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Abstract Context The genetic background of young-onset Graves disease (GD) remains largely unknown. An intronic variant in human leukocyte antigen (HLA) complex P5 (HCP5) has previously been associated with GD susceptibility and age of onset in a cohort of Polish patients. Objective We aimed to investigate the association of the HCP5 variant rs3094228 with GD susceptibility and age of onset in a UK cohort and conduct a meta-analysis of UK and Polish data. Design and Participants rs3094228 was genotyped in 469 UK patients with GD using Taqman chemistry. Genotype frequencies were compared with genotypic data available from the Wellcome Trust case-control consortium using logistic regression analysis. To determine whether rs3094228 is independently associated with age of GD onset, the HLA DRB1*0301 tagging variant, rs535777, was also genotyped. Results The C allele of rs3094228 was overrepresented in the UK GD cohort compared with controls (P allele=5.08 × 10–9, odds ratio 1.76; [95% confidence interval, 1.46-2.13]). This association was more marked in young-onset GD (<30 years) (P allele=1.70 × 10–10 vs P allele=0.0008). The meta-analysis of UK and Polish data supported the association of the C allele with GD susceptibility (P allele=1.79 × 10–5) and age of onset (P allele=5.63 × 10–8). Haplotype analysis demonstrated that rs3094228 is associated with age of GD onset (P = 2.39 × 10-6) independent of linkage disequilibrium with HLA DRB1*0301. Conclusion The rs3094228 HCP5 polymorphism is independently associated with GD susceptibility and age of onset in a UK GD cohort. Our findings indicate a potential role of long noncoding ribonucleic acids, including HCP5, in GD pathogenesis, particularly in the younger population.

The genetic background of young-onset Graves disease (GD) remains largely unknown. An intronic variant in human leukocyte antigen (HLA) complex P5 (HCP5) has previously been associated with GD susceptibility and age of onset in a cohort of Polish patients. We aimed to investigate the association of the HCP5 variant rs3094228 with GD susceptibility and age of onset in a UK cohort and conduct a meta-analysis of UK and Polish data. rs3094228 was genotyped in 469 UK patients with GD using Taqman chemistry. Genotype frequencies were compared with genotypic data available from the Wellcome Trust case-control consortium using logistic regression analysis. To determine whether rs3094228 is independently associated with age of GD onset, the HLA DRB1*0301 tagging variant, rs535777, was also genotyped. The C allele of rs3094228 was overrepresented in the UK GD cohort compared with controls (P allele=5.08 × 10-9, odds ratio 1.76; [95% confidence interval, 1.46-2.13]). This association was more marked in young-onset GD (<30 years) (P allele=1.70 × 10-10 vs P allele=0.0008). The meta-analysis of UK and Polish data supported the association of the C allele with GD susceptibility (P allele=1.79 × 10-5) and age of onset (P allele=5.63 × 10-8). Haplotype analysis demonstrated that rs3094228 is associated with age of GD onset (P = 2.39 × 10-6) independent of linkage disequilibrium with HLA DRB1*0301. The rs3094228 HCP5 polymorphism is independently associated with GD susceptibility and age of onset in a UK GD cohort. Our findings indicate a potential role of long noncoding ribonucleic acids, including HCP5, in GD pathogenesis, particularly in the younger population.

Graves’ disease is a rare disorder that continues to present clinicians and families with a series of challenges. There are no new established treatments for children or adolescents, but the outcomes of recent clinical trials and meta-analyses have helped clinicians to prepare families for the road ahead. We have a more refined understanding of how to administer antithyroid drugs, which one to use and how long to treat the young person. We also have a greater insight into how best to reduce any risks associated with surgery and radioiodine. We understand more about long-term outcomes and their determinants and have greater awareness about the impact of the disease and its treatment on quality of life. A holistic approach to management is key to supporting and counselling young people and their families about the diagnosis and management options. In this review, we will discuss the recent literature and reflect on how this should be translated into clinical practice.

ObjectivesThis study aimed to understand the role of surgical Trainee Research Collaboratives (TRCs) in conducting randomised controlled trials and identify strategies to enhance trainee engagement in trials.DesignThis is a mixed methods study. We used observation of TRC meetings, semi-structured interviews and an online survey to explore trainees’ motivations for engagement in trials and TRCs, including barriers and facilitators. Interviews were analysed thematically, alongside observation field notes. Survey responses were analysed using descriptive statistics. Strategies to enhance TRCs were developed at a workshop by 13 trial methodologists, surgical trainees, consultants and research nurses.SettingThis study was conducted within a secondary care setting in the UK.ParticipantsThe survey was sent to registered UK surgical trainees. TRC members and linked stakeholders across surgical specialties and UK regions were purposefully sampled for interviews.ResultsWe observed 5 TRC meetings, conducted 32 semi-structured interviews and analysed 73 survey responses. TRCs can mobilise trainees thus gaining wider access to patients. Trainees engaged with TRCs to improve patient care, surgical evidence and to help progress their careers. Trainees valued the TRC infrastructure, research expertise and mentoring. Challenges for trainees included clinical and other priorities, limited time and confidence, and recognition, especially by authorship. Key TRC strategies were consultant support, initial simple rapid studies, transparency of involvement and recognition for trainees (including authorship policies) and working with Clinical Trials Units and research nurses. A 6 min digital story on YouTube disseminated these strategies.ConclusionTrainee surgeons are mostly motivated to engage with trials and TRCs. Trainee engagement in TRCs can be enhanced through building relationships with key stakeholders, maximising multi-disciplinary working and offering training and career development opportunities.

BackgroundPulmonary rehabilitation (PR) is a highly effective intervention for people with chronic respiratory disease; however, it is not known how best to sustain its benefits. Clinical trials are needed to establish if participation in singing for lung health (SLH) groups following PR will improve health-related quality of life, healthcare utilisation and exercise capacity compared with usual care. A feasibility study would help to guide development of these trials.MethodsIn a multicentre, mixed-methods randomised controlled feasibility trial, PR participants at four sites were prescreened at baseline assessment. An SLH taster session was included routinely as part of the PR programmes. Eligible PR completers were invited to take part in the trial and randomised to usual care or a 12-week SLH course. Feasibility outcomes included recruitment rate, intervention compliance (at least 8/12 sessions) and health economic analysis. Interviews with participants and study personnel were undertaken and thematic analysis of the results was completed.ResultsBetween October 2022 and November 2023, 1311 patients were assessed to start PR, 838 completed. Of those completing, 243 were ineligible to take part (predominantly due to vaccination status and excluded diagnoses for PR referral), and 531 declined. 64 people (33 female, mean (SD) age 69 (12), 41 ethnically white, 33 with chronic obstructive pulmonary disease, 16 with asthma, 9 with interstitial lung disease, 6 with bronchiectasis) were recruited, with 30 (93.8%) SLH and 29 (90.6%) controls completing the study. 20 (62.5%) of the SLH group completed at least 8/12 SLH sessions. There was enthusiasm for a definitive trial from participants, clinicians and singing group leaders’ perspectives, based on positive experiences of trial involvement. Improvements to recruitment strategy, intervention structure, outcome measures and staffing were suggested.ConclusionsA definitive randomised controlled trial of SLH post-PR appears feasible, with acceptable uptake and completion rates.Trial registration numberISRCTN11056049.

Multiparametric remote measurement technologies (RMTs), which comprise smartphones and wearable devices, have the potential to revolutionize understanding of the etiology and trajectory of major depressive disorder (MDD). Engagement with RMTs in MDD research is of the utmost importance for the validity of predictive analytical methods and long-term use and can be conceptualized as both objective engagement (data availability) and subjective engagement (system usability and experiential factors). Positioning the design of user interfaces within the theoretical framework of the Behavior Change Wheel can help maximize effectiveness. In-app components containing information from credible sources, visual feedback, and access to support provide an opportunity to promote engagement with RMTs while minimizing team resources. Randomized controlled trials are the gold standard in quantifying the effects of in-app components on engagement with RMTs in patients with MDD. This study aims to evaluate whether a multiparametric RMT system with theoretically informed notifications, visual progress tracking, and access to research team contact details could promote engagement with remote symptom tracking over and above the system as usual. We hypothesized that participants using the adapted app (intervention group) would have higher engagement in symptom monitoring, as measured by objective and subjective engagement. A 2-arm, parallel-group randomized controlled trial (participant-blinded) with 1:1 randomization was conducted with 100 participants with MDD over 12 weeks. Participants in both arms used the RADAR-base system, comprising a smartphone app for weekly symptom assessments and a wearable Fitbit device for continuous passive tracking. Participants in the intervention arm (n=50, 50%) also had access to additional in-app components. The primary outcome was objective engagement, measured as the percentage of weekly questionnaires completed during follow-up. The secondary outcomes measured subjective engagement (system engagement, system usability, and emotional self-awareness). The levels of completion of the Patient Health Questionnaire-8 (PHQ-8) were similar between the control (67/97, 69%) and intervention (66/97, 68%) arms (P value for the difference between the arms=.83, 95% CI -9.32 to 11.65). The intervention group participants reported slightly higher user engagement (1.93, 95% CI -1.91 to 5.78), emotional self-awareness (1.13, 95% CI -2.93 to 5.19), and system usability (2.29, 95% CI -5.93 to 10.52) scores than the control group participants at follow-up; however, all CIs were wide and included 0. Process evaluation suggested that participants saw the in-app components as helpful in increasing task completion. The adapted system did not increase objective or subjective engagement in remote symptom tracking in our research cohort. This study provides an important foundation for understanding engagement with RMTs for research and the methodologies by which this work can be replicated in both community and clinical settings. ClinicalTrials.gov NCT04972474; https://clinicaltrials.gov/ct2/show/NCT04972474. RR2-10.2196/32653.

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. Prostate cancer (PrCa) involves a large heritable genetic component. Here, the authors perform multivariate fine-mapping of known PrCa GWAS loci, identifying variants enriched for biological function, explaining more familial relative risk, and with potential application in clinical risk profiling.

Glucocorticoids (GC) are used in paediatric practice for a broad range of conditions and all paediatricians will prescribe GC, in some form, during their career. A wide variety of GC formulations, doses and administration routes are used for periods of time ranging from days to years. Exposure to exogenous GC can result in hypothalamic-pituitary-adrenal axis suppression—otherwise known as adrenal suppression (AS). Patients with AS may be well most of the time but if GC therapy is reduced or stopped or if additional endogenous GC cannot be generated during illness, then an absolute or relative lack of GC can result in severe illness or death. Here, we highlight the relevance of AS to all paediatricians by providing an overview of the background and discussing the presentation and approaches to the management of this clinical entity.

We examined systems-level costs before and after the implementation of an emergency department paediatric sepsis screening, recognition and treatment pathway. Aggregated hospital admissions for all children aged < 18y with a diagnosis code of sepsis upon admission in Queensland, Australia were compared for 16 participating and 32 non-participating hospitals before and after pathway implementation. Monte Carlo simulation was used to generate uncertainty intervals. Policy impacts were estimated using difference-in-difference analysis comparing observed and expected results. We compared 1055 patient episodes before (77.6% in-pathway) and 1504 after (80.5% in-pathway) implementation. Reductions were likely for non-intensive length of stay (− 20.8 h [− 36.1, − 8.0]) but not intensive care (–9.4 h [− 24.4, 5.0]). Non-pathway utilisation was likely unchanged for interhospital transfers (+ 3.2% [− 5.0%, 11.4%]), non-intensive (− 4.5 h [− 19.0, 9.8]) and intensive (+ 7.7 h, [− 20.9, 37.7]) care length of stay. After difference-in-difference adjustment, estimated savings were 596 [277, 942] non-intensive and 172 [148, 222] intensive care days. The program was cost-saving in 63.4% of simulations, with a mean value of $97,019 [− $857,273, $1,654,925] over 24 months. A paediatric sepsis pathway in Queensland emergency departments was associated with potential reductions in hospital utilisation and costs.