Automated Echocardiographic Detection of Severe Coronary Artery Disease Using Artificial Intelligence.

Objectives: The purpose of this study was to establish whether an artificially intelligent (AI) system can be developed to automate stress echocardiography analysis and support clinician interpretation.

Background: Coronary artery disease is the leading global cause of mortality and morbidity and stress echocardiography remains one of the most commonly used diagnostic imaging tests.

Methods: An automated image processing pipeline was developed to extract novel geometric and kinematic features from stress echocardiograms collected as part of a large, United Kingdom-based prospective, multicenter, multivendor study.

Feasibility and safety of radical prostatectomy for oligo-metastatic prostate cancer: the Testing Radical prostatectomy in men with prostate cancer and oligo-Metastases to the bone (TRoMbone) trial.

Objectives: To test the feasibility of randomisation to radical prostatectomy (RP) plus pelvic lymphadenectomy in addition to standard-of-care (SOC) systemic therapy in men with newly diagnosed oligo-metastatic prostate cancer.

Patients And Methods: A prospective, randomised, non-blinded, feasibility clinical trial with an embedded QuinteT Recruitment Intervention (QRI) to optimise recruitment was conducted in nine nationwide tertiary care centres undertaking high-volume robotic surgery. We aimed to randomise 50 men with synchronous oligo-metastatic prostate cancer within an 18-month recruitment period to SOC systemic therapy vs SOC plus RP (intervention arm).

Unsupervised Clustering of Missense Variants in HNF1A Using Multidimensional Functional Data Aids Clinical Interpretation.

Exome sequencing in diabetes presents a diagnostic challenge because depending on frequency, functional impact, and genomic and environmental contexts, HNF1A variants can cause maturity-onset diabetes of the young (MODY), increase type 2 diabetes risk, or be benign. A correct diagnosis matters as it informs on treatment, progression, and family risk. We describe a multi-dimensional functional dataset of 73 HNF1A missense variants identified in exomes of 12,940 individuals.

Quantitative MRCP Imaging: Accuracy, Repeatability, Reproducibility, and Cohort-Derived Normative Ranges.

Background: Magnetic resonance cholangiopancreatography (MRCP) is an important tool for noninvasive imaging of biliary disease, however, its assessment is currently subjective, resulting in the need for objective biomarkers.

Purpose: To investigate the accuracy, scan/rescan repeatability, and cross-scanner reproducibility of a novel quantitative MRCP tool on phantoms and in vivo. Additionally, to report normative ranges derived from the healthy cohort for duct measurements and tree-level summary metrics.

Homozygous Hypomorphic Alleles Are a Novel Cause of Young-Onset Diabetes and Result in Sulfonylurea-Sensitive Diabetes.

Objective: Heterozygous loss-of-function mutations in cause maturity-onset diabetes of the young (MODY). Affected individuals can be treated with low-dose sulfonylureas. Individuals with homozygous mutations causing MODY have not been reported.

HYDration and Bicarbonate to Prevent Acute Renal Injury After Endovascular Aneurysm Repair With Suprarenal Fixation: Pilot/Feasibility Randomised Controlled Study (HYDRA Pilot Trial).

Objective/background: Up to 25% of patients undergoing elective endovascular aneurysm repair (EVAR) develop acute kidney injury (AKI), which is associated with short and long-term morbidity and mortality. There is no high quality randomised evidence regarding prevention of EVAR related AKI.

Methods: A novel AKI prevention strategy for EVAR was devised, based on best evidence and an expert consensus group.

Understanding the relationship between schematic beliefs, bullying, and unusual experiences in 8-14 year olds.

Background: Cognitive models of adult psychosis propose that negative schematic beliefs (NSBs) mediate the established association between victimisation and psychotic symptoms. In childhood, unusual, or psychotic-like, experiences are associated with bullying (a common form of victimisation) and NSBs. This study tests the mediating role of NSBs in the relationship between bullying and distressing unusual experiences (UEDs) in childhood.

Variation in psychosocial influences according to the dimensions and content of children's unusual experiences: potential routes for the development of targeted interventions.

The psychosocial processes implicated in the development and maintenance of psychosis differ according to both the dimensional attributes (conviction, frequency, associated distress, adverse life impact) and the content or type (e.g. grandiosity, hallucinations, paranoia) of the psychotic symptoms experienced.

A preliminary investigation of schematic beliefs and unusual experiences in children.

Background: In cognitive models of adult psychosis, schematic beliefs about the self and others are important vulnerability and maintaining factors, and are therefore targets for psychological interventions. Schematic beliefs have not previously been investigated in children with distressing unusual, or psychotic-like, experiences (UEDs). The aim of this study was firstly to investigate whether a measure of schematic beliefs, originally designed for adults with psychosis, was suitable for children; and secondly, to examine the association of childhood schematic beliefs with internalising and externalising problems and with UEDs.

Cognitive bias and unusual experiences in childhood.

Cognitive therapy is recommended for children with psychotic-like, or unusual, experiences associated with distress or impairment (UEDs; UK National Institute for Health and Care Excellence, 2013 [1]). Accurate models of the psychological underpinnings of childhood UEDs are required to effectively target therapies. Cognitive biases, such as the jumping to conclusions data-gathering bias (JTC), are implicated in the development and maintenance of psychosis in adults.

The effects of a brief CBT intervention, delivered by frontline mental health staff, to promote recovery in people with psychosis and comorbid anxiety or depression (the GOALS study): study protocol for a randomized controlled trial.

Background: NICE guidance states that cognitive behavioural therapy (CBT) should be offered to all patients with psychosis. However, there is a need to improve access to therapeutic interventions. We aim to train frontline mental health staff to deliver brief, structured CBT-based therapies.

Evaluation of common type 2 diabetes risk variants in a South Asian population of Sri Lankan descent.

Introduction: Most studies seeking common variant associations with type 2 diabetes (T2D) have focused on individuals of European ancestry. These discoveries need to be evaluated in other major ancestral groups, to understand ethnic differences in predisposition, and establish whether these contribute to variation in T2D prevalence and presentation. This study aims to establish whether common variants conferring T2D-risk in Europeans contribute to T2D-susceptibility in the South Asian population of Sri Lanka.

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci.

Modelling psychosocial influences on the distress and impairment caused by psychotic-like experiences in children and adolescents.

Psychological understanding of psychotic-like experiences (PLEs) occurring in childhood is limited, with no recognised conceptual framework to guide appropriate intervention. We examined the contribution to PLE severity of emotional, cognitive and socio-environmental mechanisms thought to influence the development and maintenance of psychosis. Forty 8-14 year olds referred to a community Child and Adolescent Mental Health Service completed a battery of questionnaires and assessments measuring severity of PLEs, emotional problems, cognitive biases, and negative life events.

Higher magnesium intake is associated with lower fasting glucose and insulin, with no evidence of interaction with select genetic loci, in a meta-analysis of 15 CHARGE Consortium Studies.

Favorable associations between magnesium intake and glycemic traits, such as fasting glucose and insulin, are observed in observational and clinical studies, but whether genetic variation affects these associations is largely unknown. We hypothesized that single nucleotide polymorphisms (SNPs) associated with either glycemic traits or magnesium metabolism affect the association between magnesium intake and fasting glucose and insulin. Fifteen studies from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided data from up to 52,684 participants of European descent without known diabetes.

Genome-wide association study identifies a novel locus contributing to type 2 diabetes susceptibility in Sikhs of Punjabi origin from India.

We performed a genome-wide association study (GWAS) and a multistage meta-analysis of type 2 diabetes (T2D) in Punjabi Sikhs from India. Our discovery GWAS in 1,616 individuals (842 case subjects) was followed by in silico replication of the top 513 independent single nucleotide polymorphisms (SNPs) (P < 10⁻³) in Punjabi Sikhs (n = 2,819; 801 case subjects). We further replicated 66 SNPs (P < 10⁻⁴) through genotyping in a Punjabi Sikh sample (n = 2,894; 1,711 case subjects).

Mutations in HNF1A result in marked alterations of plasma glycan profile.

A recent genome-wide association study identified hepatocyte nuclear factor 1-α (HNF1A) as a key regulator of fucosylation. We hypothesized that loss-of-function HNF1A mutations causal for maturity-onset diabetes of the young (MODY) would display altered fucosylation of N-linked glycans on plasma proteins and that glycan biomarkers could improve the efficiency of a diagnosis of HNF1A-MODY. In a pilot comparison of 33 subjects with HNF1A-MODY and 41 subjects with type 2 diabetes, 15 of 29 glycan measurements differed between the two groups.

Meta-analysis investigating associations between healthy diet and fasting glucose and insulin levels and modification by loci associated with glucose homeostasis in data from 15 cohorts.

Whether loci that influence fasting glucose (FG) and fasting insulin (FI) levels, as identified by genome-wide association studies, modify associations of diet with FG or FI is unknown. We utilized data from 15 U.S.

Mapping cis- and trans-regulatory effects across multiple tissues in twins.

Sequence-based variation in gene expression is a key driver of disease risk. Common variants regulating expression in cis have been mapped in many expression quantitative trait locus (eQTL) studies, typically in single tissues from unrelated individuals. Here, we present a comprehensive analysis of gene expression across multiple tissues conducted in a large set of mono- and dizygotic twins that allows systematic dissection of genetic (cis and trans) and non-genetic effects on gene expression.

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.

A genome-wide association search for type 2 diabetes genes in African Americans.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.

Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci.

We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10(-4) for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry.

Association of genetic Loci with glucose levels in childhood and adolescence: a meta-analysis of over 6,000 children.

Objective: To investigate whether associations of common genetic variants recently identified for fasting glucose or insulin levels in nondiabetic adults are detectable in healthy children and adolescents.

Research Design And Methods: A total of 16 single nucleotide polymorphisms (SNPs) associated with fasting glucose were genotyped in six studies of children and adolescents of European origin, including over 6,000 boys and girls aged 9-16 years. We performed meta-analyses to test associations of individual SNPs and a weighted risk score of the 16 loci with fasting glucose.

The architecture of gene regulatory variation across multiple human tissues: the MuTHER study.

While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL), skin, and fat. The samples (156 LCL, 160 skin, 166 fat) were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource.