-up time of 37.5 months. Outcome was judged to be satisfactory, based on frequency of lameness, in 63 (98.4%), while satisfactory outcomes were achieved in 61 (95.3%) based on severity of lameness and in 50 (78.1%) based on mobility score. Statistical analysis showed that age, bodyweight, TPA, meniscal injury and concurrent patellar surgery did not influence outcome, but time to follow-up positively correlated with mobility score., Limitations: This study involved one surgeon in one centre with outcome data based on the completion of an owner questionnaire, although this used a validated clinical metrology instrument., Conclusion: TTA-Rapid offers a treatment option for cranial cruciate-deficient stifles with a good medium to long-term outcome, and no risk factors were identified to suggest any limitations to its use., (© 2024 British Veterinary Association.)

Introduction: People who call emergency ambulances frequently are often vulnerable because of health and social circumstances, have unresolved problems or cannot access appropriate care. They have higher mortality rates. Case management by interdisciplinary teams can help reduce demand for emergency services and is available in some UK regions. We report results of interviews with people who use emergency ambulance services frequently to understand their experiences of calling and receiving treatment., Methods: We used a two-stage recruitment process. A UK ambulance service identified six people who were known to them as frequently calling emergency services. Through third-sector organisations, we also recruited nine individuals with healthcare experiences reflecting the characteristics of people who call frequently. We gained informed consent to record and transcribe all telephone interviews. We used thematic analysis to explore the results., Results: People said they make frequent calls to emergency ambulance services as a last resort when they perceive their care needs are urgent and other routes to help have failed. Those with the most complex health needs generally felt their immediate requirements were not resolved and underlying mental and physical problems led them to call again. A third of respondents were also attended to by police and were arrested for behaviour associated with their health needs. Those callers receiving case management did not know they were selected for this. Some respondents were concerned that case management could label frequent callers as troublemakers., Conclusion: People who make frequent calls to emergency ambulance services feel their health and care needs are urgent and ongoing. They cannot see alternative ways to receive help and resolve problems. Communication between health professionals and service users appears inadequate. More research is needed to understand service users' motivations and requirements to inform design and delivery of accessible and effective services., Patient or Public Contribution: People with relevant experience were involved in developing, undertaking and disseminating this research. Two public contributors helped design and deliver the study, including developing and analysing service user interviews and drafting this paper. Eight public members of a Lived Experience Advisory Panel contributed at key stages of study design, interpretation and dissemination. Two more public contributors were members of an independent Study Steering Committee., (© 2023 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Background: Several studies have reported large increases in the incidence of eosinophilic oesophagitis (EoE) in the last 20 years. We aimed to systematically review the incidence and prevalence of EoE, focused on all European countries., Methods: Systematic review and meta-analysis up to 31 December 2022, based on PubMed, CINAHL and extensive hand searching of reference lists. Twenty-five eligible studies were identified and included., Results: For both adults and children, the highest EoE incidence and prevalence have been reported from regional studies in Spain. EoE incidence for both adults and children was significantly lower (p < 0.001) in nationwide studies (meta-analysis = 3.64 per 100,000 person-years overall) compared with regional or centre-based studies (7.16). EoE incidence and prevalence were significantly higher (p < 0.001) in adults than children. All studies that reported on longitudinal trends in EoE incidence showed increases over time, more markedly during more recent years. Larger increases in incidence tend to refer to regional rather than nationwide studies; from Spain, Switzerland and Denmark, both for paediatric and adult age groups. Increases in EoE incidence 100,000 person-years were larger than for incidence per number of diagnostic endoscopies. The most frequently reported co-morbidities in adults were rhinitis, followed by asthma, food allergy and gastroesophageal reflux disease, and in children, erosive oesophagitis, asthma, food allergy and rhinitis., Conclusions: The incidence of EoE has increased in Europe over the last 30 years, exceeding increases in the volume of oesophago-gastro-duodenoscopies performed. The patchy and low incidence and prevalence of EoE generally in Europe and compared with North America, may reflect a lack of clinical awareness and research focus rather than a genuinely low incidence of EoE. A co-ordinated Europe-wide study that uses standardised methodology is urgently needed to provide a comprehensive picture of EoE incidence and prevalence across Europe., (© 2023 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Objectives: Little is known about whether distress tolerance and anxiety mediate the relationship between comorbid complex posttraumatic stress disorder (CPTSD) and alcohol use among military veterans. Here, we investigated the contribution of distress tolerance and anxiety on the strength of the CPTSD and alcohol use association. We hypothesized that the impact of a two-factor model of CPTSD derived from subscale scores on the International Trauma Questionnaire (ITQ)-namely ITQ PTSD and ITQ Disturbances in Self Organization (DSO; e.g., issues with affective regulation/self-belief and shame)-on alcohol use severity would be mediated by anxiety but not by distress tolerance., Methods: Participants included 403 community-dwelling United Kingdom (UK) veterans (91.64% male, M age  = 51.15 years, SD = 12.48) recruited as part of a larger, online study., Results: Findings indicated that the influence of CPTSD symptoms on alcohol use severity was mediated by anxiety, not by distress tolerance, with greater relative impact due to ITQ DSO status than ITQ PTSD status., Conclusions: We identified the mediational influence of anxiety and distress tolerance on the association between CPTSD subscales and alcohol use in UK veterans. Interventions for anxiety may be adapted for reducing problematic alcohol use and the impact of CPTSD symptoms in veterans with comorbid PTSD and alcohol use disorder., (© 2023 The Authors. Journal of Clinical Psychology published by Wiley Periodicals LLC.)

Background: More than 90% of deaf children are born to hearing families who know little about deafness. Benefits from hearing screening at birth are often lost, as families find little information about pathways for deaf children but are key to ensuring deaf children receive relevant language and communication support. Systems surrounding deaf children and family members are crucial for children's health and social development. Experiences of hearing parents raising deaf children and understanding factors that influence families' experience of navigating pathways for deaf children through health and education services are currently underreported., Methods: An exploratory study was conducted in Wales, UK. Twenty participants were interviewed, including 10 hearing parents of deaf children and 10 people who work with deaf children using semistructured interviews. Bronfenbrenner's ecological systems theory was used as a lens to explore the micro-, meso-, exo-, macro- and chronosystems that surround children and families. This study explores potential supports and barriers in those systems., Findings: Findings are reported under two broad headings: enablers and barriers. Under enablers, it was found that provision of resources, supporting people and knowledge were key factors. Under barriers, a lack of knowledge, lack of provision and battling services and attitudes were key issues that need addressing., Conclusion: Hearing parents of deaf children in Wales, UK reported experiencing a range of enablers and barriers that impact upon their experiences of raising a deaf child. Further provision is needed by policymakers and governments to recognise support needs to improve the outcomes for deaf children., Patient or Public Contribution: This project was developed from initial discussions with the stakeholder reference group and progressed with the group's deaf panel and hearing parents with deaf children. The project's steering group was involved in study design, recruitment and continuous feedback on all stages of the research process., (© 2023 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Objectives: To explore the perceptions of patients and healthcare professionals on Raman-faecal immunochemical test (FIT) as an alternative test for colorectal cancer exclusion in primary care., Design: Semi-structured interviews within a feasibility study., Setting: Patients presenting to primary care with colorectal symptoms and healthcare professionals working in primary and secondary care., Participants: A total of 23 patients and 12 healthcare professionals., Methods: Patient participants were asked to complete a novel combined Raman-FIT test before being seen in secondary care. This study sought their opinions about the test. We also sought the views of healthcare professionals., Findings: Patients and healthcare professionals agreed that Raman-FIT was a suitable test to be given in primary care. It aligned with routine practice and was a simple test for most patients to complete., Conclusions: Patients are willing and able to complete the Raman-FIT test in primary care. Raman-FIT may accelerate access to diagnosis with the potential to improve cancer outcomes., Patient and Public Involvement: Lay members (J. H. and I. H.) with experience and knowledge of colorectal cancer and screening contributed to developing, undertaking, and disseminating all aspects of the research. They were supported to collaborate as equal members of the research team. They were involved in developing the study as coapplicants, using personal experience to ensure that the research and its methods were relevant to the patient and public needs. Both prepared participant information sheets, coanalysed data, and contributed to study reporting and dissemination through papers, conference presentations and a lay summary., (© 2023 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

The British and Irish Chapter of the International Society for Magnetic Resonance in Medicine (BIC-ISMRM) held a workshop entitled "Steps on the path to clinical translation" in Cardiff, UK, on 7th September 2022. The aim of the workshop was to promote discussion within the MR community about the problems and potential solutions for translating quantitative MR (qMR) imaging and spectroscopic biomarkers into clinical application and drug studies. Invited speakers presented the perspectives of radiologists, radiographers, clinical physicists, vendors, imaging Contract/Clinical Research Organizations (CROs), open science networks, metrologists, imaging networks, and those developing consensus methods. A round-table discussion was held in which workshop participants discussed a range of questions pertinent to clinical translation of qMR imaging and spectroscopic biomarkers. Each group summarized their findings via three main conclusions and three further questions. These questions were used as the basis of an online survey of the broader UK MR community., (© 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

The transition in the field of bone tissue engineering from bone regeneration to in vitro models has come with the challenge of recreating a dense and anisotropic bone-like extracellular matrix (ECM). Although the mechanism by which bone ECM gains its structure is not fully understood, mechanical loading and curvature have been identified as potential contributors. Here, guided by computational simulations, we evaluated cell and bone-like tissue growth and organization in a concave channel with and without directional fluid flow stimulation. Human mesenchymal stromal cells were seeded on donut-shaped silk fibroin scaffolds and osteogenically stimulated for 42 days statically or in a flow perfusion bioreactor. After 14, 28, and 42 days, constructs were investigated for cell and tissue growth and organization. As a result, directional fluid flow was able to improve organic tissue growth but not organization. Cells tended to orient in the tangential direction of the channel, possibly attributed to its curvature. Based on our results, we suggest that organic ECM production but not anisotropy can be stimulated through the application of fluid flow. With this study, an initial attempt in three-dimensions was made to improve the resemblance of in vitro produced bone-like ECM to the physiological bone ECM., (© 2023 The Authors. Biotechnology and Bioengineering published by Wiley Periodicals LLC.)

Hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) is a feature of many solid tumours and is a key pathogenic driver in the inherited condition Tuberous Sclerosis Complex (TSC). Modulation of the tumour microenvironment by extracellular vesicles (EVs) is known to facilitate the development of various cancers. The role of EVs in modulating the tumour microenvironment and their impact on the development of TSC tumours, however, remains unclear. This study, therefore, focuses on the poorly defined contribution of EVs to tumour growth in TSC. We characterised EVs secreted from TSC2-deficient and TSC2-expressing cells and identified a distinct protein cargo in TSC2-deficient EVs, containing an enrichment of proteins thought to be involved in tumour-supporting signalling pathways. We show EVs from TSC2-deficient cells promote cell viability, proliferation and growth factor secretion from recipient fibroblasts within the tumour microenvironment. Rapalogs (mTORC1 inhibitors) are the current therapy for TSC tumours. Here, we demonstrate a previously unknown intercellular therapeutic effect of rapamycin in altering EV cargo and reducing capacity to promote cell proliferation in the tumour microenvironment. Furthermore, EV cargo proteins have the potential for clinical applications as TSC biomarkers, and we reveal three EV-associated proteins that are elevated in plasma from TSC patients compared to healthy donor plasma., (© 2023 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

Background and Purpose: Although psychiatric diagnoses are recognized in idiopathic dystonia, no previous studies have examined the temporal relationship between idiopathic dystonia and psychiatric diagnoses at scale. Here, we determine rates of psychiatric diagnoses and psychiatric medication prescription in those diagnosed with idiopathic dystsuponia compared to matched controls., Methods: A longitudinal population-based cohort study using anonymized electronic health care data in Wales (UK) was conducted to identify individuals with idiopathic dystonia and comorbid psychiatric diagnoses/prescriptions between 1 January 1994 and 31 December 2017. Psychiatric diagnoses/prescriptions were identified from primary and secondary health care records., Results: Individuals with idiopathic dystonia (n = 52,589) had higher rates of psychiatric diagnosis and psychiatric medication prescription when compared to controls (n = 216,754, 43% vs. 31%, p &lt; 0.001; 45% vs. 37.9%, p &lt; 0.001, respectively), with depression and anxiety being most common (cases: 31% and 28%). Psychiatric diagnoses predominantly predated dystonia diagnosis, particularly in the 12 months prior to diagnosis (incidence rate ratio [IRR] = 1.98, 95% confidence interval [CI] = 1.9-2.1), with an IRR of 12.4 (95% CI = 11.8-13.1) for anxiety disorders. There was, however, an elevated rate of most psychiatric diagnoses throughout the study period, including the 12 months after dystonia diagnosis (IRR = 1.96, 95% CI = 1.85-2.07)., Conclusions: This study suggests a bidirectional relationship between psychiatric disorders and dystonia, particularly with mood disorders. Psychiatric and motor symptoms in dystonia may have common aetiological mechanisms, with psychiatric disorders potentially forming prodromal symptoms of idiopathic dystonia., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Although the COVID-19 pandemic has been shown to be detrimental to mental health, it may hold a parallel potential for positive change. Little is known about posttraumatic growth (PTG) as a potential outcome for individuals with lived experience of psychiatric disorders following trauma exposure, especially in the context of the COVID-19 pandemic. Participants were 1,424 adults with lived experience of a psychiatric disorder who took part in a longitudinal study of mental health during the COVID-19 pandemic conducted by the National Centre for Mental Health. PTG was measured using the Posttraumatic Growth Inventory-Short Form (PTGI-SF). Factors hypothesized to be associated with PTG were investigated using linear regression. The mean participant PTGI score was 12.64 (SD = 11.01). On average, participants reported the highest scores on items related to appreciation of life and lowest on those related to spiritual change subscale. We found the strongest evidence of associations between higher levels of PTG and higher scores on assessment items related to perceived social support, B = 2.86; perceptions of the pandemic as traumatic, B = 4.89; and higher psychological well-being, B = 0.40. Taken together, we did not observe evidence of widespread PTG related to the COVID-19 pandemic among individuals with lived experiences of psychiatric disorders., (© 2022 The Authors. Journal of Traumatic Stress published by Wiley Periodicals LLC on behalf of International Society for Traumatic Stress Studies.)

Background: To investigate the incidence of implant-related complications when humeral unicondylar fractures in immature dogs are stabilised with a transcondylar bone screw and epicondylar Kirschner wire (K-wire)/pin., Methods: Records of cases treated by the author in this clinic over a 10-year period were screened for those involving humeral condylar fractures. These were then reduced to include those patients who were less than 7 months of age with unicondylar fractures and follow-up radiographs., Results: Thirty fractures in 29 dogs met the inclusion criteria. All of these had been stabilised with a transcondylar bone screw and epicondylar K-wire. Fracture healing was documented in all dogs. Surgical site infection was not recorded. Implant-related major complications were reported in four (13%) dogs and successfully treated by either implant removal or replacement. Short-term outcome was judged as excellent in 23 out of 30 and good in seven out of 30 of these fractures., Conclusion: The use of a transcondylar bone screw in combination with an epicondylar K-wire is an appropriate fixation method for humeral unicondylar fractures seen in puppies less than 7 months of age., (© 2022 British Veterinary Association.)

Background: Public involvement in health services research is encouraged. Descriptions of public involvement across the whole research cycle of a major study are uncommon and its effects on research conduct are poorly understood., Aim: This study aimed to describe how we implemented public involvement, reflect on process and effects in a large-scale multi-site research study and present learning for future involvement practice., Method: We recorded public involvement roles and activities throughout the study and compared these to our original public involvement plan included in our project proposal. We held a group interview with study co-applicants to explore their experiences, transcribed the recorded discussion and conducted thematic analysis. We synthesized the findings to develop recommendations for future practice., Results: Public contributors' activities went beyond strategic study planning and management to include active involvement in data collection, analysis and dissemination. They attended management, scrutiny, planning and task meetings. They also facilitated public involvement through annual planning and review sessions, conducted a Public Involvement audit and coordinated public and patient input to stakeholder discussions at key study stages. Group interview respondents said that involvement exceeded their expectations. They identified effects such as changes to patient recruitment, terminology clarification and extra dissemination activities. They identified factors enabling effective involvement including team and leader commitment, named support contact, building relationships and demonstrating equality and public contributors being confident to challenge and flexible to meet researchers' timescales and work patterns. There were challenges matching resources to roles and questions about the risk of over-professionalizing public contributors., Conclusion: We extended our planned approach to public involvement and identified benefits to the research process that were both specific and general. We identified good practice to support effective public involvement in health services research that study teams should consider in planning and undertaking research., Public Contribution: This paper was co-conceived, co-planned and co-authored by public contributors to contribute research evidence, based on their experiences of active involvement in the design, implementation and dissemination of a major health services research study., (© 2022 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

A high proportion of depressed patients fail to respond to antidepressant drug treatment. Treatment-resistant depression (TRD) is a major challenge for the psychopharmacology of mood disorders. Only in the past decade have novel treatments, including deep brain stimulation (DBS) and ketamine, been discovered that provide rapid and sometimes prolonged relief to a high proportion of TRD sufferers. In this review, we consider the current status of TRD from four perspectives: the challenge of developing an appropriate regulatory framework for novel rapidly acting antidepressants; the efficacy of non-pharmacological somatic therapies; the development of an animal model of TRD and its use to understand the neural basis of antidepressant non-response; and the potential for rapid antidepressant action from targets (such as 5-HT 1A receptors) beyond the glutamate receptor. LINKED ARTICLES: This article is part of a themed issue on New discoveries and perspectives in mental and pain disorders. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.17/issuetoc., (© 2021 The British Pharmacological Society.)

Background: Prevalence estimates of COVID-19-related posttraumatic stress disorder (PTSD) have ranged from 1% to over 60% in the general population. Individuals with lived experience of a psychiatric disorder may be particularly vulnerable to COVID-19-related PTSD but this has received inadequate attention., Methods: Participants were 1571 adults with lived experience of psychiatric disorder who took part in a longitudinal study of mental health during the COVID-19 pandemic. PTSD was assessed by the International Trauma Questionnaire (ITQ) anchored to the participant's most troubling COVID-19-related experiencevent. Factors hypothesised to be associated with traumatic stress symptoms were investigated by linear regression., Results: 40.10% of participants perceived some aspect of the pandemic as traumatic. 5.28% reported an ICD-11 PTSD qualifying COVID-19 related traumatic exposure and 0.83% met criteria for probable ICD-11 COVID-19-related PTSD. Traumatic stress symptoms were associated with younger age, lower income, lower social support, and financial worries, and lived experience of PTSD/complex PTSD. Depression and anxiety measured in June 2020 predicted traumatic stress symptoms at follow-up approximately 20 weeks later in November 2020., Conclusions: We did not find evidence of widespread COVID-19-related PTSD among individuals with lived experience of a psychiatric disorder. There is a need for future research to derive valid prevalence estimates of COVID-19-related PTSD., (© The Authors. Depression and Anxiety published by Wiley Periodicals LLC.)

Flecainide is used to treat catecholaminergic polymorphic ventricular tachycardia (CPVT), an arrhythmia caused by disrupted cellular Ca 2+ handling following β-adrenergic stimulation. The clinical efficacy of flecainide in this context involves complex effects on multiple ion channels that may be influenced by the disease state. A compelling narrative has been constructed around flecainide's nonselective block of sarcoplasmic reticulum (SR) lumen-to-cytoplasm Ca 2+ release through intracellular calcium release channels (RyR2). However, ion fluxes across the SR membrane during heart contraction are bidirectional, and here, we review experimental evidence that flecainide's principal action on RyR2 involves the partial block of ion flow in the cytoplasm-to-lumen direction (i.e., flecainide inhibits RyR2-mediated SR 'countercurrent'). Experimental approaches that could advance new knowledge on the mechanism of RyR2 block by flecainide are proposed. Some impediments to progress in this area, that must be overcome to enable the development of superior drugs to treat CPVT, are also considered., (© 2021 The British Pharmacological Society.)

The Neoproterozoic included changes in oceanic redox conditions, the configuration of continents and climate, extreme ice ages (Sturtian and Marinoan), and the rise of complex life forms. A much-debated topic in geobiology concerns the influence of atmospheric oxygenation on Earth and the origin and diversification of animal lineages, with the most widely popularized hypotheses relying on causal links between oxygen levels and the rise of animals. The vast majority of extant animals use aerobic metabolism for growth and homeostasis; hence, the binding and transportation of oxygen represent a vital physiological task. Considering the blood pigment hemocyanin (Hc) is present in sponges and ctenophores, and likely to be present in the common ancestor of animals, we investigated the evolution and date of Hc emergence using bioinformatics approaches on both transcriptomic and genomic data. Bayesian molecular dating suggested that the ancestral animal Hc gene arose approximately 881 Ma during the Tonian Period (1000-720 Ma), prior to the extreme glaciation events of the Cryogenian Period (720-635 Ma). This result is corroborated by a recently discovered fossil of a putative sponge ~890 Ma and modern molecular dating for the origin of metazoans of ~1,000-650 Ma (but does contradict previous inferences regarding the origin of Hc ~700-600 Ma). Our data reveal that crown-group animals already possessed hemocyanin-like blood pigments, which may have enhanced the oxygen-carrying capacity of these animals in hypoxic environments at that time or acted in the transport of hormones, detoxification of heavy metals, and immunity pathways., (© 2021 John Wiley & Sons Ltd.)

Objective: To evaluate the implementation of non-invasive prenatal testing (NIPT) on pregnant women's choices in a national NHS antenatal screening programme for Down's syndrome, Edwards' syndrome and Patau's syndrome., Method: An observational study of all pregnant women with a singleton pregnancy and higher chance (≤1:150) combined or quadruple screening result from 30 April 2018 to 25 September 2020 in Wales, UK. Pregnant women's journey through the pathway was determined including uptake of NIPT, performance of NIPT in a non-research setting and invasive procedures performed., Results: Of the 1273 women with a higher chance initial screening, 1073 (84%) chose NIPT contingent test, 174 (14%) no further testing and 26 (2%) invasive procedure. There were 1001 (93%) low chance NIPT results; 11 (1%) failed results and 61 (6%) high chance results. Average annual incidence of 27 invasive procedures undertaken compared to 229 pre-NIPT implementation, a nearly ninefold reduction. Down's syndrome annual live birth rate remained unchanged across the implementation period., Discussion: This study demonstrates that NIPT contingent screening was highly acceptable to women with a resulting reduction in invasive procedures performed., Conclusion: The high uptake of NIPT in NHS antenatal screening pathway conditions should inform planning for other national screening programmes., (© 2022 John Wiley & Sons Ltd.)

Context: Too many people living with chronic kidney disease are opting for and starting on hospital-based dialysis compared to a home-based kidney replacement therapy. Dialysis services are becoming financially unsustainable., Objective: This study aimed to assess the efficacy of coproductive research in chronic kidney disease service improvement to achieve greater sustainability., Design: A 2-year coproductive service improvement study was conducted with multiple stakeholders with the specific intention of maximizing engagement with the national health kidney services, patients and public., Setting and Participants: A national health kidney service (3 health boards, 18 dialysis units), patients and families (n = 50), multidisciplinary teams including doctors, nurses, psychologists, social workers, and so forth (n = 68), kidney charities, independent dialysis service providers and wider social services were part of this study., Findings: Coproductive research identified underutilized resources (e.g., patients on home dialysis and social services) and their potential, highlighted unmet social care needs for patients and families and informed service redesign. Education packages were reimagined to support the home dialysis agenda including opportunities for wider service input. The impacts of one size fits all approaches to dialysis on specialist workforce skills were made clearer and also professional, patient and public perceptions of key sustainability policies., Discussion and Conclusions: Patient and key stakeholders mapped out new ways to link services to create more sustainable models of kidney health and social care. Maintaining principles of knowledge coproduction could help achieve financial sustainability and move towards more prudent adult chronic kidney disease services., Patient or Public Contribution: Involved in developing research questions, study design, management and conduct, interpretation of evidence and dissemination., (© 2021 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Fractional flow reserve (FFR) provides the functional relevance of coronary atheroma. The FFR-guided strategy has been shown to reduce unnecessary stenting, improve overall health outcome, and to be cost-saving. The non-invasive, coronary computerised tomography (CT) angiography-derived FFR (cFFR) is an emerging method in reducing invasive catheter based measurements. This computational fluid dynamics-based method is laborious as it requires expertise in multidisciplinary analysis of combining image analysis and computational mechanics. In this work, we present a rapid method, powered by unsupervised learning, to automatically calculate cFFR from CT scans without manual intervention., (© 2021 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd.)