Outcomes of non-invasive diagnostic modalities for the detection of coronary artery disease: network meta-analysis of diagnostic randomised controlled trials

Objective: To evaluate differences in downstream testing, coronary revascularisation, and clinical outcomes following non-invasive diagnostic modalities used to detect coronary artery disease. Design: Systematic review and network meta-analysis. Data sources: Medline, Medline in process, Embase, Cochrane Library for clinical trials, PubMed, Web of Science, SCOPUS, WHO International Clinical Trials Registry Platform, and Clinicaltrials.gov. Eligibility criteria for selecting studies: Diagnostic randomised controlled trials comparing non-invasive diagnostic modalities in patients presenting with symptoms suggestive of low risk acute coronary syndrome or stable coronary artery disease. Data synthesis: A random effects network meta-analysis synthesised available evidence from trials evaluating the effect of non-invasive diagnostic modalities on downstream testing and patient oriented outcomes in patients with suspected coronary artery disease. Modalities included exercise electrocardiograms, stress echocardiography, single photon emission computed tomography-myocardial perfusion imaging, real time myocardial contrast echocardiography, coronary computed tomographic angiography, and cardiovascular magnetic resonance. Unpublished outcome data were obtained from 11 trials. Results: 18 trials of patients with low risk acute coronary syndrome (n=11 329) and 12 trials of those with suspected stable coronary artery disease (n=22 062) were included. Among patients with low risk acute coronary syndrome, stress echocardiography, cardiovascular magnetic resonance, and exercise electrocardiograms resulted in fewer invasive referrals for coronary angiography than coronary computed tomographic angiography (odds ratio 0.28 (95% confidence interval 0.14 to 0.57), 0.32 (0.15 to 0.71), and 0.53 (0.28 to 1.00), respectively). There was no effect on the subsequent risk of myocardial infarction, but estimates were imprecise. Heterogeneity and inconsistency were low. In patients with suspected stable coronary artery disease, an initial diagnostic strategy of stress echocardiography or single photon emission computed tomography-myocardial perfusion imaging resulted in fewer downstream tests than coronary computed tomographic angiography (0.24 (0.08 to 0.74) and 0.57 (0.37 to 0.87), respectively). However, exercise electrocardiograms yielded the highest downstream testing rate. Estimates for death and myocardial infarction were imprecise without clear discrimination between strategies. Conclusions: For patients with low risk acute coronary syndrome, an initial diagnostic strategy of stress echocardiography or cardiovascular magnetic resonance is associated with fewer referrals for invasive coronary angiography and revascularisation procedures than non-invasive anatomical testing, without apparent impact on the future risk of myocardial infarction. For suspected stable coronary artery disease, there was no clear discrimination between diagnostic strategies regarding the subsequent need for invasive coronary angiography, and differences in the risk of myocardial infarction cannot be ruled out. Systematic review registration: PROSPERO registry no CRD42016049442

Use of diffusion tensor imaging to assess the impact of normobaric hyperoxia within at-risk pericontusional tissue after traumatic brain injury

Ischemia and metabolic dysfunction remain important causes of neuronal loss after head injury, and we have shown that normobaric hyperoxia may rescue such metabolic compromise. This study examines the impact of hyperoxia within injured brain using diffusion tensor imaging (DTI). Fourteen patients underwent DTI at baseline and after 1 hour of 80% oxygen. Using the apparent diffusion coefficient (ADC) we assessed the impact of hyperoxia within contusions and a 1 cm border zone of normal appearing pericontusion, and within a rim of perilesional reduced ADC consistent with cytotoxic edema and metabolic compromise. Seven healthy volunteers underwent imaging at 21%, 60%, and 100% oxygen. In volunteers there was no ADC change with hyperoxia, and contusion and pericontusion ADC values were higher than volunteers (P < 0.01). There was no ADC change after hyperoxia within contusion, but an increase within pericontusion (P < 0.05). We identified a rim of perilesional cytotoxic edema in 13 patients, and hyperoxia resulted in an ADC increase towards normal (P=0.02). We demonstrate that hyperoxia may result in benefit within the perilesional rim of cytotoxic edema. Future studies should address whether a longer period of hyperoxia has a favorable impact on the evolution of tissue injury

Normobaric hyperoxia does not improve derangements in diffusion tensor imaging found distant from visible contusions following acute traumatic brain injury

We have previously shown that normobaric hyperoxia may benefit peri-lesional brain and white matter following traumatic brain injury (TBI). This study examined the impact of brief exposure to hyperoxia using diffusion tensor imaging (DTI) to identify axonal injury distant from contusions. Fourteen patients with acute moderate/severe TBI underwent baseline DTI and following one hour of 80% oxygen. Thirty-two controls underwent DTI, with 6 undergoing imaging following graded exposure to oxygen. Visible lesions were excluded and data compared with controls. We used the 99% prediction interval (PI) for zero change from historical control reproducibility measurements to demonstrate significant change following hyperoxia. Following hyperoxia DTI was unchanged in controls. In patients following hyperoxia, mean diffusivity (MD) was unchanged despite baseline values lower than controls (p < 0.05), and fractional anisotropy (FA) was lower within the left uncinate fasciculus, right caudate and occipital regions (p < 0.05). 16% of white and 14% of mixed cortical and grey matter patient regions showed FA decreases greater than the 99% PI for zero change. The mechanistic basis for some findings are unclear, but suggest that a short period of normobaric hyperoxia is not beneficial in this context. Confirmation following a longer period of hyperoxia is required.Dr. Veenith was supported by clinical research training fellowship from National institute of Academic Anaesthesia and Raymond Beverly Sackler studentship. VFJN is supported by a Health Foundation/Academy of Medical Sciences Clinician Scientist Fellowship. JPC was supported by Wellcome trust project grant. DKM is supported by an NIHR Senior Investigator Award. This work was supported by a Wellcome Trust Project Grant (WT093267) and Medical Research Council (UK) Program Grant (Acute brain injury: heterogeneity of mechanisms, therapeutic targets and outcome effects (G9439390 ID 65883)), the UK National Institute of Health Research Biomedical Research Centre at Cambridge, and the Technology Platform funding provided by the UK Department of Health. The funders had no role in study design, data collection and analyses, decision to publish, or preparation of the manuscript

Neuroimaging of Inflammation in Memory and Related Other Disorders (NIMROD) study protocol: a deep phenotyping cohort study of the role of brain inflammation in dementia, depression and other neurological illnesses

$\textit{Introduction}$ Inflammation of the central nervous system is increasingly regarded as having a role in cognitive disorders such as dementia and depression, but it is not clear how such neuroinflammation relates to other aspects of neuropathology (e.g., tau and amyloid pathology) as well as to structural and functional changes in the brain and symptoms (as assessed via MRI and clinical and neuropsychological assessment). This study will explore these pathophysiological mechanisms using positron emission tomography (PET) which allows $\textit{in vivo}$ imaging of inflammation, amyloid and tau deposition, together with neuropsychological profiling, magnetic resonance imaging (MRI) and peripheral biomarker analysis. \textit{Methods & analysis} Using PET imaging of the ligand [11C]PK11195 we will test for increased neuroinflammation $\textit{in vivo}$ in patients with Alzheimer’s disease, Lewy body dementia, frontotemporal dementia, progressive supranuclear palsy, late onset depression and mild cognitive impairment, when compared to healthy controls. We will assess whether areas of inflammatory change are associated with amyloid and tau deposition (assessed using $^{11}$C-labelled Pittsburgh Compound B ([$^{11}$C]PiB) and $^{18}$F-labelled AV-1451 respectively), as well as structural and functional connectivity changes found on MRI. Inflammatory biomarker analysis and immune-phenotyping of peripheral blood monocytes will determine the correlation between central (i.e., neural) and peripheral inflammation. Finally, we will examine whether neuroinflammatory changes seen on PET imaging are associated with global and domain specific cognitive impairments, or predict cognitive decline over 12 months. \textit{Ethics & dissemination} The study protocol was approved by the local ethics committee, East of England - Cambridge Central Research Ethics Committee (reference: 13/EE/0104). The study is also ARSAC approved as part of this process. Data will be disseminated by presentation at national and international conferences and by publication, predominantly in journals of neuroscience as well as clinical neurology and psychiatry. $\textit{Strengths}$ Multimodal deep phenotyping Comparisons between diseases as well as with controls Longitudinal neuropsychology data Comparison of central and peripheral inflammation $\textit{Weaknesses}$ Lack of longitudinal neuroimaging Not a prospective study, unable to assess causationThe study is funded by the UK National Institute of Health Research Cambridge Biomedical Research Unit in Dementia (Project 4 - RNAG/293). JBR is supported by the Wellcome Trust (103838). JPC is supported by the UK National Institute of Health Research Biomedical Research Centre at Cambridge. PVR is supported by the PSP Association

Proof of concept of faecal egg nematode counting as a practical means of veterinary engagement with planned livestock health management in a lower income country

Abstract Background The wellbeing and livelihood of farmers in impoverished regions of the world is intrinsically linked to the health and welfare of their livestock; hence improved animal health is a pragmatic component of poverty alleviation. Prerequisite knowledge and understanding of the animal health challenges facing cattle keepers in Malawi is constrained by the lack of veterinary infrastructure, which inevitably accompanies under-resourced rural development in a poor country. Methods We collaborated with public and private paraveterinary services to locate 62 village Zebu calves and 60 dairy co-operative calves dispersed over a wide geographical area. All calves were visited twice about 2 to 3 weeks apart, when they were clinically examined and faecal samples were collected. The calves were treated with 7.5 mg/kg of a locally-available albendazole drench on the first visit, and pre- and post- treatment trichostrongyle and Toxocara faecal egg counts were performed using a modified McMaster method. Results Our clinical findings point towards a generally poor level of animal health, implying a role of ticks and tick-transmitted diseases in village calves and need for improvement in neonatal calf husbandry in the dairy co-operative holdings. High faecal trichostrongyle egg counts were not intuitive, based on our interpretation of the animal management information that was provided. This shows the need for better understanding of nematode parasite epidemiology within the context of local husbandry and environmental conditions. The albendazole anthelmintic was effective against Toxocara, while efficacy against trichostrongyle nematodes was poor in both village and dairy co-operative calves, demonstrating the need for further research to inform sustainable drug use. Conclusions Here we describe the potential value of faecal nematode egg counting as a platform for communicating with and gaining access to cattle keepers and their animals, respectively, in southern Malawi, with the aim of providing informative background knowledge and understanding that may aid in the establishment of effective veterinary services in an under-resourced community

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

INTRODUCTION Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. METHODS More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer 'stem' cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account. RESULTS The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working. CONCLUSIONS With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years

Systematic review of studies generating individual participant data on the efficacy of drugs for treating soil-transmitted helminthiases and the case for data-sharing

Preventive chemotherapy and transmission control (PCT) by mass drug administration is the cornerstone of the World Health Organization (WHO)’s policy to control soil-transmitted helminthiases (STHs) caused by Ascaris lumbricoides (roundworm), Trichuris trichiura (whipworm) and hookworm species (Necator americanus and Ancylostama duodenale) which affect over 1 billion people globally. Despite consensus that drug efficacies should be monitored for signs of decline that could jeopardise the effectiveness of PCT, systematic monitoring and evaluation is seldom implemented. Drug trials mostly report aggregate efficacies in groups of participants, but heterogeneities in design complicate classical meta-analyses of these data. Individual participant data (IPD) permit more detailed analysis of drug efficacies, offering increased sensitivity to identify atypical responses potentially caused by emerging drug resistance

Investigation of attentional bias in obsessive compulsive disorder with and without depression in visual search

Copyright: © 2013 Morein-Zamir et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedWhether Obsessive Compulsive Disorder (OCD) is associated with an increased attentional bias to emotive stimuli remains controversial. Additionally, it is unclear whether comorbid depression modulates abnormal emotional processing in OCD. This study examined attentional bias to OC-relevant scenes using a visual search task. Controls, non-depressed and depressed OCD patients searched for their personally selected positive images amongst their negative distractors, and vice versa. Whilst the OCD groups were slower than healthy individuals in rating the images, there were no group differences in the magnitude of negative bias to concern-related scenes. A second experiment employing a common set of images replicated the results on an additional sample of OCD patients. Although there was a larger bias to negative OC-related images without pre-exposure overall, no group differences in attentional bias were observed. However, OCD patients subsequently rated the images more slowly and more negatively, again suggesting post-attentional processing abnormalities. The results argue against a robust attentional bias in OCD patients, regardless of their depression status and speak to generalized difficulties disengaging from negative valence stimuli. Rather, post-attentional processing abnormalities may account for differences in emotional processing in OCD.Peer reviewedFinal Published versio

Holographic Vitrification

We establish the existence of stable and metastable stationary black hole bound states at finite temperature and chemical potentials in global and planar four-dimensional asymptotically anti-de Sitter space. We determine a number of features of their holographic duals and argue they represent structural glasses. We map out their thermodynamic landscape in the probe approximation, and show their relaxation dynamics exhibits logarithmic aging, with aging rates determined by the distribution of barriers.Comment: 100 pages, 25 figure