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Background and Aims This study assessed whether a model incorporating clinical features and a polygenic score for ascending aortic diameter would improve diameter estimation and prediction of adverse thoracic aortic events over clinical features alone. Methods Aortic diameter estimation models were built with a 1.1 million-variant polygenic score (AORTA Gene) and without it. Models were validated internally in 4394 UK Biobank participants and externally in 5469 individuals from Mass General Brigham (MGB) Biobank, 1298 from the Framingham Heart Study (FHS), and 610 from All of Us. Model fit for adverse thoracic aortic events was compared in 401 453 UK Biobank and 164 789 All of Us participants. Results AORTA Gene explained more of the variance in thoracic aortic diameter compared to clinical factors alone: 39.5% (95% confidence interval 37.3%–41.8%) vs. 29.3% (27.0%–31.5%) in UK Biobank, 36.5% (34.4%–38.5%) vs. 32.5% (30.4%–34.5%) in MGB, 41.8% (37.7%–45.9%) vs. 33.0% (28.9%–37.2%) in FHS, and 34.9% (28.8%–41.0%) vs. 28.9% (22.9%–35.0%) in All of Us. AORTA Gene had a greater area under the receiver operating characteristic curve for identifying diameter ≥ 4 cm: 0.836 vs. 0.776 (P <.0001) in UK Biobank, 0.808 vs. 0.767 in MGB (P <.0001), 0.856 vs. 0.818 in FHS (P <.0001), and 0.827 vs. 0.791 (P =.0078) in All of Us. AORTA Gene was more informative for adverse thoracic aortic events in UK Biobank (P =.0042) and All of Us (P =.049). Conclusions A comprehensive model incorporating polygenic information and clinical risk factors explained 34.9%–41.8% of the variation in ascending aortic diameter, improving the identification of ascending aortic dilation and adverse thoracic aortic events compared to clinical risk factors. [ABSTRACT FROM AUTHOR]

The disorder of autism is widely recognised throughout the world. However, the diagnostic criteria and theories of autism are based on research predominantly conducted in Western cultures. Here we compare the expression of autistic traits in a sample of neurotypical individuals from one Western culture (UK) and two Eastern cultures (India and Malaysia), using the Autism-spectrum Quotient (AQ) in order to identify possible cultural differences in the expression of autistic traits. Behaviours associated with autistic traits were reported to a greater extent in the Eastern cultures than the Western culture. Males scored higher than females and science students scored higher than non-science students in each culture. Indian students scored higher than both other groups on the Imagination sub-scale, Malaysian students scored higher than both other groups on the Attention Switching sub-scale. The underlying factor structures of the AQ for each population were derived and discussed.

The role of international students as catalysts for internationalization and related reforms in the UK higher education sector is increasing. With the growing number of international students, administrators and academics are identifying ways to enable international students to adapt to the UK environment and enhance their experiences as students. This article examines the academic and other social problems that international students who pursue programmes offered by the universities in the UK encounter. It also suggests mechanisms that universities may adopt so that international students have a smooth academic progression and a comfortable social life. Describing the roles of different stakeholders in supporting international students, and the need to create a university-wide awareness of the importance of the presence of the international students in the university campus, the article suggests how universities may track the performance of drivers that foster the experiences of international students. (Contains 2 figures.)

Recent findings indicate that individuals with autism spectrum disorders (ASD) could, surprisingly, infer traits from behavioural descriptions. Now we need to know whether or not individuals with ASD are able to use trait information to identify people by their faces. In this study participants with and without ASD were presented with pairs of faces each accompanied by a sentence. One sentence allowed a trait to be inferred (e.g. "This is Ross who smiled and said hello to everyone at the party.") and one allowed a fact to be inferred (e.g. "This is Ben who has to bend down to enter most doors."). Subsequently, the same face stimuli were presented with a single descriptive trait, fact or name cue (e.g. friendly or tall and Ross or Ben respectively in the above examples). Participants had to choose which of the faces best related to the cue word. Participants with ASD performed surprisingly well in associating traits, facts, and names to the appropriate person significantly above what would be expected by chance. Indeed, they performed as well as participants without ASD. (Contains 2 tables and 3 figures.)

Aims: To compare voice quality as defined by formant analysis using a sustained vowel in patients who have undergone a partial glossectomy with a group of normal subjects. Methods & Procedures: The design consisted of a single centre, cross-sectional cohort study. The setting was an Adult Tertiary Referral Unit. A total of 26 patients (19 males) who underwent partial glossectomy and 31 normal volunteers (18 males) participated in the study. Group comparisons using the first three formant frequencies (F1, F2 and F3) using linear predictive coding (Laryngograph Ltd, London, UK) were performed. The existence of any significant difference of F1, F2 and F3 between the two groups using the sustained vowel /i/ and the effects of other factors, namely age, first presentation versus recurrence, site (oral cavity, oropharynx), subsite (anterior two-thirds of the tongue, tongue base), stage, radiation, complication, and neck dissection, were analysed. Outcomes & Results: Formant frequencies F1, F2 and F3 were normally distributed. F1 and F2 were significantly different in normal males versus females. F1, F2 and F3 were not different statistically between male and female glossectomees. Comparison of only women showed significant differences between normal subjects and patients in F2 and F3, but none in F1. This was the opposite in men where F1 was significantly different. Age, tumour presentation, site, subsite, radiation and neck dissection showed no significant difference. Postoperative complications significantly affected the F1 formant frequency. Conclusions: The study found that the formant values in patients following a partial glossectomy were altered significantly as compared with the normal control subjects. Only gender and complications and not the age, site, subsite, radiation and neck dissection were seen to influence the formant scores. (Contains 6 figures and 3 tables.)

In recent years, social work with migrants and ethnic minorities has developed as a field of research and practice. Further, it is recognised in the literature that the increased processes of human mobility in today’s societies have driven a growing focus on inclusive cities, especially in larger urban areas where ethnic diversity and cultural heterogeneity can be found alongside newly arrived migrants seeking a better quality of life, safety, and sanctuary. There is a strong link between indi‐ viduals’ well‐being and their relationship with spaces, institutions, and resources. Cities and their urban environment have been increasingly identified as key arenas where social, economic, and ecological societal challenges should be addressed. In the context of migration, municipalities have invested in dealing with both inclusive and sustainable policies. However, cities are not uniformly experienced by all. This scoping review seeks to answer how an inclusive city is conceptualised in the Swedish and the UK’s social work literature concerning migration. Using social exclusion and inclusion as the theoret‐ ical points of view, we conduct analysis using Arksey and O’Malley’s (2005) six‐stage methodological framework. Despite social work playing a major role in the social inclusion of immigrant minorities in cities, through promoting participation, there is a lack of knowledge and research on social work engagement with social inclusion, both in the fields of social policy and practices. This article contributes to an enhanced understanding of what an inclusive city is, and the role of social work in defining and developing social policies and professional interventions for inclusive cities to support the integration of migrants with distinct needs. We offer a much‐needed review of the similarities and differences between the two geogra‐ phies by analysing the social work perspectives from Sweden and the UK. [ABSTRACT FROM AUTHOR]

Machine learning tools have proven useful across biological disciplines, allowing researchers to draw conclusions from large datasets, and opening up new opportunities for interpreting complex and heterogeneous biological data. Alongside the rapid growth of machine learning, there have also been growing pains: some models that appear to perform well have later been revealed to rely on features of the data that are artifactual or biased; this feeds into the general criticism that machine learning models are designed to optimize model performance over the creation of new biological insights. A natural question arises: how do we develop machine learning models that are inherently interpretable or explainable? In this manuscript, we describe the SWIF(r) reliability score (SRS), a method building on the SWIF(r) generative framework that reflects the trustworthiness of the classification of a specific instance. The concept of the reliability score has the potential to generalize to other machine learning methods. We demonstrate the utility of the SRS when faced with common challenges in machine learning including: 1) an unknown class present in testing data that was not present in training data, 2) systemic mismatch between training and testing data, and 3) instances of testing data that have missing values for some attributes. We explore these applications of the SRS using a range of biological datasets, from agricultural data on seed morphology, to 22 quantitative traits in the UK Biobank, and population genetic simulations and 1000 Genomes Project data. With each of these examples, we demonstrate how the SRS can allow researchers to interrogate their data and training approach thoroughly, and to pair their domain-specific knowledge with powerful machine-learning frameworks. We also compare the SRS to related tools for outlier and novelty detection, and find that it has comparable performance, with the advantage of being able to operate when some data are missing. The SRS, and the broader discussion of interpretable scientific machine learning, will aid researchers in the biological machine learning space as they seek to harness the power of machine learning without sacrificing rigor and biological insight. Author summary: Machine learning methods are incredibly powerful at performing tasks such as classification and clustering, but they also pose unique problems that can limit new insights. Complex machine learning models may reach conclusions that are difficult or impossible for researchers to understand after-the-fact, sometimes producing biased or meaningless results. It is therefore essential that researchers have tools that allow them to understand how machine learning tools reach their conclusions, so that they can effectively design models. This paper builds on the machine learning method SWIF(r), originally designed to detect regions in the genome targeted by natural selection. Our new method, the SWIF(r) Reliability Score (SRS), can help researchers evaluate how trustworthy the prediction of a SWIF(r) model is when classifying a specific instance of data. We also show how SWIF(r) and the SRS can be used for biological problems outside the original scope of SWIF(r). We show that the SRS is helpful in situations where the data used to train the machine learning model fails to represent the testing data in some way. The SRS can be used across many different disciplines, and has unique properties for scientific machine learning research. [ABSTRACT FROM AUTHOR]

Background: Lifelong dietary treatment remains the mainstay for many with phenylketonuria (PKU); however, adherence is known to reduce with age. It remains unclear whether knowledge and perceptions of the PKU diet amongst adults with PKU influence dietary behaviours. Methods: A nationwide questionnaire survey was performed to investigate the knowledge and perceptions, and associated diet behaviours of adults with PKU in the UK. The survey was sent to adults with PKU under the care of the host hospital and members of the National Society of PKU. Results: One hundred and thirty‐seven respondents (n = 78 females, 56.9%) completed the survey with a mean age of 34 years and 4 months (16–65 years). Sixty (43.8%) respondents had always followed a PKU diet, 39 (28.5%) returned to diet and 35 (25.5%) were off diet. Overall mean ± SD knowledge score was 75.2% ± 13.4%, with significantly higher scores for knowledge of PKU (80.7% ± 16.2%) compared to knowledge specifically of the PKU diet (72.6% ± 14.5%, p < 0.001). Knowledge was associated with dietary adherence. Respondents who always followed a PKU diet had similar knowledge to those who returned to diet, whereas respondents off diet had significantly lower scores. Perception of the diet was not a predictor of dietary adherence, with the exception of whether patients had concerns for their long‐term health when on diet or felt well when not following a diet. Conclusions: The present study highlights the importance of ongoing dietetic input in building knowledge and skills for dietary management. Further research is needed to understand the motivators and beliefs that influence dietary adherence. Key points: Lifelong dietary treatment remains the mainstay for many with phenylketonuria (PKU); however, adherence is known to reduce with age. The present study aimed to determine whether knowledge and perceptions of the PKU diet amongst adults with PKU influence dietary behaviours. Knowledge of PKU and the PKU diet was associated with dietary adherence, highlighting the importance of ongoing dietetic input in building knowledge and skills for dietary management. Perception of the diet was not a predictor of dietary adherence. Further research is needed to understand the motivators and beliefs that influence dietary adherence. [ABSTRACT FROM AUTHOR]

Polygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) ≥1%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRScommon) with a rare variant PRS (PRSrare) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m2), obesity (BMI ≥ 30 kg/m2), and extreme obesity (BMI ≥ 40 kg/m2). We built PRSscommon and PRSsrare using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRScommon explained 10.1% of variation in BMI, and 18.3% and 22.5% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRSrare explained 1.49%, and 2.97% and 3.68%, respectively. The PRSrare was associated with an increased risk of obesity and extreme obesity (ORobesity = 1.37 per SDPRS, P obesity = 1.7x10-85; ORextremeobesity = 1.55 per SDPRS, P extremeobesity = 3.8x10-40), which was attenuated, after adjusting for PRScommon (ORobesity = 1.08 per SDPRS, P obesity = 9.8x10-6; ORextremeobesity= 1.09 per SDPRS, P extremeobesity = 0.02). When PRSrare and PRScommon are combined, the increase in explained variance attributed to PRSrare was small (incremental Nagelkerke R2 = 0.24% for obesity and 0.51% for extreme obesity). Consistently, combining PRSrare to PRScommon provided little improvement to the prediction of obesity (PRSrare AUC = 0.591; PRScommon AUC = 0.708; PRScombined AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRSrare provides limited improvement over PRScommon in the prediction of obesity risk, based on these large populations. [ABSTRACT FROM AUTHOR]

Genome‐wide association studies (GWAS) have identified several risk loci for nonalcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case‐control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co‐existing hepatic pathology, adjusting for body mass index (BMI) and adjusting for alcohol intake. A total of 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components, and genotyping batch. We performed a GWAS meta‐analysis using available summary association statistics. Six risk loci were identified (P < 5*10−8) (apolipoprotein E [APOE], patatin‐like phospholipase domain containing 3 [PNPLA3, transmembrane 6 superfamily member 2 [TM6SF2], glucokinase regulator [GCKR], mitochondrial amidoxime reducing component 1 [MARC1], and tribbles pseudokinase 1 [TRIB1]). All loci retained significance in sensitivity analyses without co‐existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals), with others demonstrating consistent direction and magnitude of effect. All six loci were significant on meta‐analysis. Rs429358 (P = 2.17*10−11) is a missense variant within the APOE gene determining ϵ4 versus ϵ2/ϵ3 alleles. The ϵ4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95% confidence interval 0.78‐0.90] and homozygotes 0.64 [0.50‐0.79]). Conclusion: This GWAS replicates six known NAFLD‐susceptibility loci and confirms that the ϵ4 allele of APOE is associated with protection against NAFLD. The results are consistent with published GWAS using histological and radiological measures of NAFLD, confirming that NAFLD identified through diagnostic codes from consensus guidelines is a valid alternative to more invasive and costly approaches. [ABSTRACT FROM AUTHOR]

The ORNATE India project is an interdisciplinary, multifaceted United Kingdom (UK)-India collaborative study aimed to build research capacity and capability in India and the UK to tackle the burden of diabetes-related visual impairment. For 51 months (October 2017-December 2021), this project built collaboration between six institutions in the UK and seven in India, including the Government of Kerala. Diabetic retinopathy (DR) screening models were evaluated in the public system in Kerala. An epidemiological study of diabetes and its complications was conducted through 20 centers across India covering 10 states and one union territory. The statistical analysis is not yet complete. In the UK, risk models for diabetes and its complications and artificial intelligence-aided tools are being developed. These were complemented by joint studies on various aspects of diabetes between collaborators in the UK and India. This interdisciplinary team enabled increased capability in several workstreams, resulting in an increased number of publications, development of cost-effective risk models, algorithms for risk-based screening, and policy for state-wide implementation of sustainable DR screening and treatment programs in primary care in Kerala. The increase in research capacity included multiple disciplines from field workers, administrators, project managers, project leads, screeners, graders, optometrists, nurses, general practitioners, and research associates in various disciplines. Cross-fertilization of these disciplines enabled the development of several collaborations external to this project. This collaborative project has made a significant impact on research capacity development in both India and the UK. [ABSTRACT FROM AUTHOR]

In this article, we present Biologically Annotated Neural Networks (BANNs), a nonlinear probabilistic framework for association mapping in genome-wide association (GWA) studies. BANNs are feedforward models with partially connected architectures that are based on biological annotations. This setup yields a fully interpretable neural network where the input layer encodes SNP-level effects, and the hidden layer models the aggregated effects among SNP-sets. We treat the weights and connections of the network as random variables with prior distributions that reflect how genetic effects manifest at different genomic scales. The BANNs software uses variational inference to provide posterior summaries which allow researchers to simultaneously perform (i) mapping with SNPs and (ii) enrichment analyses with SNP-sets on complex traits. Through simulations, we show that our method improves upon state-of-the-art association mapping and enrichment approaches across a wide range of genetic architectures. We then further illustrate the benefits of BANNs by analyzing real GWA data assayed in approximately 2,000 heterogenous stock of mice from the Wellcome Trust Centre for Human Genetics and approximately 7,000 individuals from the Framingham Heart Study. Lastly, using a random subset of individuals of European ancestry from the UK Biobank, we show that BANNs is able to replicate known associations in high and low-density lipoprotein cholesterol content. Author summary: A common goal in genome-wide association (GWA) studies is to characterize the relationship between genotypic and phenotypic variation. Linear models are widely used tools in GWA analyses, in part, because they provide significance measures which detail how individual single nucleotide polymorphisms (SNPs) are statistically associated with a trait or disease of interest. However, traditional linear regression largely ignores non-additive genetic variation, and the univariate SNP-level mapping approach has been shown to be underpowered and challenging to interpret for certain trait architectures. While nonlinear methods such as neural networks are well known to account for complex data structures, these same algorithms have also been criticized as "black box" since they do not naturally carry out statistical hypothesis testing like classic linear models. This limitation has prevented nonlinear regression approaches from being used for association mapping tasks in GWA applications. Here, we present Biologically Annotated Neural Networks (BANNs): a flexible class of feedforward models with partially connected architectures that are based on biological annotations. The BANN framework uses approximate Bayesian inference to provide interpretable probabilistic summaries which can be used for simultaneous (i) mapping with SNPs and (ii) enrichment analyses with SNP-sets (e.g., genes or signaling pathways). We illustrate the benefits of our method over state-of-the-art approaches using extensive simulations. We also demonstrate the ability of BANNs to recover novel and previously discovered genomic associations using quantitative traits from the Wellcome Trust Centre for Human Genetics, the Framingham Heart Study, and the UK Biobank. [ABSTRACT FROM AUTHOR]

The endonasal transsphenoidal approach (TSA) has emerged as the preferred approach in order to treat pituitary adenoma and related sellar pathologies. The recently adopted expanded endonasal approach (EEA) has improved access to the ventral skull base whilst retaining the principles of minimally invasive surgery. Despite the advantages these approaches offer, cerebrospinal fluid (CSF) rhinorrhoea remains a common complication. There is currently a lack of comparative evidence to guide the best choice of skull base reconstruction, resulting in considerable heterogeneity of current practice. This study aims to determine: (1) the scope of the methods of skull base repair; and (2) the corresponding rates of postoperative CSF rhinorrhoea in contemporary neurosurgical practice in the UK and Ireland. We will adopt a multicentre, prospective, observational cohort design. All neurosurgical units in the UK and Ireland performing the relevant surgeries (TSA and EEA) will be eligible to participate. Eligible cases will be prospectively recruited over 6 months with 6 months of postoperative follow-up. Data points collected will include: demographics, tumour characteristics, operative data), and postoperative outcomes. Primary outcomes include skull base repair technique and CSF rhinorrhoea (biochemically confirmed and/or requiring intervention) rates. Pooled data will be analysed using descriptive statistics. All skull base repair methods used and CSF leak rates for TSA and EEA will be compared against rates listed in the literature. Formal institutional ethical board review was not required owing to the nature of the study – this was confirmed with the Health Research Authority, UK. The need for this multicentre, prospective, observational study is highlighted by the relative paucity of literature and the resultant lack of consensus on the topic. It is hoped that the results will give insight into contemporary practice in the UK and Ireland and will inform future studies. [ABSTRACT FROM AUTHOR]

Introduction: We have previously reported rates of diagnosis of male hypogonadism in United Kingdom (UK) general practices. We aimed to identify factors associated with testosterone prescribing in UK general practice. Methods: We determined for 6741 general practices in England, the level of testosterone prescribing in men and the relation between volume of testosterone prescribing and (1) demographic characteristics of the practice, (2) % patients with specific comorbidities and (3) national GP patient survey results. Results: The largest volume (by prescribing volume) agents were injectable preparations at a total cost in the 12‐month period 2018/19 of £8,172,519 with gel preparations in second place: total cost £4,795,057. Transdermal patches, once the only alternative to testosterone injections or implants, were little prescribed: total cost £222,022. The analysis accounted for 0.27 of the variance in testosterone prescribing between general practices. Thus, most of this variance was not accounted for by the analysis. There was a strong univariant relation (r =.95, P <.001) between PDE5‐I prescribing and testosterone prescribing. Other multivariant factors independently linked with more testosterone prescribing were as follows: HIGHER proportion of men with type 2 diabetes(T2DM) on target control (HbA1c ≤ 58 mmol/mol) and HIGHER overall practice rating on the National Patient Survey for good experience, while non‐white ethnicity and socio‐economic deprivation were associated with less testosterone prescribing. There were a number of comorbidity factors associated with less prescribing of testosterone (such as T2DM, hypertension and stroke/TIA). Conclusion: Our analysis has indicated that variation between general practices in testosterone prescribing in a well developed health economy is only related to small degree (r2 = 0.27) to factors that we can define. This suggests that variation in amount of testosterone prescribed is largely related to general practitioner choice/other factors not studied and may be amenable to measures to increase knowledge/awareness of male hypogonadism, with implications for men's health. [ABSTRACT FROM AUTHOR]

The Ottawa subarachnoid haemorrhage (SAH) rule and the Emerald SAH rule are clinical decision tools to aid in the decision for computed tomography (CT) of the head in patients attending an emergency department (ED) with acute non-traumatic headache. The objective of this study was to analyse the performance of these rules in a contemporary UK cohort. Methods We performed a retrospective external validation study. Patients undergoing CT of the head for the evaluation and treatment of non-traumatic headaches over a 6-month period in the ED at two tertiary centres were assessed. Each patient's Ottawa rule and Emerald rule were calculated and compared with their final diagnosis. Results The cohort consisted of 366 patients and there were 16 cases of SAH (based on CT findings or the presence of xanthochromia in cerebrospinal fluid). The Ottawa rule identified 288 patients requiring CT of the head. The sensitivity of the Ottawa rule was 100% (95% confidence interval (CI) 71--100%) and the specificity was 22% (95% CI 18--27%). The Emerald rule identified 267 patients who required CT, and achieved a sensitivity of 81% (95% CI 54--96%) and a specificity of 27% (95% CI 23--32%). Conclusions The Ottawa SAH rule correctly identified all patients with SAH in this contemporary cohort. The Emerald rule did not perform as well in this cohort and is unsuitable for clinical use. The Ottawa rule is a useful tool to aid in the decision for CT of the head in patients presenting with acute non-traumatic headache to the ED. [ABSTRACT FROM AUTHOR]

Purpose: A potential method to relieve the pain from medial osteoarthritis of the knee is to offload the medial compartment. The Latella™ Knee Implant is a novel device designed to offload the medial compartment. The objective of the Cotera-1 study was to evaluate the preliminary safety and feasibility of the Latella implant to treat patients with medial OA of the knee, by a 2-year follow-up of a prospective multicenter feasibility study (Cotera-1) performed in the Netherlands and UK Methods: In this first-in-man study, 11 participants received the Latella implant and were followed for 2 years, documenting physician assessment, Patient-Reported Outcome (PRO) scoring (KOOS, IKDC, Kujala, SF-36); Patient Global Assessment (PGA), radiographic analysis and MRI analysis, complications, reoperation rate and hip–knee–ankle axis. Results: The Latella Knee Implant system proved to be well tolerated and demonstrated a low-risk safety profile up to 24 months post-treatment. A responder analysis was performed of the subjects who still had the Latella implanted at 24-month time point (n = 9). Based on a MCID of eight for KOOS pain sub-scale, 78% of the subjects at the 24 month time point would be considered as responders. Similarly, based on improvement in the medial knee pain compared to baseline using the NRS scale of 1–10, 89% of the subjects at the 24-month time point would be considered as responders. Two patients were revised during follow-up: one for arthrofibrosis and one converted to TKA for progression of OA. Conclusions: The early clinical experience with the Latella Knee Implant in this pilot feasibility study has been encouraging. It appears to be a safe implant with possible effect on medial OA. Additional studies need to be performed to assess the safety and efficacy of the procedure in a larger patient population. Level of evidence: II [ABSTRACT FROM AUTHOR]

Traditional univariate genome-wide association studies generate false positives and negatives due to difficulties distinguishing associated variants from variants with spurious nonzero effects that do not directly influence the trait. Recent efforts have been directed at identifying genes or signaling pathways enriched for mutations in quantitative traits or case-control studies, but these can be computationally costly and hampered by strict model assumptions. Here, we present gene-ε, a new approach for identifying statistical associations between sets of variants and quantitative traits. Our key insight is that enrichment studies on the gene-level are improved when we reformulate the genome-wide SNP-level null hypothesis to identify spurious small-to-intermediate SNP effects and classify them as non-causal. gene-ε efficiently identifies enriched genes under a variety of simulated genetic architectures, achieving greater than a 90% true positive rate at 1% false positive rate for polygenic traits. Lastly, we apply gene-ε to summary statistics derived from six quantitative traits using European-ancestry individuals in the UK Biobank, and identify enriched genes that are in biologically relevant pathways. Author summary: Enrichment tests augment the standard univariate genome-wide association (GWA) framework by identifying groups of biologically interacting mutations that are enriched for associations with a trait of interest, beyond what is expected by chance. These analyses model local linkage disequilibrium (LD), allow many different mutations to be disease-causing across patients, and generate biologically interpretable hypotheses for disease mechanisms. However, existing enrichment analyses are hampered by high computational costs, and rely on GWA summary statistics despite the high false positive rate of the standard univariate GWA framework. Here, we present the gene-level association framework gene-ε (pronounced "genie"), an empirical Bayesian approach for identifying statistical associations between sets of mutations and quantitative traits. The central innovation of gene-ε is reformulating the GWA null model to distinguish between (i) mutations that are statistically associated with the disease but are unlikely to directly influence it, and (ii) mutations that are most strongly associated with a disease of interest. We find that, with our reformulated SNP-level null hypothesis, our gene-level enrichment model outperforms existing enrichment methods in simulation studies and scales well for application to emerging biobank datasets. We apply gene-ε to six quantitative traits in the UK Biobank and recover novel and functionally validated gene-level associations. [ABSTRACT FROM AUTHOR]

Background: Alirocumab is a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) and has been previously shown, in the phase III ODYSSEY clinical trial program, to provide significant lowering of low-density lipoprotein cholesterol (LDL-C) and reduction in risk of major adverse cardiovascular events. However, real-world evidence to date is limited. Objective: The primary objective was to describe baseline characteristics, clinical history, and prior lipid-lowering therapy (LLT) use of patients initiated on alirocumab in UK clinical practice following publication of health technology appraisal (HTA) body recommendations. Secondary objectives included description of alirocumab use and lipid parameter outcomes over a 4-month follow-up period. Methods: In this retrospective, single-arm, observational, multicenter study, data were collected for 150 patients initiated on alirocumab. Results: Mean (standard deviation; SD) age of patients was 61.4 (10.5) years and baseline median (interquartile range; IQR) LDL-C level was 4.8 (4.2–5.8) mmol/l. Alirocumab use occurred predominantly in patients with heterozygous familial hypercholesterolemia (HeFH) (n = 100/150, 66%) and those with statin intolerance (n = 123/150, 82%). Most patients started on alirocumab 75 mg (n = 108/150 [72%]) and 35 (23.3%) were up-titrated to 150 mg. Clinically significant reductions in atherogenic lipid parameters were observed with alirocumab, including LDL-C (median [IQR] change from baseline, − 53.6% [− 62.9 to − 34.9], P < 0.001). Conclusion: This study highlights the unmet need for additional LLT in patients with uncontrolled hyperlipidemia and demonstrates the clinical utility of alirocumab in early real-world practice, where dosing flexibility is an important attribute of this therapeutic option. [ABSTRACT FROM AUTHOR]

Abstract In the last decade preterm birth rates have continued to rise hand in hand with improving neonatal care. Unfortunately rates of severe disability have remained static. National benchmarking of key outcomes shows significant variations in adaptation of best practices across United Kingdom (UK). While emerging technologies give us a glimpse of fascinating possibilities, widespread adoption of evidence-based interventions should remain a priority. In this article we have attempted to outline mechanisms of preterm brain injury and identify the most promising strategies currently available to minimize it. Quality improvement strategies (QI) that can help perinatal teams adopt best practices and promising new therapies are discussed. [ABSTRACT FROM AUTHOR]

Neonatal hyperbilirubinaemia is an extremely common condition which continues to be a significant cause of readmission of neonates to hospitals. The aim of early recognition and appropriate treatment is to prevent bilirubin encephalopathy which can cause severe neurodisability. This article reviews the national guidelines issued by various organizations like American Academy of Paediatrics in USA and National Institute of Clinical Excellence in the UK which have attempted to standardize approaches to diagnosis and management. This review highlights how early detection with measurement of bilirubin as opposed to visual estimation and appropriate use of high intensity phototherapy based on recommended treatment threshold charts reduces the incidence of severe jaundice requiring exchange transfusion and how evaluation and support of new mothers and their babies in the community by trained nurses with access to transcutaneous bilirubinometers can reduce hospital referrals while providing safe care at home. [ABSTRACT FROM AUTHOR]

Background: Musculoskeletal symptoms are common reasons for patients seeking medical attention. Basic competency in musculoskeletal medicine is therefore essential for all clinicians. To our knowledge, this is the first assessment of the competency in musculoskeletal medicine of medical students in the United Kingdom. Methods: Medical students were enrolled after passing final university examinations and being awarded degrees of Bachelor of Medicine, Bachelor of Surgery (MBBS) or Medicinae Baccalaureus, Baccalaureus Chirurgiae (MBChB) in 2013 and were assessed with use of the Freedman and Bernstein musculoskeletal cognitive examination tool. Results: Two hundred and thirty students were recruited, of whom 210 were suitable for inclusion. Only 21% (forty-four students) passed the assessment. Mandatory exposure to musculoskeletal medicine during medical school consisted of orthopaedics for 100% of participants for a mean duration of 2.65 weeks, rheumatology for 96% of participants for a mean duration of 2.5 weeks, and sports medicine for 1% of participants for a mean duration of two weeks. There was a significant difference (p = 0.002) in scores between those with career interests in musculoskeletal specialties (69.3%) and the rest of the cohort (54.9%). There was also a significant difference (p = 0.001) in scores between participants with career interests in general practice (42%) and the rest of the cohort (56%). Only 40% of participants considered themselves competent in musculoskeletal medicine. Fifty-five percent thought that musculoskeletal conditions would be an important component of their future practice. Conclusions: Our findings suggest that medical schools may be currently failing to ensure that medical students have a basic competence in musculoskeletal medicine. Further investigation is warranted to fully assess the current training provided by U.K. medical schools in musculoskeletal medicine, and appropriate steps must be taken to improve the quantity and quality of training in musculoskeletal medicine in the United Kingdom. [ABSTRACT FROM AUTHOR]

Twenty-three chronic schizophrenic patients and 23 controls, all males between 20 and 40 years of age, were evaluated by CT scan. The lateral, third and fourth ventricles, the Sylvian fissures, and the largest sulcus from each of the frontal, parietal, and occipital lobes, were measured in order to determine whether the previously reported ventriculomegaly in schizophrenics was perhaps due to a disturbance of CSF flow or to atrophy, two common causes of ventricular enlargement. We found that in the schizophrenic group the third and fourth ventricles and both Sylvian fissures were significantly enlarged, but not the lateral ventricles or cerebral sulci. Our data suggest that these ventricular changes are not due to a disturbance of CSF flow or to cerebral atrophy. Other possible explanations are discussed. [ABSTRACT FROM AUTHOR]

Abstract: Statistical analysis of previous fire incidents in the UK has been carried out with the intent of providing an evidence base in the creation of a decision support system tool for UK fire engineering consultants to aid in the design of cost effective fire engineered structures. Analysis of the fire incident data has shown that the data collected until 2008 in the UK is very binary in nature and this has made it difficult to create an accurately predicting damage model. Even though statistical modelling of the data proved to be inaccurate, cost comparisons of other data sets (loss adjustors costs and UK building costs) was carried out and discussed, allowing the cost of fires to be calculated using over time should the data provided by the new Fire and Rescue Service data collection methods allow for collection of data in a non binary form. [Copyright &y& Elsevier]

Background: The definitions of performance, competence and competency are not very clear in the literature. The assessment of performance and the selection of tools for this purpose depend upon a deep understanding of each of the above terms and the factors influencing performance. Aim: In this article, we distinguish between competence and competency and explain the relationship of competence and performance in the light of the Dreyfus model of skills acquisition. We briefly critique the application of the principles described by Miller to the modern assessment tools and distinguish between assessment of actual performance in workplace settings and the observed performance, demonstrated by the candidates in the workplace or simulated settings. Results: We describe a modification of the Dreyfus model applicable to assessments in healthcare and propose a new model for the assessment of performance and performance rating scale (PRS) based on this model. Conclusion: We propose that the use of adapted versions of this PRS will result in benchmarking of performance and allowing the candidates to track their progression of skills in various areas of clinical practice. [ABSTRACT FROM AUTHOR]

Summary Background The nonstructural 3 serine protease inhibitors ( PIs), boceprevir and telaprevir, represent the first in a new generation of directly acting antivirals against genotype 1 hepatitis C ( HCV) infection. When used in combination with pegylated interferon and ribavirin, these drugs greatly improve sustained virological response rates in both treatment-naïve patients and patients who have had previous virological failure on treatment. However, the addition of these new agents will increase the complexity of therapeutic regimens, the rates of side-effects and costs. Aims To review concisely the current evidence and to suggest current best practice, for the use of telaprevir and boceprevir in the management of chronic genotype 1 HCV infection. Methods These guidelines for the use of boceprevir and telaprevir have been formulated following extensive review of the current literature, are based on the consensus opinion of a panel of national experts, and have been openly discussed and debated at a national meeting of HCV care providers. Results We have made recommendations on a number of the key practical issues facing HCV care providers: (i) Which patients to treat?; (ii) Standards for the provision of care; (iii) Pre-treatment considerations; (iv) Which treatment regimens to use?; (v) Stopping rules; and (vi) Management of adverse effects. Finally, we have produced suggested algorithms for the assessment and treatment of these patients. Conclusions These UK Consensus guidelines indicate the current best practice for the use of boceprevir and telaprevir in the management of genotype 1 chronic HCV infection. [ABSTRACT FROM AUTHOR]

Purpose - High-secure hospital patients often have complex presentations that are marked by co-morbidity, violence, histories of poor concordance with oral medication, and treatment resistance. The ability to give a long-acting medication with a low propensity for extra pyramidal side effects is of potential value to clinicians treating these patients. Risperidone Long-acting Injection (RLAI) is the first long-acting atypical antipsychotic medication and may be potentially useful in this population. This paper aims to investigate this issue.Design/methodology/approach - This was a retrospective, naturalistic study to investigate the use and effectiveness, using hard outcome measures, of RLAI in the four UK high-secure psychiatric hospitals. Hospital pharmacy databases at Ashworth, Broadmoor, Carstairs and Rampton hospitals were used to identify all patients who had been prescribed RLAI. Anonymised data were then obtained from the pharmacy databases and case notes which were then pooled.Findings - A total of 159 patients were prescribed RLAI, most of whom had schizophrenia. The mean length of treatment with RLAI was 65 weeks (range two to 260 weeks) and the mean maximum dose was 43.2mg every two weeks (range 25-75mg every two weeks). No serious adverse effects were reported. In total, 42 per cent (67) patients responded to RLAI in as much as that they either remained on it in the long-term or were discharged to conditions of lower security whilst taking it. As there was no control group, it is not possible to determine if RLAI was a significant factor in such discharges to conditions of lower security. Of those patients who failed to respond to RLAI, 44 per cent were subsequently treated with clozapine.Originality/value - This pragmatic multi-centre study of a small but complex patient group demonstrated that RLAI was effective in 42 per cent of patients and was well-tolerated. [ABSTRACT FROM AUTHOR]

The article shows the role of biogas as one of the energy sources in the United States of America and several European Union countries. The advantages of biogas recovery and increased financial support from state and federal programs have led to a substantial increase in the number of systems in the United States. Great Britain and Germany are the leading European countries in terms of crude biogas production and utilization. Sweden has problems with the inefficient utilization of manure instruments. There is no activity regarding of waste treatment in Spain. A chart of estimated energy production from biogas in the year 2020 is presented.

This paper examines how the Bank of England conducts monetary policy in practice and assesses its policy preferences. Our empirical results using monthly ex post inflation forecast suggest that pursued policy can be characterized by a nonlinear policy reaction function with a deflation bias. We also find evidence of a target range as opposed to a point target for the 1992–5 period. These results are however, not robust to the use of the Bank's own forecast which suggests that pursued policy is consistent with a symmetric point target for inflation. In practice however, inflation has been consistently below the Bank's inflation target in recent years. We argue that a plausible explanation for this is that the MPC had systematically over predicted inflation, which in turn may have resulted in overly restrictive policy. [ABSTRACT FROM AUTHOR]

The article analyzes the impact of British guidelines on the treatment of chronic hepatitis C. It discusses the effect that the guidelines would have on decisions facing clinicians. It explores the goal of the guidelines to shorten the treatment duration. The concern over the increased rate of side effects of the treatment of chronic hepatitis C is also addressed.

The article focuses on chlamydia, the most commonly known bacterial sexually transmitted infection. Complications of untreated chlamydia infection include pelvic inflammatory disease that could lead to infertility or ectopic pregnancy, sexually acquired reactive arthritis and epididymo-orchitis. The British Association for Sexual Health and human immunodeficiency virus (HIV) has produced guidelines on the management of chlamydia. Part of chlamydia management is the identification and treatment of sexual contacts.

• Fasting status when checking serum testosterone (T) is the subject of much debate. • No significant difference was seen between paired non-fasting vs fasting T levels. • Wide variation in T levels was observed in non-fasting & fasting samples. • Analytical & intra-subject biological variation account for much of the difference. • Non-requirement of fasting would remove a hurdle in the diagnosis of hypogonadism. As circulating testosterone may be suppressed in the post-prandial state, it has been recommended that measurements are carried out with the patient fasted. In this regard, we assessed the effect of fasting/non-fasting status on total testosterone (T) levels in men. Data was collected in a single UK Hospital in men with two serum T requests taken within a 6-month period of each other and sampled at a time of day ≤ 2 h apart. Three groups were established, with T levels compared via signed-rank test in men with both a fasting and non-fasting sample (Group 1; n = 69), and in men with paired non-fasting (Group 2; n = 126) and paired fasting (Group 3; n = 18) samples. The differences in T levels between the paired samples was compared between the three groups using the rank-sum test and also via multiple regression analysis with the groups factorised. Median (Interquartile Range, IQR) age did not vary significantly between Groups 1, 2 and 3 at 49 (38–56), 51.5 (42–60) and 51.5 (40–59) years, respectively. No significant difference (p = 0.89) was found between the T levels in Group 1 with non-fasting (median (IQR) T = 11.1 (9.3–13.6) nmol/L) versus fasting samples T = 10.8 (8.9–14.1) nmol/L). Paired T levels did not significantly differ in each of the other two groups (2 and 3). There was no significant association between the differences in paired T levels between the three groups, even when the model was adjusted for age and time, with Group 1 (as reference) versus Group 2 (p = 0.79) and versus Group 3 (p = 0.63). We found no significant differences between fasting and non-fasting T levels. A definitive confirmatory study is required to determine whether fasting status is necessary to diagnose hypogonadism. Non-requirement of fasting status when checking testosterone levels would remove a major hurdle in the diagnosis of hypogonadism. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes is a serious clinical problem in both India and the UK. Adoption of a healthy lifestyle through dietary and physical activity modification can help prevent type 2 diabetes. However, implementing lifestyle modification programmes to high risk groups is expensive and alternative cheaper methods are needed. We are using a short messaging service (SMS) programme in our study as a tool to provide healthy lifestyle advice and an aid to motivation. The aim of the study is to assess the efficacy and user acceptability of text messaging employed in this way for people with pre-diabetes (HbA1c 6.0% to ≤6.4%; 42–47 mmol/mol) in the UK and India. Methods/design: This is a randomised, controlled trial with participants followed up for 2 years. After being screened and receiving a structured education programme for prediabetes, participants are randomised to a control or intervention group. In the intervention group, text messages are delivered 2–3 times weekly and contain educational, motivational and supportive content on diet, physical activity, lifestyle and smoking. The control group undergoes monitoring only. In India, the trial involves 5 visits after screening (0, 6, 12, 18 and 24 months). In the UK there are 4 visits after screening (0, 6, 12 and 24 months). Questionnaires (EQ-5D, RPAQ, Transtheoretical Model of Behavioural Change, and food frequency (UK)/24 h dietary recall (India)) and physical activity monitors (Actigraph GT3X+ accelerometers) are assessed at baseline and all follow-up visits. The SMS acceptability questionnaires are evaluated in all follow-up visits. The primary outcome is progression to type 2 diabetes as defined by an HbA1c of 6.5% or over(India) and by any WHO criterion(UK). Secondary outcomes are the changes in body weight, body mass index, waist circumference, blood pressure, fasting plasma glucose; lipids; proportion of participants achieving HbA1c ≤6.0%; HOMA-IR; HOMA-β; acceptability of SMS; dietary parameters; physical activity and quality of life. Discussion: The study is designed to assess the efficacy of tailored text messaging in addition to standard lifestyle advice to reduce the progression from prediabetes to type 2 diabetes in the two different countries. Trial registration: ClinicalTrials.gov; NCT01570946, 4th April 2012 (India); NCT01795833, 21st February 2013 (UK). [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses clinical anaesthetics training in medical schools in Great Britain.

LD score regression (LDSC) is a method to estimate narrow-sense heritability from genome-wide association study (GWAS) summary statistics alone, making it a fast and popular approach. In this work, we present interaction-LD score (i-LDSC) regression: an extension of the original LDSC framework that accounts for interactions between genetic variants. By studying a wide range of generative models in simulations, and by re-analyzing 25 well-studied quantitative phenotypes from 349,468 individuals in the UK Biobank and up to 159,095 individuals in BioBank Japan, we show that the inclusion of a cis-interaction score (i.e. interactions between a focal variant and proximal variants) recovers genetic variance that is not captured by LDSC. For each of the 25 traits analyzed in the UK Biobank and BioBank Japan, i-LDSC detects additional variation contributed by genetic interactions. The i-LDSC software and its application to these biobanks represent a step towards resolving further genetic contributions of sources of non-additive genetic effects to complex trait variation. [ABSTRACT FROM AUTHOR]

Presents information on a study which determined whether the Framingham model accurately predicts the risk of coronary heart disease among white men and women in Great Britain. Methods used in the study; Proportion of men and women who had developed heart disease; Number of coronary events predicted by the Framingham model and the number observed during follow up.

Examines a case of symtomatic fever having encephalopathy with clinical features of brain-stem involvement in Great Britain. Mortality rate from the complication of typhoid fever; Pathological process in the brain causing typhoid encephalopathy in the patient; Factors attributing to the occurrence of neurological manifestations.

A letter to the editor is presented discussing the BioMedical Admissions Test (BMAT) and the United Kingdom Clinical Aptitude Test (UKCAT), responding to the 2009 "Medical Education" article "The predictive validity of the BioMedical Admissions Test for pre-clinical examination performance," by J. L. Emery and J. F. Bell.

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with an increased risk of cardiovascular diseases (CVDs), putatively via inflammasome activation. We pursued an inflammatory gene modifier scan for CHIP-associated CVD risk among 424,651 UK Biobank participants. We identified CHIP using whole-exome sequencing data of blood DNA and modeled as a composite, considering all driver genes together, as well as separately for common drivers (DNMT3A, TET2, ASXL1, and JAK2). We developed predicted gene expression scores for 26 inflammasome-related genes and assessed how they modify CHIP-associated CVD risk. We identified IL1RAP as a potential key molecule for CHIP-associated CVD risk across genes and increased AIM2 gene expression leading to heightened JAK2- and ASXL1-associated CVD risk. We show that CRISPR-induced Asxl1-mutated murine macrophages had a particularly heightened inflammatory response to AIM2 agonism, associated with an increased DNA damage response, as well as increased IL-10 secretion, mirroring a CVDprotective effect of IL10 expression in ASXL1 CHIP. Our study supports the role of inflammasomes in CHIP-associated CVD and provides evidence to support gene-specific strategies to address CHIP-associated CVD risk. [ABSTRACT FROM AUTHOR]

The VOL4002 study assessed the efficacy and safety of volanesorsen in 22 adults with genetically confirmed familial chylomicronaemia syndrome (FCS) treated in the UK Early Access to Medicines Scheme (EAMS), with ("prior exposure") or without ("treatment naive") previous treatment in the APPROACH and/or APPROACH-OLE volanesorsen phase 3 studies. Data collection focused on triglyceride (TG) levels, platelet counts and pancreatitis events. Pancreatitis incidence during volanesorsen treatment was compared against the 5-year period preceding volanesorsen exposure. Volanesorsen 285 mg was self-administered subcutaneously once every 2 weeks. Individual patient volanesorsen exposure ranged from 6 to 51 months (total cumulative exposure, 589 months). Among treatment-naive patients (n = 12), volanesorsen treatment resulted in an averaged median 52% reduction (−10.6 mmol/L) from baseline (26.4 mmol/L) in TG levels at 3 months, which were maintained through time points over 15 months of treatment (47%–55% reductions). Similarly, prior-exposure patients (n = 10) experienced a 51% reduction (−17.8 mmol/L) from pre-treatment baseline (28.0 mmol/L), with reductions of 10%–38% over 21 months of treatment. A comparison of pancreatitis event rates found a 74% reduction from the 5-year period before (one event/2.8 years) and during (one event/11.0 years) volanesorsen treatment. Platelet declines were consistent with observations in phase 3 clinical trials. No patient recorded a platelet count <50 × 109/L. This longitudinal study supports the efficacy of volanesorsen in patients with FCS for lowering TG levels over treatment periods up to 51 months with no apparent safety signals related to increased duration of exposure. [Display omitted] • Volanesorsen is approved in Europe to treat familial chylomicronaemia syndrome. • Long-term triglyceride reduction (up to 51 months) is maintained with volanesorsen. • No new safety signals were associated with increased exposure to volanesorsen. • Volanesorsen is an effective treatment option for familial chylomicronaemia syndrome. [ABSTRACT FROM AUTHOR]

Since 2005, genome-wide association (GWA) datasets have been largely biased toward sampling European ancestry individuals, and recent studies have shown that GWA results estimated from self-identified European individuals are not transferable to non-European individuals because of various confounding challenges. Here, we demonstrate that enrichment analyses that aggregate SNP-level association statistics at multiple genomic scales—from genes to genomic regions and pathways—have been underutilized in the GWA era and can generate biologically interpretable hypotheses regarding the genetic basis of complex trait architecture. We illustrate examples of the robust associations generated by enrichment analyses while studying 25 continuous traits assayed in 566,786 individuals from seven diverse self-identified human ancestries in the UK Biobank and the Biobank Japan as well as 44,348 admixed individuals from the PAGE consortium including cohorts of African American, Hispanic and Latin American, Native Hawaiian, and American Indian/Alaska Native individuals. We identify 1,000 gene-level associations that are genome-wide significant in at least two ancestry cohorts across these 25 traits as well as highly conserved pathway associations with triglyceride levels in European, East Asian, and Native Hawaiian cohorts. [Display omitted] [ABSTRACT FROM AUTHOR]

Purpose: Hypofractionated radiation therapy can be used to treat patients with muscle-invasive bladder cancer unable to have radical therapy. Toxicity is a key concern, but adaptive plan-of the day (POD) image-guided radiation therapy delivery could improve outcomes by minimizing the volume of normal tissue irradiated. The HYBRID trial assessed the multicenter implementation, safety, and efficacy of this strategy.Methods: HYBRID is a Phase II randomized trial that was conducted at 14 UK hospitals. Patients with T2-T4aN0M0 muscle-invasive bladder cancer unsuitable for radical therapy received 36 Gy in 6 weekly fractions, randomized (1:1) to standard planning (SP) or adaptive planning (AP) using a minimization algorithm. For AP, a pretreatment cone beam computed tomography (CT) was used to select the POD from 3 plans (small, medium, and large). Follow-up included standard cystoscopic, radiologic, and clinical assessments. The primary endpoint was nongenitourinary Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 (≥G3) toxicity within 3 months of radiation therapy. A noncomparative single stage design aimed to exclude ≥30% toxicity rate in each planning group in patients who received ≥1 fraction of radiation therapy. Local control at 3-months (both groups combined) was a key secondary endpoint.Results: Between April 15, 2014, and August 10, 2016, 65 patients were enrolled (SP, n = 32; AP, n = 33). The median follow-up time was 38.8 months (interquartile range [IQR], 36.8-51.3). The median age was 85 years (IQR, 81-89); 68% of participants (44 of 65) were male; and 98% of participants had grade 3 urothelial cancer. In 63 evaluable participants, CTCAE ≥G3 nongenitourinary toxicity rates were 6% (2 of 33; 95% confidence interval [CI], 0.7%-20.2%) for the AP group and 13% (4 of 30; 95% CI, 3.8%-30.7%) for the SP group. Disease was present in 9/48 participants assessed at 3 months, giving a local control rate of 81.3% (95% CI, 67.4%-91.1%).Conclusions: POD adaptive radiation therapy was successfully implemented across multiple centers. Weekly ultrahypofractionated 36 Gy/6 fraction radiation therapy is safe and provides good local control rates in this older patient population. [ABSTRACT FROM AUTHOR]

Emerging large-scale biobanks pairing genotype data with phenotype data present new opportunities to prioritize shared genetic associations across multiple phenotypes for molecular validation. Past research, by our group and others, has shown gene-level tests of association produce biologically interpretable characterization of the genetic architecture of a given phenotype. Here, we present a new method, Ward clustering to identify Internal Node branch length outliers using Gene Scores (WINGS), for identifying shared genetic architecture among multiple phenotypes. The objective of WINGS is to identify groups of phenotypes, or "clusters," sharing a core set of genes enriched for mutations in cases. We validate WINGS using extensive simulation studies and then combine gene-level association tests with WINGS to identify shared genetic architecture among 81 case-control and seven quantitative phenotypes in 349,468 European-ancestry individuals from the UK Biobank. We identify eight prioritized phenotype clusters and recover multiple published gene-level associations within prioritized clusters. [ABSTRACT FROM AUTHOR]

Meiotic nondisjunction and resulting aneuploidy can lead to severe health consequences in humans. Aneuploidy rescue can restore euploidy but may result in uniparental disomy (UPD), the inheritance of both homologs of a chromosome from one parent with no representative copy from the other. Current understanding of UPD is limited to ∼3,300 case subjects for which UPD was associated with clinical presentation due to imprinting disorders or recessive diseases. Thus, the prevalence of UPD and its phenotypic consequences in the general population are unknown. We searched for instances of UPD across 4,400,363 consented research participants from the personal genetics company 23andMe, Inc., and 431,094 UK Biobank participants. Using computationally detected DNA segments identical-by-descent (IBD) and runs of homozygosity (ROH), we identified 675 instances of UPD across both databases. We estimate that UPD is twice as common as previously thought, and we present a machine-learning framework to detect UPD using ROH. While we find a nominally significant association between UPD of chromosome 22 and autism risk, we do not find significant associations between UPD and deleterious traits in the 23andMe database. [ABSTRACT FROM AUTHOR]

• Semi-automated workflows are useful to contour lesions, calculate prostate volume, and create a structured report for accurate biopsy targeting. • Second reads could be helpful to reduce the number of indeterminate lesions, which harboured clinically significant disease after targeted biopsy only in a minority of cases. • Second reads using customised workflows could help defer biopsies, reducing the number of side effects. To investigate the utility of a prostate magnetic resonance imaging (MRI) second read using a semi-automated software program in the one-stop clinic, where patients undergo multiparametric MRI, review and biopsy planning in one visit. We looked at concordance between readers for patients with equivocal scans and the possibility for biopsy deferral in this group. We present data from 664 consecutive patients. Scans were reported by seven different expert genitourinary radiologists using dedicated software (MIM®) and a Likert scale. All scans were rescored by another expert genitourinary radiologist using a customised workflow for second reads that includes annotated biopsy contours for accurate visual targeting. The number of scans in which a biopsy could have been deferred using biopsy results and prostate specific antigen density was assessed. Gleason score ≥ 3 + 4 was considered clinically significant disease. Concordance between first and second reads for equivocal scans (Likert 3) was evaluated. A total of 209/664 (31%) patients scored Likert 3 on first read, 128 of which (61%) were concordant after second read. 103/209 (49%) of patients with Likert 3 scans were biopsied, with clinically significant disease in 31 (30%) cases. Considering Likert 3 scans that were both downgraded and biopsied using the workflow-generated biopsy contours, 25/103 (24%) biopsies could have been deferred. Implementing a semi-automated workflow for accurate lesion contouring and targeting biopsies is helpful during the one-stop clinic. We observed a reduction of indeterminate scans after second reading and almost a quarter of biopsies could have been deferred, reducing the potential biopsy-related side effects. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: This randomised controlled trial was performed in India and the UK in people with prediabetes to study whether mobile phone short message service (SMS) text messages can be used to motivate and educate people to follow lifestyle modifications, to prevent type 2 diabetes., Methods: The study was performed in people with prediabetes (n = 2062; control: n = 1031; intervention: n = 1031) defined by HbA 1c ≥42 and ≤47 mmol/mol (≥6.0% and ≤6.4%). Participants were recruited from public and private sector organisations in India (men and women aged 35-55 years) and by the National Health Service (NHS) Health Checks programme in the UK (aged 40-74 years without pre-existing diabetes, cardiovascular disease or kidney disease). Allocation to the study groups was performed using a computer-generated sequence (1:1) in India and by stratified randomisation in permuted blocks in the UK. Investigators in both countries remained blinded throughout the study period. All participants received advice on a healthy lifestyle at baseline. The intervention group in addition received supportive text messages using mobile phone SMS messages 2-3 times per week. Participants were assessed at baseline and at 6, 12 and 24 months. The primary outcome was conversion to type 2 diabetes and secondary outcomes included anthropometry, biochemistry, dietary and physical activity changes, blood pressure and quality of life., Results: At the 2 year follow-up (n = 2062; control: n = 1031; intervention: n = 1031), in the intention-to-treat population the HR for development of type 2 diabetes calculated using a discrete-time proportional hazards model was 0.89 (95% CI 0.74, 1.07; p = 0.22). There were no significant differences in the secondary outcomes., Conclusions/interpretation: This trial in two countries with varied ethnic and cultural backgrounds showed no significant reduction in the progression to diabetes in 2 years by lifestyle modification using SMS messaging., Trial Registration: The primary study was registered on www.ClinicalTrials.gov (India, NCT01570946; UK, NCT01795833)., Funding: The study was funded jointly by the Indian Council for Medical Research and the UK Medical Research Council.

Objectives: To report our experience in providing cardiac technician led paediatric echocardiography services in a district general hospital in the United Kingdom., Methods: We have collected prospectively the numbers of referrals, and the proportion of abnormal echocardiograms, since inception of the service in 2000. In additional, for a period of 12 months, we have audited in detail the patterns of referral to the service, and outcomes, assessing the effect of the service on the outreach clinic run by a visiting paediatric cardiologist., Results: Use of the system resulted in detection of a wide range of abnormalities, with our audit showing that the patients received appropriate management. The total referrals to the service increased 10 fold over the 4 year period of the study. The proportion of abnormal hearts detected by echocardiography, however, dropped from 90 per cent to 16 per cent over the same period. The numbers of patients seen in the outreach cardiology clinic remained unaltered., Conclusions: Having been proved to be an effective model for the triage of children with suspected congenital cardiac disease, adoption of a cardiac technician led echocardiographic service has seen a dramatic increase in the numbers of echocardiograms requested, without decreasing the workload of the visiting paediatric cardiologist.