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Objective: We conducted a survey of UK endocrine clinicians between June 2022 and August 2022 to understand current practices regarding GH treatment discontinuation in adults with growth hormone deficiency. Design and methods: Using Survey Monkey®, a web-based multiple-choice questionnaire was disseminated to the UK Society for Endocrinology membership. It consisted of 15 questions on demographics, number of patients receiving GH and current practice on GH treatment discontinuation. Results: In total, 102 endocrine clinicians completed the survey. Of these, 65 respondents (33 endocrinologists and 32 specialist nurses) indicated active involvement in managing patients with growth hormone deficiency. In total, 27.7% of clinicians were routinely offering a trial of GH discontinuation to adults receiving long-term GH therapy. Only 6% had a clinical guideline to direct such practice. In total, 29.2% stated that GH discontinuation should be routinely offered as an option to patients on long-term treatment, whilst 60% were not clearly in favour or against this approach but stated that it should probably be considered, and 9.2% were against. During the GH withdrawal period, most clinicians monitor signs and symptoms (75.4%), measure IGF-1 (84.6%), and complete a quality-of-life assessment (89.2%). Conclusion: The practice of offering a trial of GH discontinuation in growth hormone deficiency adults on long-term GH therapy is highly variable, reflecting the lack of high-quality evidence. Around a quarter of clinicians offer GH withdrawal for a number of reasons, but only a few have a local clinical guidance. A further 60% of clinicians stated they would probably consider such an approach. Methodologically sound studies underpinning the development of safe and cost-effective guidance are needed. Significance statement In this UK survey of endocrine clinicians managing adults with growth hormone deficiency on long-term GH therapy, we explored for the first-time current practice and views on offering GH treatment discontinuation. In total, 27.7% of clinicians were routinely offering this option for a variety of reasons. Only 6% have local clinical guideline available to direct their practice on this. The majority of clinicians (60%), were not clearly in favour or against this approach but indicated it should probably be considered. In the absence of robust evidence on consequences of GH withdrawal, clinicians proposed monitoring of various clinical, biochemical and quality-of-life parameters during the period of discontinuation. Methodologically sound studies that will underpin the development of a safe, cost-effective guidance are needed.

Abstract Dendritic cell (DC)-targeted vaccination is a new mode of antigen delivery that relies on the use of monoclonal antibodies (mAb) to target antigen to specific DC subsets. The neonatal Fc receptor (FcRn) is a non-classical Fc receptor that binds to immunoglobulin G (IgG) in acidified endosomes and controls its intracellular transport and recycling. FcRn is known to participate in the antigen presentation of immune complexes, however its contribution to DC-targeted vaccination has not previously been examined. Here we have investigated the role of FcRn in antigen presentation using antigen conjugated to IgG mAb which target specific DC receptors, including DEC205 and Clec9A expressed by the conventional DC 1 (cDC1) subset. We show that FcRn is expressed at high levels by cDC1, both at steady-state and following activation and plays a significant role in MHC I cross-presentation and MHC II presentation of antigens that are targeted to cDC1 via mAb specific for DEC205. This effect of FcRn is intrinsic to cDC1 and FcRn impacts the efficacy of anti-DEC205-mediated vaccination against B cell lymphoma. In contrast, FcRn does not impact presentation of antigens targeted to Clec9A and does not regulate presentation of cell-associated antigen. These data highlight a new and unique role of FcRn in controlling the immunogenicity of anti-DEC205-based vaccination, with consequences for exploiting this pathway to improve DC-targeted vaccine outcomes.

ImportanceUnderstanding the causes of infant mortality shapes public health, surveillance, and research investments. However, the association of single-locus (mendelian) genetic diseases with infant mortality is poorly understood.ObjectiveTo determine the association of genetic diseases with infant mortality.Design, setting, and participantsThis cohort study was conducted at a large pediatric hospital system in San Diego County (California) and included 546 infants (112 infant deaths [20.5%] and 434 infants [79.5%] with acute illness who survived; age, 0 to 1 year) who underwent diagnostic whole-genome sequencing (WGS) between January 2015 and December 2020. Data analysis was conducted between 2015 and 2022.ExposureInfants underwent WGS either premortem or postmortem with semiautomated phenotyping and diagnostic interpretation.Main outcomes and measuresProportion of infant deaths associated with single-locus genetic diseases.ResultsAmong 112 infant deaths (54 girls [48.2%]; 8 [7.1%] African American or Black, 1 [0.9%] American Indian or Alaska Native, 8 [7.1%] Asian, 48 [42.9%] Hispanic, 1 [0.9%] Native Hawaiian or Pacific Islander, and 34 [30.4%] White infants) in San Diego County between 2015 and 2020, single-locus genetic diseases were the most common identifiable cause of infant mortality, with 47 genetic diseases identified in 46 infants (41%). Thirty-nine (83%) of these diseases had been previously reported to be associated with childhood mortality. Twenty-eight death certificates (62%) for 45 of the 46 infants did not mention a genetic etiology. Treatments that can improve outcomes were available for 14 (30%) of the genetic diseases. In 5 of 7 infants in whom genetic diseases were identified postmortem, death might have been avoided had rapid, diagnostic WGS been performed at time of symptom onset or regional intensive care unit admission.Conclusions and relevanceIn this cohort study of 112 infant deaths, the association of genetic diseases with infant mortality was higher than previously recognized. Strategies to increase neonatal diagnosis of genetic diseases and immediately implement treatment may decrease infant mortality. Additional study is required to explore the generalizability of these findings and measure reduction in infant mortality.

Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype-phenotype correlation analysis elucidated specific MCD gene sets associated with distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains indicate critical roles in excitatory neurogenic pools during brain development and in promoting neuronal hyperexcitability after birth.

TMEM161B encodes an evolutionarily conserved widely expressed novel 8-pass transmembrane protein of unknown function in human. Here we identify TMEM161B homozygous hypomorphic missense variants in our recessive polymicrogyria (PMG) cohort. Patients carrying TMEM161B mutations exhibit striking neocortical PMG and intellectual disability. Tmem161b knockout mice fail to develop midline hemispheric cleavage, whereas knock-in of patient mutations and patient-derived brain organoids show defects in apical cell polarity and radial glial scaffolding. We found that TMEM161B modulates actin filopodia, functioning upstream of the Rho-GTPase CDC42. Our data link TMEM161B with human PMG, likely regulating radial glia apical polarity during neocortical development.

Universal newborn screening (NBS) is a highly successful public health intervention. Archived dried bloodspots (DBS) collected for NBS represent a rich resource for population genomic studies. To fully harness this resource in such studies, DBS must yield high-quality genomic DNA (gDNA) for whole genome sequencing (WGS). In this pilot study, we hypothesized that gDNA of sufficient quality and quantity for WGS could be extracted from archived DBS up to 20 years old without PCR (Polymerase Chain Reaction) amplification. We describe simple methods for gDNA extraction and WGS library preparation from several types of DBS. We tested these methods in DBS from 25 individuals who had previously undergone diagnostic, clinical WGS and 29 randomly selected DBS cards collected for NBS from the California State Biobank. While gDNA from DBS had significantly less yield than from EDTA blood from the same individuals, it was of sufficient quality and quantity for WGS without PCR. All samples DBS yielded WGS that met quality control metrics for high-confidence variant calling. Twenty-eight variants of various types that had been reported clinically in 19 samples were recapitulated in WGS from DBS. There were no significant effects of age or paper type on WGS quality. Archived DBS appear to be a suitable sample type for WGS in population genomic studies.

Introduction: Point-of care-ultrasound (POCUS) has become ubiquitous in emergency medicine practice for the management of emergent pathophysiology. There is growing interest in its potential as a diagnostic tool in the prehospital setting. Few studies have examined the feasibility or efficacy of curricula targeted at teaching POCUS to prehospital personnel. Our objective in this study was to investigate a curriculum for the extended focused assessment with sonography in trauma (eFAST) exam in helicopter emergency medical services (HEMS) crews.Methods: This was a pre/post intervention study of HEMS personnel at a tertiary care center. Subjects were administered a pre-intervention written test and an observed structured clinical evaluation (OSCE). Subsequently, they participated in an educational intervention intended to impart proficiency in performing the eFAST. Subjects underwent post-intervention written exams and OSCEs. We analyzed pre- and post-intervention test performance along with the number and quality of practice ultrasound examinations achieved.Results: Sixteen subjects were enrolled (62.5% male, mean age 44.1). After undergoing the intervention, the mean written test score increased 22.1% (t=3.41; P

There are growing expectations in Australia and internationally that school educators will engage with and use research to improve their practice. In order to support educators to respond to such expectations, there is a need to be able to accurately assess the levels of educators' research engagement. At present, however, few psychometrically sound instruments are available. Drawing on two studies of Australian educators (n = 1,311) and utilising Rasch analysis, supported by confirmatory factor analysis, this paper reports on the development of a brief eight-item scale that demonstrates validity and reliability and evidenced unidimensionality in the second study. The scale is intended as a quick, easy-to-use tool for educators to gain insights into their beliefs about the value of engaging with research, their actions around using research, and their confidence in finding, interpreting, and judging the quality of relevant research. Notwithstanding the need for further testing, this paper argues that the scale has the potential to be applicable to other educational contexts and to contribute to future research into educators' research engagement and its assessment. The scale can also provide school and education system leaders, as well as evaluators and researchers, with data regarding educators' research engagement over time, allowing for research use supports and resources to be better targeted.

ABSTRACT Monitoring alien species is critical to their management. However, early detection of invading alien freshwater fish can be challenging due to the difficulty of observing fish in low abundance. Environmental DNA (eDNA) has emerged as a new and potentially more sensitive method for sampling invasive species as compared to conventional methods, but the comparative financial cost is not often assessed. Adoption of eDNA by managers requires studies that showcase its cost‐effectiveness relative to conventional approaches. Here we use eDNA to assist in the management of an aggressive alien fish, the pearl cichlid (Geophagus brasiliensis), that is invading an urban river in south‐western Australia. We applied an occupancy model to survey data collected 6 years apart (2015, 2021) to assess how the species' distribution had changed and to evaluate whether an instream barrier had the potential to limit upstream invasion. To understand the effectiveness of eDNA, we used our model to quantify the relative efficiency (capture probability) of two eDNA sampling methods (active eDNA and passive eDNA) and fyke netting, as well as the number of replicate samples required per site to deliver >95% detection. We coupled the number of replicates needed with the cost per replicate to determine the cost‐efficiency of each method. We found that G. brasiliensis abundance was higher in downstream reaches in both survey years, and there was no evidence that its distribution had changed through time. However, G. brasiliensis was present above the instream barrier. Active eDNA sampling was considerably better at detecting G. brasiliensis than the other methods, making it the most cost‐effective method. Fyke nets came in a close second, and passive eDNA was a very distant third. Our results directly inform management in the study river and broadly highlight the cost‐effectiveness of active eDNA as a freshwater biosecurity tool.

Digital medicine is already well established in respiratory medicine through remote monitoring digital devices which are used in the day-to-day care of patients with asthma, COPD and sleep disorders. Image recognition software, deployed in thoracic radiology for many applications including lung cancer screening, is another application of digital medicine. Used as clinical decision support, this software will soon become part of day-to-day practice once concerns regarding generalisability have been addressed. Embodied in the electronic health record, digital medicine also plays a substantial role in the day-to-day clinical practice of respiratory medicine. Given the considerable work the electronic health record demands from clinicians, the next tangible impact of digital medicine may be artificial intelligence that aids administration, makes record keeping easier and facilitates better digital communication with patients. Future promises of digital medicine are based on their potential to analyse and characterise the large amounts of digital clinical data that are collected in routine care. Offering the potential to predict outcomes and personalise therapy, there is much to be excited by in this new epoch of innovation. However, these digital tools are by no means a silver bullet. It remains uncertain whether, let alone when, the promises of better models of personalisation and prediction will translate into clinically meaningful and cost-effective products for clinicians.

Summary: Background: NOTCH3 encodes a transmembrane receptor critical for vascular smooth muscle cell function. NOTCH3 variants are the leading cause of hereditary cerebral small vessel disease (SVD). While monoallelic cysteine-involving missense variants in NOTCH3 are well-studied in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), patients with biallelic variants in NOTCH3 are extremely rare and not well characterised. Methods: In this study, we present clinical and genetic data from 25 patients with biallelic NOTCH3 variants and conduct a literature review of another 25 cases (50 patients in total). Brain magnetic resonance imaging (MRI) were analysed by expert neuroradiologists to better understand the phenotype associated with biallelic NOTCH3 variants. Findings: Our systematic analyses verified distinct genotype-phenotype correlations for the two types of biallelic variants in NOTCH3. Biallelic loss-of-function variants (26 patients) lead to a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Conversely, patients with biallelic cysteine-involving missense variants (24 patients) fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. White matter lesion volume is comparable between patients with biallelic cysteine-involving missense variants and individuals with CADASIL. Notably, monoallelic carriers of loss-of-function variants are predominantly asymptomatic, with only a few cases reporting nonspecific headaches. Interpretation: We propose a NOTCH3-SVD classification depending on dosage and variant type. This study not only expands our knowledge of biallelic NOTCH3 variants but also provides valuable insight into the underlying mechanisms of the disease, contributing to a more comprehensive understanding of NOTCH3-related SVD. Funding: The Wellcome Trust, the MRC.

This review compared the efficacy of personalized psychological interventions to standardized interventions for adolescents. We conducted a scoping review and meta-analysis of randomized controlled trials that compared personalized interventions with standardized interventions in adolescents. Data was analyzed using Bayesian multilevel random effects meta-analysis. Eligible studies were identified through five databases: Scopus, PsycINFO, MEDLINE, Web of Science, and EMBASE. Moderation analysis was conducted to explain potential sources of effect size heterogeneity. Eight studies across 13 articles (participant N = 2,490) met inclusion criteria for the review with seven studies across 10 articles (N = 1,347) providing sufficient data for inclusion in the meta-analysis. A small but significant effect size favoring personalized interventions was found (d = 0.21, 95% CrI [0.02, 0.39]), indicating that personalized interventions are associated with superior treatment outcomes compared to standardized interventions. Moderate between-study heterogeneity was found (I2 = 53.3%). There was no evidence of publication bias. The review also found significant variation in methods of treatment personalization. This review provides evidence that personalization of adolescent psychological interventions is an effective way to improve treatment outcomes. Given the large number of adolescents worldwide who will experience some sort of mental health problem, personalization could have a significantly large impact on global mental health outcomes.Systematic review registrationhttps://doi.org/10.17605/OSF.IO/XRNCG.

Introduction Missed fractures are the most frequent diagnostic error attributed to clinicians in UK emergency departments and a significant cause of patient morbidity. Recently, advances in computer vision have led to artificial intelligence (AI)-enhanced model developments, which can support clinicians in the detection of fractures. Previous research has shown these models to have promising effects on diagnostic performance, but their impact on the diagnostic accuracy of clinicians in the National Health Service (NHS) setting has not yet been fully evaluated.Methods and analysis A dataset of 500 plain radiographs derived from Oxford University Hospitals (OUH) NHS Foundation Trust will be collated to include all bones except the skull, facial bones and cervical spine. The dataset will be split evenly between radiographs showing one or more fractures and those without. The reference ground truth for each image will be established through independent review by two senior musculoskeletal radiologists. A third senior radiologist will resolve disagreements between two primary radiologists. The dataset will be analysed by a commercially available AI tool, BoneView (Gleamer, Paris, France), and its accuracy for detecting fractures will be determined with reference to the ground truth diagnosis. We will undertake a multiple case multiple reader study in which clinicians interpret all images without AI support, then repeat the process with access to AI algorithm output following a 4-week washout. 18 clinicians will be recruited as readers from four hospitals in England, from six distinct clinical groups, each with three levels of seniority (early-stage, mid-stage and later-stage career). Changes in the accuracy, confidence and speed of reporting will be compared with and without AI support. Readers will use a secure web-based DICOM (Digital Imaging and Communications in Medicine) viewer (www.raiqc.com), allowing radiograph viewing and abnormality identification. Pooled analyses will be reported for overall reader performance as well as for subgroups including clinical role, level of seniority, pathological finding and difficulty of image.Ethics and dissemination The study has been approved by the UK Healthcare Research Authority (IRAS 310995, approved on 13 December 2022). The use of anonymised retrospective radiographs has been authorised by OUH NHS Foundation Trust. The results will be presented at relevant conferences and published in a peer-reviewed journal.Trial registration numbers This study is registered with ISRCTN (ISRCTN19562541) and ClinicalTrials.gov (NCT06130397). The paper reports the results of a substudy of STEDI2 (Simulation Training for Emergency Department Imaging Phase 2).

BackgroundEvidence-based parenting programs delivered using online technology are an important way to enhance program uptake. To date, programs that address emotion socialization processes, such as Tuning in to Kids, have always been delivered in person, via group or one-to-one delivery. This study used a randomized control design to examine the efficacy of the self-paced Tuning in to Kids OnLine (TIKOL).MethodParticipants were 150 parents of children aged 4-10 years old with challenging behaviors, randomized into intervention or 10-month waitlist control. Parents and teachers completed questionnaires at baseline and 6 months after the intervention (equivalent time points for controls) measuring parent wellbeing, parent emotion socialization, parent efficacy, child behavior, and anxiety.ResultsAnalyses, using mixed methods multilevel modeling, showed that intervention parents reported significantly reduced emotion dismissiveness and increased emotion coaching, empathy and efficacy compared to controls who did not. Parents participating in TIKOL also reported that their children's behavior problems and anxiety were significantly improved. Greater engagement (modules watched and duration of support calls) was associated with more significant improvements.ConclusionFindings provide preliminary support for the efficacy of TIKOL in improving parents' emotion socialization and reducing child behavior problems and anxiety, especially when efforts to support online engagement are utilized. Further evaluation using independent observations and a sample representing a wider demographic would strengthen these findings.Clinical trial registrationAustralian and New Zealand Clinical Trials Registry No. ACTRN12618000310268.

Background The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown. Methods Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease (i.e., asthma, COPD or bronchiectasis) were compared to the non-airways group. Results A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p

Background The updated Shape of Training curriculum has shortened the duration of specialty training. We present the potential role of out of programme clinical fellowships.Method An electronic online survey was sent to all current fellows to understand their experiences, training opportunities and motivations.Data were collected on fellows’ endoscopic experiences and publications using PubMed for all previous doctors who have completed the Sheffield Fellowship Programme.Results Since 2004, 39 doctors have completed the Sheffield Fellowship.Endoscopic experience: current fellows completed a median average of 350 (IQR 150–500) gastroscopies and 150 (IQR 106–251) colonoscopies per year. Fellows with special interests completed either 428 hepato-pancreato-biliary procedures or 70 endoscopic mucosal resections per year.Medline publications: Median average 9 publications(IQR 4–17). They have also received multiple national or international awards and 91% achieved a doctoral degree.The seven current fellows in the new Shape of Training era (57% male, 29% Caucasian, aged 31–40 years) report high levels of enjoyment due to their research projects, supervisory teams and social aspects. The most cited reasons for undertaking the fellowship were to develop a subspecialty interest, take time off the on-call rota and develop endoscopic skills. The most reported drawback was a reduced income.All current fellows feel that the fellowship has enhanced their clinical confidence and prepared them to become consultants.Conclusion Out of programme clinical fellowships offer the opportunity to develop the required training competencies, subspecialty expertise and research skills in a supportive environment.

BackgroundHigh alcohol intake is associated with increased mortality. We aimed to identify factors affecting mortality in people drinking extreme amounts of alcohol.MethodsWe obtained information from the UK Biobank on approximately 500,000 participants aged 40-70 years at baseline assessment in 2006-2010. Habitual alcohol intake, lifestyle and physiological data, laboratory test results, and hospital diagnoses and death certificate data (to June 2020) for 5136 men (2.20% of male participants) and 1504 women (0.60%) who reported consuming ≥80 or ≥50 g/day, respectively, were used in survival analysis.ResultsMortality hazard ratios for these excessive drinkers, compared to all other participants, were 2.02 (95% CI 1.89-2.17) for all causes, 1.89 (1.69-2.12) for any cancer, 1.87 (1.61-2.17) for any circulatory disease, and 9.40 (7.00-12.64) for any liver disease. Liver disease diagnosis or abnormal liver function tests predicted not only deaths attributed to liver disease but also those from cancers or circulatory diseases. Mortality among excessive drinkers was also associated with quantitative alcohol intake; diagnosed alcohol dependence, harmful use, or withdrawal syndrome; and current smoking at assessment.ConclusionsPeople with chronic excessive alcohol intake experience decreased average survival, but there is substantial variation in their mortality, with liver abnormality and alcohol dependence or other alcohol use disorders associated with a worse prognosis. Clinically, patients with these risk factors and high alcohol intake should be considered for early or intensive management. Research can usefully focus on the factors predisposing to dependence or liver abnormality.