Showing papers by "John Radcliffe Hospital published in 2019"

Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases.

Abstract: Microbiome-wide association studies on large population cohorts have highlighted associations between the gut microbiome and complex traits, including type 2 diabetes (T2D) and obesity1. However, the causal relationships remain largely unresolved. We leveraged information from 952 normoglycemic individuals for whom genome-wide genotyping, gut metagenomic sequence and fecal short-chain fatty acid (SCFA) levels were available2, then combined this information with genome-wide-association summary statistics for 17 metabolic and anthropometric traits. Using bidirectional Mendelian randomization (MR) analyses to assess causality3, we found that the host-genetic-driven increase in gut production of the SCFA butyrate was associated with improved insulin response after an oral glucose-tolerance test (P = 9.8 × 10-5), whereas abnormalities in the production or absorption of another SCFA, propionate, were causally related to an increased risk of T2D (P = 0.004). These data provide evidence of a causal effect of the gut microbiome on metabolic traits and support the use of MR as a means to elucidate causal relationships from microbiome-wide association findings.

Five-Year Outcomes after PCI or CABG for Left Main Coronary Disease

Abstract: Background Long-term outcomes after percutaneous coronary intervention (PCI) with contemporary drug-eluting stents, as compared with coronary-artery bypass grafting (CABG), in patients wit...

Oral versus intravenous antibiotics for bone and joint infection

Abstract: Background The management of complex orthopedic infections usually includes a prolonged course of intravenous antibiotic agents. We investigated whether oral antibiotic therapy is noninfer...

Eculizumab in Aquaporin-4-Positive Neuromyelitis Optica Spectrum Disorder

Abstract: Background Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing, autoimmune, inflammatory disorder that typically affects the optic nerves and spinal cord. At least two thirds of ...

Colonic epithelial cell diversity in health and inflammatory bowel disease

Abstract: The colonic epithelium facilitates host–microorganism interactions to control mucosal immunity, coordinate nutrient recycling and form a mucus barrier. Breakdown of the epithelial barrier underpins inflammatory bowel disease (IBD). However, the specific contributions of each epithelial-cell subtype to this process are unknown. Here we profile single colonic epithelial cells from patients with IBD and unaffected controls. We identify previously unknown cellular subtypes, including gradients of progenitor cells, colonocytes and goblet cells within intestinal crypts. At the top of the crypts, we find a previously unknown absorptive cell, expressing the proton channel OTOP2 and the satiety peptide uroguanylin, that senses pH and is dysregulated in inflammation and cancer. In IBD, we observe a positional remodelling of goblet cells that coincides with downregulation of WFDC2—an antiprotease molecule that we find to be expressed by goblet cells and that inhibits bacterial growth. In vivo, WFDC2 preserves the integrity of tight junctions between epithelial cells and prevents invasion by commensal bacteria and mucosal inflammation. We delineate markers and transcriptional states, identify a colonic epithelial cell and uncover fundamental determinants of barrier breakdown in IBD. Profiling of single epithelial cells in healthy and inflamed colons identifies specialized cellular subpopulations, including a type of goblet cell that secretes the antibacterial protein WFDC2, which preserves the integrity of the epithelial barrier layer.

Advanced imaging for detection and differentiation of colorectal neoplasia: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.

Abstract: This Guideline is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE). It addresses the role of advanced endoscopic imaging for the detection and differentiation of colorectal neoplasia. Main recommendations 1 ESGE suggests the routine use of high definition white-light endoscopy systems for detecting colorectal neoplasia in average risk populations (weak recommendation, moderate quality evidence). 2 ESGE recommends the routine use of high definition systems and pancolonic conventional or virtual (narrow band imaging [NBI], i-SCAN) chromoendoscopy in patients with known or suspected Lynch syndrome (strong recommendation, low quality evidence). 2b ESGE recommends the routine use of high definition systems and pancolonic conventional or virtual (NBI) chromoendoscopy in patients with known or suspected serrated polyposis syndrome (strong recommendation, low quality evidence). 3 ESGE recommends the routine use of 0.1 % methylene blue or 0.1 % – 0.5 % indigo carmine pancolonic chromoendoscopy with targeted biopsies for neoplasia surveillance in patients with long-standing colitis. In appropriately trained hands, in the situation of quiescent disease activity and adequate bowel preparation, nontargeted, four-quadrant biopsies can be abandoned (strong recommendation, high quality evidence). 4 ESGE suggests that virtual chromoendoscopy (NBI, FICE, i-SCAN) and conventional chromoendoscopy can be used, under strictly controlled conditions, for real-time optical diagnosis of diminutive (≤ 5 mm) colorectal polyps to replace histopathological diagnosis. The optical diagnosis has to be reported using validated scales, must be adequately photodocumented, and can be performed only by experienced endoscopists who are adequately trained and audited (weak recommendation, high quality evidence). 5 ESGE suggests the use of conventional or virtual (NBI) magnified chromoendoscopy to predict the risk of invasive cancer and deep submucosal invasion in lesions such as those with a depressed component (0-IIc according to the Paris classification) or nongranular or mixed-type laterally spreading tumors (weak recommendation, moderate quality evidence). Conclusion Advanced imaging techniques will need to be applied in specific patient groups in routine clinical practice and to be taught in endoscopic training programs.

Trial of Satralizumab in Neuromyelitis Optica Spectrum Disorder

Abstract: Background Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system and is associated with autoantibodies to anti–aquaporin-4 (AQP4-IgG) in app...

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Abstract: Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.

Bilateral versus Single Internal-Thoracic-Artery Grafts at 10 Years.

Abstract: Background Multiple arterial grafts may result in longer survival than single arterial grafts after coronary-artery bypass grafting (CABG) surgery. We evaluated the use of bilateral intern...

Bowel preparation for colonoscopy: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Update 2019.

Abstract: ESGE recommends a low fiber diet on the day preceding colonoscopy.Strong recommendation, moderate quality evidence.ESGE recommends the use of enhanced instructions for bowel preparation.Strong recommendation, moderate quality evidence.ESGE suggests adding oral simethicone to bowel preparation.Weak recommendation, moderate quality evidence.ESGE recommends split-dose bowel preparation for elective colonoscopy.Strong recommendation, high quality evidence.ESGE recommends, for patients undergoing afternoon colonoscopy, a same-day bowel preparation as an acceptable alternative to split dosing.Strong recommendation, high quality evidence.ESGE recommends to start the last dose of bowel preparation within 5 hours of colonoscopy, and to complete it at least 2 hours before the beginning of the procedure.Strong recommendation, moderate quality evidence.ESGE recommends the use of high volume or low volume PEG-based regimens as well as that of non-PEG-based agents that have been clinically validated for routine bowel preparation. In patients at risk for hydroelectrolyte disturbances, the choice of laxative should be individualized.Strong recommendation, moderate quality evidence.

The challenge of antimicrobial resistance: What economics can contribute

Abstract: As antibiotic consumption grows, bacteria are becoming increasingly resistant to treatment. Antibiotic resistance undermines much of modern health care, which relies on access to effective antibiotics to prevent and treat infections associated with routine medical procedures. The resulting challenges have much in common with those posed by climate change, which economists have responded to with research that has informed and shaped public policy. Drawing on economic concepts such as externalities and the principal-agent relationship, we suggest how economics can help to solve the challenges arising from increasing resistance to antibiotics. We discuss solutions to the key economic issues, from incentivizing the development of effective new antibiotics to improving antibiotic stewardship through financial mechanisms and regulation.

ISUOG Practice Guidelines: ultrasound assessment of fetal biometry and growth

Abstract: INTRODUCTION: These Guidelines aim to describe appropriate assessment of fetal biometry and diagnosis of fetal growth disorders. These disorders consist mainly of fetal growth restriction (FGR), also referred to as intrauterine growth restriction (IUGR) and often associated with small‐for‐gestational age (SGA), and large‐for‐gestational age (LGA), which may lead to fetal macrosomia; both have been associated with a variety of adverse maternal and perinatal outcomes. Screening for, and adequate management of, fetal growth abnormalities are essential components of antenatal care, and fetal ultrasound plays a key role in assessment of these conditions. The fetal biometric parameters measured most commonly are biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur diaphysis length (FL). These biometric measurements can be used to estimate fetal weight (EFW) using various different formulae1. It is important to differentiate between the concept of fetal size at a given timepoint and fetal growth, the latter being a dynamic process, the assessment of which requires at least two ultrasound scans separated in time. Maternal history and symptoms, amniotic fluid assessment and Doppler velocimetry can provide additional information that may be used to identify fetuses at risk of adverse pregnancy outcome. Accurate estimation of gestational age is a prerequisite for determining whether fetal size is appropriate‐for‐gestational age (AGA). Except for pregnancies arising from assisted reproductive technology, the date of conception cannot be determined precisely. Clinically, most pregnancies are dated by the last menstrual period, though this may sometimes be uncertain or unreliable. Therefore, dating pregnancies by early ultrasound examination at 8–14 weeks, based on measurement of the fetal crown–rump length (CRL), appears to be the most reliable method to establish gestational age. Once the CRL exceeds 84 mm, HC should be used for pregnancy dating2–4. HC, with or without FL, can be used for estimation of gestational age from the mid‐trimester if a first‐trimester scan is not available and the menstrual history is unreliable. When the expected delivery date has been established by an accurate early scan, subsequent scans should not be used to recalculate the gestational age1. Serial scans can be used to determine if interval growth has been normal. In these Guidelines, we assume that the gestational age is known and has been determined as described above, the pregnancy is singleton and the fetal anatomy is normal. Details of the grades of recommendation used in these Guidelines are given in Appendix 1. Reporting of levels of evidence is not applicable to these Guidelines.

Ultrasound Neuromodulation: A Review of Results, Mechanisms and Safety.

Abstract: Ultrasonic neuromodulation is a rapidly growing field, in which low-intensity ultrasound (US) is delivered to nervous system tissue, resulting in transient modulation of neural activity. This review summarizes the findings in the central and peripheral nervous systems from mechanistic studies in cell culture to cognitive behavioral studies in humans. The mechanisms by which US mechanically interacts with neurons and could affect firing are presented. An in-depth safety assessment of current studies shows that parameters for the human studies fall within the safety envelope for US imaging. Challenges associated with accurately targeting US and monitoring the response are described. In conclusion, the literature supports the use of US as a safe, non-invasive brain stimulation modality with improved spatial localization and depth targeting compared with alternative methods. US neurostimulation has the potential to be used both as a scientific instrument to investigate brain function and as a therapeutic modality to modulate brain activity.

Incidence and prevalence of dementia associated with transient ischaemic attack and stroke: analysis of the population-based Oxford Vascular Study

Abstract: Summary Background Risk of dementia after stroke is a major concern for patients and carers. Reliable data for risk of dementia, particularly after transient ischaemic attack or minor stroke, are scarce. We studied the risks of, and risk factors for, dementia before and after transient ischaemic attack and stroke. Methods The Oxford Vascular Study is a prospective incidence study of all vascular events in a population of 92 728 people residing in Oxfordshire, UK. Patients with transient ischaemic attack or stroke occurring between April 1, 2002, and March 31, 2012, were ascertained with multiple methods, including assessment in a dedicated daily emergency clinic and daily review of all hospital admissions. Pre-event and post-event (incident) dementia were diagnosed at initial assessment and during 5-years' follow-up on the basis of cognitive testing supplemented by data obtained from hand searches of all hospital and primary care records. We assessed the association between post-event dementia and stroke severity (as measured with the US National Institutes of Health Stroke Scale [NIHSS] score), location (ie, dysphasia), previous events, markers of susceptibility or reserve (age, low education, pre-morbid dependency, leucoaraiosis), baseline cognition, and vascular risk factors with Cox regression models adjusted for age, sex, and education. We compared incidence and prevalence of dementia in our population with published UK population age-matched and sex-matched rates. Findings Among 2305 patients (mean age 74·4 years [SD 13·0]), 688 (30%) had transient ischaemic attacks and 1617 (70%) had strokes. Pre-event dementia was diagnosed in 225 patients; prevalence was highest in severe stroke (ie, NIHSS >10) and lowest in transient ischaemic attack. Of 2080 patients without pre-event dementia, 1982 (95%) were followed up to the end of study or death. Post-event dementia occurred in 432 of 2080 patients during 5 years of follow-up. The incidence of post-event dementia at 1 year was 34·4% (95% CI 29·7–41·5) in patients with severe stroke (NIHSS score >10), 8·2% (6·2–10·2) in those with minor stroke (NIHSS score Interpretation The incidence of dementia in patients who have had a transient ischaemic attack or stroke varies substantially depending on clinical characteristics including lesion burden and susceptibility factors. Incidence of dementia is nearly 50 times higher in the year after a major stroke compared with that in the general population, but excess risk is substantially lower after transient ischaemic attack and minor stroke. Funding Wellcome Trust, Wolfson Foundation, British Heart Foundation, National Institute for Health Research, and the National Institute for Health Research Oxford Biomedical Research Centre.

Survival of patients with chronic heart failure in the community: a systematic review and meta-analysis.

Abstract: © 2019 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. Aim: To provide reliable survival estimates for people with chronic heart failure and explain variation in survival by key factors including age at diagnosis, left ventricular ejection fraction, decade of diagnosis, and study setting. Methods and results: We searched in relevant databases from inception to August 2018 for non-interventional studies reporting survival rates for patients with chronic or stable heart failure in any ambulatory setting. Across the 60 included studies, there was survival data for 1.5 million people with heart failure. In our random effects meta-analyses the pooled survival rates at 1 month, 1, 2, 5 and 10 years were 95.7% (95% confidence interval 94.3–96.9), 86.5% (85.4–87.6), 72.6% (67.0–76.6), 56.7% (54.0–59.4) and 34.9% (24.0–46.8), respectively. The 5-year survival rates improved between 1970–1979 and 2000–2009 across healthcare settings, from 29.1% (25.5–32.7) to 59.7% (54.7–64.6). Increasing age at diagnosis was significantly associated with a reduced survival time. Mortality was lowest in studies conducted in secondary care, where there were higher reported prescribing rates of key heart failure medications. There was significant heterogeneity among the included studies in terms of heart failure diagnostic criteria, participant co-morbidities, and treatment rates. Conclusion: These results can inform health policy and individual patient advanced care planning. Mortality associated with chronic heart failure remains high despite steady improvements in survival. There remains significant scope to improve prognosis through greater implementation of evidence-based treatments. Further research exploring the barriers and facilitators to treatment is recommended.

Vessel co-option in cancer.

Abstract: All solid tumours require a vascular supply in order to progress. Although the ability to induce angiogenesis (new blood vessel growth) has long been regarded as essential to this purpose, thus far, anti-angiogenic therapies have shown only modest efficacy in patients. Importantly, overshadowed by the literature on tumour angiogenesis is a long-standing, but continually emerging, body of research indicating that tumours can grow instead by hijacking pre-existing blood vessels of the surrounding nonmalignant tissue. This process, termed vessel co-option, is a frequently overlooked mechanism of tumour vascularization that can influence disease progression, metastasis and response to treatment. In this Review, we describe the evidence that tumours located at numerous anatomical sites can exploit vessel co-option. We also discuss the proposed molecular mechanisms involved and the multifaceted implications of vessel co-option for patient outcomes. Despite much hope, anti-angiogenic agents have largely failed to achieve the promise demonstrated in preclinical models. In this Review, the authors discuss an alternative hypothesis — vessel co-option — that might explain many of these failures and describe the evidence for a role of this largely overlooked aspect of tumour biology.

A novel machine learning-derived radiotranscriptomic signature of perivascular fat improves cardiac risk prediction using coronary CT angiography

Abstract: BACKGROUND Coronary inflammation induces dynamic changes in the balance between water and lipid content in perivascular adipose tissue (PVAT), as captured by perivascular Fat Attenuation Index (FAI) in standard coronary CT angiography (CCTA). However, inflammation is not the only process involved in atherogenesis and we hypothesized that additional radiomic signatures of adverse fibrotic and microvascular PVAT remodelling, may further improve cardiac risk prediction. METHODS AND RESULTS We present a new artificial intelligence-powered method to predict cardiac risk by analysing the radiomic profile of coronary PVAT, developed and validated in patient cohorts acquired in three different studies. In Study 1, adipose tissue biopsies were obtained from 167 patients undergoing cardiac surgery, and the expression of genes representing inflammation, fibrosis and vascularity was linked with the radiomic features extracted from tissue CT images. Adipose tissue wavelet-transformed mean attenuation (captured by FAI) was the most sensitive radiomic feature in describing tissue inflammation (TNFA expression), while features of radiomic texture were related to adipose tissue fibrosis (COL1A1 expression) and vascularity (CD31 expression). In Study 2, we analysed 1391 coronary PVAT radiomic features in 101 patients who experienced major adverse cardiac events (MACE) within 5 years of having a CCTA and 101 matched controls, training and validating a machine learning (random forest) algorithm (fat radiomic profile, FRP) to discriminate cases from controls (C-statistic 0.77 [95%CI: 0.62-0.93] in the external validation set). The coronary FRP signature was then tested in 1575 consecutive eligible participants in the SCOT-HEART trial, where it significantly improved MACE prediction beyond traditional risk stratification that included risk factors, coronary calcium score, coronary stenosis, and high-risk plaque features on CCTA (Δ[C-statistic] = 0.126, P < 0.001). In Study 3, FRP was significantly higher in 44 patients presenting with acute myocardial infarction compared with 44 matched controls, but unlike FAI, remained unchanged 6 months after the index event, confirming that FRP detects persistent PVAT changes not captured by FAI. CONCLUSION The CCTA-based radiomic profiling of coronary artery PVAT detects perivascular structural remodelling associated with coronary artery disease, beyond inflammation. A new artificial intelligence (AI)-powered imaging biomarker (FRP) leads to a striking improvement of cardiac risk prediction over and above the current state-of-the-art.

Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort.

Abstract: Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (>10 min) febrile seizures; febrile or afebrile status epilepticus (>30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children's hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9-57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26-14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93-12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24-9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07-7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy.

Biological and clinical insights from genetics of insomnia symptoms

Abstract: Insomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes. The underlying pathophysiological processes and causal relationships of insomnia with disease are poorly understood. Here we identified 57 loci for self-reported insomnia symptoms in the UK Biobank (n = 453,379) and confirmed their effects on self-reported insomnia symptoms in the HUNT Study (n = 14,923 cases and 47,610 controls), physician-diagnosed insomnia in the Partners Biobank (n = 2,217 cases and 14,240 controls), and accelerometer-derived measures of sleep efficiency and sleep duration in the UK Biobank (n = 83,726). Our results suggest enrichment of genes involved in ubiquitin-mediated proteolysis and of genes expressed in multiple brain regions, skeletal muscle, and adrenal glands. Evidence of shared genetic factors was found between frequent insomnia symptoms and restless legs syndrome, aging, and cardiometabolic, behavioral, psychiatric, and reproductive traits. Evidence was found for a possible causal link between insomnia symptoms and coronary artery disease, depressive symptoms, and subjective well-being.

An improved neuroanatomical model of the default-mode network reconciles previous neuroimaging and neuropathological findings.

Abstract: The brain is constituted of multiple networks of functionally correlated brain areas, out of which the default-mode network (DMN) is the largest. Most existing research into the DMN has taken a corticocentric approach. Despite its resemblance with the unitary model of the limbic system, the contribution of subcortical structures to the DMN may be underappreciated. Here, we propose a more comprehensive neuroanatomical model of the DMN including subcortical structures such as the basal forebrain, cholinergic nuclei, anterior and mediodorsal thalamic nuclei. Additionally, tractography of diffusion-weighted imaging was employed to explore the structural connectivity, which revealed that the thalamus and basal forebrain are of central importance for the functioning of the DMN. The contribution of these neurochemically diverse brain nuclei reconciles previous neuroimaging with neuropathological findings in diseased brains and offers the potential for identifying a conserved homologue of the DMN in other mammalian species.