Summary Background In patients with suspected coronary heart disease, single-photon emission computed tomography (SPECT) is the most widely used test for the assessment of myocardial ischaemia, but ...its diagnostic accuracy is reported to be variable and it exposes patients to ionising radiation. The aim of this study was to establish the diagnostic accuracy of a multiparametric cardiovascular magnetic resonance (CMR) protocol with x-ray coronary angiography as the reference standard, and to compare CMR with SPECT, in patients with suspected coronary heart disease. Methods In this prospective trial patients with suspected angina pectoris and at least one cardiovascular risk factor were scheduled for CMR, SPECT, and invasive x-ray coronary angiography. CMR consisted of rest and adenosine stress perfusion, cine imaging, late gadolinium enhancement, and MR coronary angiography. Gated adenosine stress and rest SPECT used99m Tc tetrofosmin. The primary outcome was diagnostic accuracy of CMR. This trial is registered at controlled-trials.com , number ISRCTN77246133. Findings In the 752 recruited patients, 39% had significant CHD as identified by x-ray angiography. For multiparametric CMR the sensitivity was 86·5% (95% CI 81·8–90·1), specificity 83·4% (79·5–86·7), positive predictive value 77·2%, (72·1–81·6) and negative predictive value 90·5% (87·1–93·0). The sensitivity of SPECT was 66·5% (95% CI 60·4–72·1), specificity 82·6% (78·5–86·1), positive predictive value 71·4% (65·3–76·9), and negative predictive value 79·1% (74·8–82·8). The sensitivity and negative predictive value of CMR and SPECT differed significantly (p<0·0001 for both) but specificity and positive predictive value did not (p=0·916 and p=0·061, respectively). Interpretation CE-MARC is the largest, prospective, real world evaluation of CMR and has established CMR's high diagnostic accuracy in coronary heart disease and CMR's superiority over SPECT. It should be adopted more widely than at present for the investigation of coronary heart disease. Funding British Heart Foundation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
These updated guidelines from the British Association for Psychopharmacology replace the original version published in 2011. They address the scope and targets of pharmacological treatment for ...schizophrenia. A consensus meeting was held in 2017, involving experts in schizophrenia and its treatment. They were asked to review key areas and consider the strength of the evidence on the risk-benefit balance of pharmacological interventions and the clinical implications, with an emphasis on meta-analyses, systematic reviews and randomised controlled trials where available, plus updates on current clinical practice. The guidelines cover the pharmacological management and treatment of schizophrenia across the various stages of the illness, including first-episode, relapse prevention, and illness that has proved refractory to standard treatment. It is hoped that the practice recommendations presented will support clinical decision making for practitioners, serve as a source of information for patients and carers, and inform quality improvement.
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A non-invasive functional-brain-imaging system based on optically-pumped-magnetometers (OPM) is presented. The OPM-based magnetoencephalography (MEG) system features 20 OPM channels conforming to the ...subject's scalp. We have conducted two MEG experiments on three subjects: assessment of somatosensory evoked magnetic field (SEF) and auditory evoked magnetic field (AEF) using our OPM-based MEG system and a commercial MEG system based on superconducting quantum interference devices (SQUIDs). We cross validated the robustness of our system by calculating the distance between the location of the equivalent current dipole (ECD) yielded by our OPM-based MEG system and the ECD location calculated by the commercial SQUID-based MEG system. We achieved sub-centimeter accuracy for both SEF and AEF responses in all three subjects. Due to the proximity (12 mm) of the OPM channels to the scalp, it is anticipated that future OPM-based MEG systems will offer enhanced spatial resolution as they will capture finer spatial features compared to traditional MEG systems employing SQUIDs.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The evolution of herbicide resistance in weed populations is a highly replicated example of adaptation surmounting the race against extinction, but the factors determining its rate and nature remain ...poorly understood. Here, we explore theory and empirical evidence for the importance of population genetic parameters-including effective population size, dominance, mutational target size, and gene flow-in influencing the probability and mode of herbicide resistance adaptation and its variation across species. We compiled data on the number of resistance mutations across populations for 79 herbicide-resistant species. Our findings are consistent with theoretical predictions that self-fertilization reduces resistance adaptation from standing variation within populations, but increases independent adaptation across populations. Furthermore, we provide evidence for a ploidy-mating system interaction that may reflect trade-offs in polyploids between increased effective population size and greater masking of beneficial mutations. We highlight the power of population genomic approaches to provide insights into the evolutionary dynamics of herbicide resistance with important implications for understanding the limits of adaptation.
In winter 2013/14 a succession of storms hit the UK leading to record rainfall and flooding in many regions including south east England. In the Thames river valley there was widespread flooding, ...with clean-up costs of over £1 billion. There was no observational precedent for this level of rainfall. Here we present analysis of a large ensemble of high-resolution initialised climate simulations to show that this event could have been anticipated, and that in the current climate there remains a high chance of exceeding the observed record monthly rainfall totals in many regions of the UK. In south east England there is a 7% chance of exceeding the current rainfall record in at least one month in any given winter. Expanding our analysis to some other regions of England and Wales the risk increases to a 34% chance of breaking a regional record somewhere each winter.A succession of storms during the 2013-2014 winter led to record flooding in the UK. Here, the authors use high-resolution climate simulations to show that this event could have been anticipated and that there remains a high chance of exceeding observed record monthly rainfall totals in many parts of the UK.
The past few years have seen an emergence of approaches that leverage temporal changes in whole-brain patterns of functional connectivity (the chronnectome). In this chronnectome study, we ...investigate the replicability of the human brain's inter-regional coupling dynamics during rest by evaluating two different dynamic functional network connectivity (dFNC) analysis frameworks using 7 500 functional magnetic resonance imaging (fMRI) datasets. To quantify the extent to which the emergent functional connectivity (FC) patterns are reproducible, we characterize the temporal dynamics by deriving several summary measures across multiple large, independent age-matched samples. Reproducibility was demonstrated through the existence of basic connectivity patterns (FC states) amidst an ensemble of inter-regional connections. Furthermore, application of the methods to conservatively configured (statistically stationary, linear and Gaussian) surrogate datasets revealed that some of the studied state summary measures were indeed statistically significant and also suggested that this class of null model did not explain the fMRI data fully. This extensive testing of reproducibility of similarity statistics also suggests that the estimated FC states are robust against variation in data quality, analysis, grouping, and decomposition methods. We conclude that future investigations probing the functional and neurophysiological relevance of time-varying connectivity assume critical importance.
•Replicability in dynamic functional connectivity state measures was investigated.•Twenty-eight samples each with two hundred and fifty rest-fMRI datasets were studied.•State profiles were modelled using two (clustering and fuzzy meta-state) approaches.•Both approaches showed high consistency for a range of model orders.•Surrogate testing confirmed state summary measures to be statistically significant.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Evapotranspiration (ET) is critical in linking global water, carbon and energy cycles. However, direct measurement of global terrestrial ET is not feasible. Here, we first reviewed the basic theory ...and state-of-the-art approaches for estimating global terrestrial ET, including remote-sensing-based physical models, machine-learning algorithms and land surface models (LSMs). We then utilized 4 remote-sensing-based physical models, 2 machine-learning algorithms and 14 LSMs to analyze the spatial and temporal variations in global terrestrial ET. The results showed that the ensemble means of annual global terrestrial ET estimated by these three categories of approaches agreed well, with values ranging from 589.6 mm/yr (6.56×10^4 cu.km/yr) to 617.1 mm/yr (6.87×10^4 cu.km/yr). For the period from 1982 to 2011, both the ensembles of remote-sensing-based physical models and machine-learning algorithms suggested increasing trends in global terrestrial ET (0.62 mm/sq.yr with a significance level of p<0.05 and 0.38 mm yr−2 with a significance level of p<0.05, respectively). In contrast, the ensemble mean of the LSMs showed no statistically significant change (0.23 mm/sq.yr, p>0.05), although many of the individual LSMs reproduced an increasing trend. Nevertheless, all 20 models used in this study showed that anthropogenic Earth greening had a positive role in increasing terrestrial ET. The concurrent small interannual variability, i.e., relative stability, found in all estimates of global terrestrial ET, suggests that a potential planetary boundary exists in regulating global terrestrial ET, with the value of this boundary being around 600 mm/yr. Uncertainties among approaches were identified in specific regions, particularly in the Amazon Basin and arid/semiarid regions. Improvements in parameterizing water stress and canopy dynamics, the utilization of new available satellite retrievals and deep-learning methods, and model–data fusion will advance our predictive understanding of global terrestrial ET.
OBJECTIVE:To investigate the incidence of LARS in patients undergoing elective anterior resection within the MRC/NIHR ROLARR trial and to explore perioperative variables that might be associated with ...major LARS.
SUMMARY BACKGROUND DATA:Sphincter-preserving rectal cancer surgery is frequently accompanied by defaecatory dysfunction known as Low anterior resection syndrome (LARS). This is distressing for patients and is an unmet clinical challenge.
METHODS:An international, retrospective cohort study of patients undergoing anterior resection within the ROLARR trial was undertaken. Trial participants with restoration of gastrointestinal continuity and free from disease recurrence completed the validated LARS questionnaire between August 2015 and April 2017. The primary outcome was the incidence of LARS and secondary outcome was severity (minor versus major).
RESULTS:LARS questionnaires were received from 132/155 (85%) eligible patients. The median time from surgery to LARS assessment was 1065 days (range 174–1655 d). The incidence of LARS was 82.6% (n = 109/132), which was minor in 26/132 (19.7%) and major in 83/132 (62.9%). The most common symptoms were incontinence to flatus (n = 86/132; 65.2%) and defaecatory clustering (88/132; 66.7%). In a multivariate model, predictors of major LARS were1 cm decrease in tumor height above the anal verge (OR = 1.290, 95% CI1.101,1.511); and an ASA grade greater than 1 (OR = 2.920, 95% CI1.239, 6.883). Treatment allocation (laparoscopic vs robotic) did not predict major LARS.
CONCLUSIONS:LARS is a common after rectal cancer surgery and patients should be appropriately counselled preoperatively, particularly before surgery for low tumors or in comorbid populations.
A major challenge in biology is to understand how complex gene expression patterns are encoded in the genome. While transcriptional enhancers have been studied extensively, few transcriptional ...silencers have been identified, and they remain poorly understood. Here, we used a novel strategy to screen hundreds of sequences for tissue-specific silencer activity in whole Drosophila embryos. Almost all of the transcriptional silencers that we identified were also active enhancers in other cellular contexts. These elements are bound by more transcription factors than non-silencers. A subset of these silencers forms long-range contacts with promoters. Deletion of a silencer caused derepression of its target gene. Our results challenge the common practice of treating enhancers and silencers as separate classes of regulatory elements and suggest the possibility that thousands or more bifunctional CRMs remain to be discovered in Drosophila and 104–105 in humans.
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•Silencers are bifunctional and can act as enhancers in other cellular contexts•A subset of silencers forms long-range contacts to promoters•Deletion of a silencer by genome editing caused derepression of its target gene•Results suggest that thousands of bifunctional elements in flies remain to be discovered
Gisselbrecht et al. performed a screen in developing Drosophila embryos for genomic sequences that can act as transcriptional silencers. They report that nearly all silencers are enhancers in other tissues or at other developmental stages. Their silencers fall into two classes, one of which forms physical chromosomal contacts with promoters.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The variation in weight within a shared environment is largely attributable to genetic factors. Whilst many genes/loci confer susceptibility to obesity, little is known about the genetic architecture ...of healthy thinness. Here, we characterise the heritability of thinness which we found was comparable to that of severe obesity (h2 = 28.07 vs 32.33% respectively), although with incomplete genetic overlap (r = -0.49, 95% CI -0.17, -0.82, p = 0.003). In a genome-wide association analysis of thinness (n = 1,471) vs severe obesity (n = 1,456), we identified 10 loci previously associated with obesity, and demonstrate enrichment for established BMI-associated loci (pbinomial = 3.05x10-5). Simulation analyses showed that different association results between the extremes were likely in agreement with additive effects across the BMI distribution, suggesting different effects on thinness and obesity could be due to their different degrees of extremeness. In further analyses, we detected a novel obesity and BMI-associated locus at PKHD1 (rs2784243, obese vs. thin p = 5.99x10-6, obese vs. controls p = 2.13x10-6 pBMI = 2.3x10-13), associations at loci recently discovered with much larger sample sizes (e.g. FAM150B and PRDM6-CEP120), and novel variants driving associations at previously established signals (e.g. rs205262 at the SNRPC/C6orf106 locus and rs112446794 at the PRDM6-CEP120 locus). Our ability to replicate loci found with much larger sample sizes demonstrates the value of clinical extremes and suggest that characterisation of the genetics of thinness may provide a more nuanced understanding of the genetic architecture of body weight regulation and may inform the identification of potential anti-obesity targets.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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