Automated quantification of stroke damage on brain computed tomography scans: e-ASPECTS

Emergency radiological diagnosis of acute ischaemic stroke requires the accurate detection and appropriate interpretation of relevant imaging findings. Non-contrast computed tomography (CT) provides fast and low-cost assessment of the early signs of ischaemia and is the most widely used diagnostic modality for acute stroke. The Alberta Stroke Program Early CT Score (ASPECTS) is a quantitative and clinically validated method to measure the extent of ischaemic signs on brain CT scans. The CE-marked electronic-ASPECTS (e-ASPECTS) software automates the ASPECTS score. Anglia Ruskin Clinical Trials Unit (ARCTU) independently carried out a clinical investigation of the e-ASPECTS software, an automated scoring system which can be integrated into the diagnostic pathway of an acute ischaemic stroke patient, thereby assisting the physician with expert interpretation of the brain CT scan. Here we describe a literature review of the clinical importance of reliable assessment of early ischaemic signs on plain CT scans, and of technologies automating these processed scoring systems in ischaemic stroke on CT scans focusing on the e-ASPECTS software. To be suitable for critical appraisal in this evaluation, the published studies needed a sample size of a minimum of 10 cases. All randomised studies were screened and data deemed relevant to demonstration of performance of ASPECTS were appraised. The literature review focused on three domains: i) interpretation of brain CT scans of stroke patients, ii) the application of the ASPECTS score in ischaemic stroke, and iii) automation of brain CT analysis. Finally, the appraised references are discussed in the context of the clinical impact of e-ASPECTS and the expected performance, which will be independently evaluated by a non-inferiority study conducted by the ARCTU

\u3cem\u3eDACH1\u3c/em\u3e Mutation Frequency in Endometrial Cancer Is Associated with High Tumor Mutation Burden

OBJECTIVE: DACH1 is a transcriptional repressor and tumor suppressor gene frequently mutated in melanoma, bladder, and prostate cancer. Loss of DACH1 expression is associated with poor prognostic features and reduced overall survival in uterine cancer. In this study, we utilized the Oncology Research Information Exchange Network (ORIEN) Avatar database to determine the frequency of DACH1 mutations in patients with endometrial cancer in our Kentucky population. METHODS: We obtained clinical and genomic data for 65 patients with endometrial cancer from the Markey Cancer Center (MCC). We examined the clinical attributes of the cancers by DACH1 status by comparing whole-exome sequencing (WES), RNA Sequencing (RNASeq), microsatellite instability (MSI), and tumor mutational burden (TMB). RESULTS: Kentucky women with endometrial cancer had an increased frequency of DACH1 mutations (12/65 patients, 18.5%) compared to The Cancer Genome Atlas (TCGA) endometrial cancer population (25/586 patients, 3.8%) with p-value = 1.04E-05. DACH1 mutations were associated with increased tumor mutation count in both TCGA (median 65 vs. 8972, p-value = 7.35E-09) and our Kentucky population (490 vs. 2160, p-value = 6.0E-04). DACH1 mutated patients have a higher tumor mutation burden compared to DACH1 wild-type (24 vs. 6.02, p-value = 4.29E-05). DACH1 mutations showed significant gene co-occurrence patterns with POLE, MLH1, and PMS2. DACH1 mutations were not associated with an increase in microsatellite instability at MCC (MSI-H) (p-value = 0.1342). CONCLUSIONS: DACH1 mutations are prevalent in Kentucky patients with endometrial cancer. These mutations are associated with high tumor mutational burden and co-occur with genome destabilizing gene mutations. These findings suggest DACH1 may be a candidate biomarker for future trials with immunotherapy, particularly in endometrial cancers

Managing macropods without poisoning ecosystems

A recent review of the management of hyperabundant macropods in Australia proposed that expanded professional shooting is likely to lead to better biodiversity and animal welfare outcomes. While the tenets of this general argument are sound, it overlooks one important issue for biodiversity and animal health and welfare: reliance on toxic lead-based ammunition. Lead poisoning poses a major threat to Australia's wildlife scavengers. Current proposals to expand professional macropod shooting would see tons of an extremely toxic and persistent heavy metal continue to be introduced into Australian environments. This contrasts with trends in many other countries, where lead ammunition is, through legislation or voluntary programs, being phased out. Fortunately, there are alternatives to lead ammunition that could be investigated and adopted for improved macropod management. A transition to lead-free ammunition would allow the broad environmental and animal welfare goals desired from macropod management to be pursued without secondarily and unintentionally poisoning scavengers. Through this article, we hope to increase awareness of this issue and encourage discussion of this potential change.publishedVersio

Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis

ReadDepth: A Parallel R Package for Detecting Copy Number Alterations from Short Sequencing Reads

Copy number alterations are important contributors to many genetic diseases, including cancer. We present the readDepth package for R, which can detect these aberrations by measuring the depth of coverage obtained by massively parallel sequencing of the genome. In addition to achieving higher accuracy than existing packages, our tool runs much faster by utilizing multi-core architectures to parallelize the processing of these large data sets. In contrast to other published methods, readDepth does not require the sequencing of a reference sample, and uses a robust statistical model that accounts for overdispersed data. It includes a method for effectively increasing the resolution obtained from low-coverage experiments by utilizing breakpoint information from paired end sequencing to do positional refinement. We also demonstrate a method for inferring copy number using reads generated by whole-genome bisulfite sequencing, thus enabling integrative study of epigenomic and copy number alterations. Finally, we apply this tool to two genomes, showing that it performs well on genomes sequenced to both low and high coverage. The readDepth package runs on Linux and MacOSX, is released under the Apache 2.0 license, and is available at http://code.google.com/p/readdepth/

Really responsive risk-based regulation

Regulators in a number of countries are increasingly developing "risk-based" strategies to manage their resources, and their reputations as "risk-based regulators" have become much lauded by regulatory reformers. This widespread endorsement of risk-based regulation, together with the experience of regulatory failure, prompts us to consider how risk-based regulators can attune the logics of risk analyses to the complex problems and the dynamics of regulation in practice. We argue, first, that regulators have to regulate in a way that is responsive to five elements: (1) regulated firms' behavior, attitude, and culture; (2) regulation's institutional environments; (3) interactions of regulatory controls; (4) regulatory performance; and (5) change. Secondly, we argue that the challenges of regulation to which regulators have to respond vary across the different regulatory tasks of detection, response development, enforcement, assessment, and modification. Using the "really responsive" framework, we highlight some of the strengths and limitations of using risk-based regulation to manage risk and uncertainty within the constraints that flow from practical circumstances and, indeed, from the framework of risk-based regulation itself. The need for a revised, more nuanced conception of risk-based regulation is stressed

hardRain: An R package for quick, automated rainfall detection in ecoacoustic datasets using a threshold-based approach

The increasing demand for cost-efficient biodiversity data at large spatiotemporal scales has led to an increase in the collection of large ecoacoustic datasets. Whilst the ease of collection and storage of audio data has rapidly increased and costs fallen, methods for robust analysis of the data have not developed so quickly. Identification and classification of audio signals to species level is extremely desirable, but reliability can be highly affected by non-target noise, especially rainfall. Despite this demand, there are few easily applicable pre-processing methods available for rainfall detection for conservation practitioners and ecologists. Here, we use threshold values of two simple measures, Power Spectrum Density (amplitude) and Signal-to-Noise Ratio at two frequency bands, to differentiate between the presence and absence of heavy rainfall. We assess the effect of using different threshold values on Accuracy and Specificity. We apply the method to four datasets from both tropical and temperate regions, and find that it has up to 99% accuracy on tropical datasets (e.g. from the Brazilian Amazon), but performs less well in temperate environments. This is likely due to the intensity of rainfall in tropical forests and its falling on dense, broadleaf vegetation amplifying the sound. We show that by choosing between different threshold values, informed trade-offs can be made between Accuracy and Specificity, thus allowing the exclusion of large amounts of audio data containing rainfall in all locations without the loss of data not containing rain. We assess the impact of using different sample sizes of audio data to set threshold values, and find that 200 15 s audio files represents an optimal trade-off between effort, accuracy and specificity in most scenarios. This methodology and accompanying R package ‘hardRain’ is the first automated rainfall detection tool for pre-processing large acoustic datasets without the need for any additional rain gauge data

Epidermal Neural Crest Stem Cell (EPI-NCSC)—Mediated Recovery of Sensory Function in a Mouse Model of Spinal Cord Injury

Here we show that epidermal neural crest stem cell (EPI-NCSC) transplants in the contused spinal cord caused a 24% improvement in sensory connectivity and a substantial recovery of touch perception. Furthermore we present a novel method for the ex vivo expansion of EPI-NCSC into millions of stem cells that takes advantage of the migratory ability of neural crest stem cells and is based on a new culture medium and the use of microcarriers. Functional improvement was shown by two independent methods, spinal somatosensory evoked potentials (SpSEP) and the Semmes-Weinstein touch test. Subsets of transplanted cells differentiated into myelinating oligodendrocytes. Unilateral injections of EPI-NCSC into the lesion of midline contused mouse spinal cords elicited bilateral improvements. Intraspinal EPI-NCSC did not migrate laterally in the spinal cord or invade the spinal roots and dorsal root ganglia, thus implicating diffusible factors. EPI-NCSC expressed neurotrophic factors, angiogenic factors, and metalloproteases. The strength of EPI-NCSC thus is that they can exert a combination of pertinent functions in the contused spinal cord, including cell replacement, neuroprotection, angiogenesis and modulation of scar formation. EPI-NCSC are uniquely qualified for cell-based therapy in spinal cord injury, as neural crest cells and neural tube stem cells share a higher order stem cell and are thus ontologically closely related

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London