Incidence of Clostridioides difficile infection (CDI) related to antibiotic prescribing by GP surgeries in Wales

Background Clostridioides difficile infection (CDI) is a healthcare-acquired infection (HAI) causing significant morbidity and mortality. Welsh CDI rates are high in comparison with those in England and Scotland. Objectives This retrospective ecological study used aggregated disease surveillance data to understand the impact of total and high-risk Welsh GP antibiotic prescribing on total and stratified inpatient/non-inpatient CDI incidence. Methods All cases of confirmed CDI, during the financial years 2014–15 to 2017–18, were linked to aggregated rates of antibiotic prescribing in their GP surgery and classified as ‘inpatient’, ‘non-inpatient’ or ‘unknown’ by Public Health Wales. Multivariable negative-binomial regression models, comparing CDI incidence with antibiotic prescribing rates, were adjusted for potential confounders: location; age; social deprivation; comorbidities (estimated from prevalence of key health indicators) and proton pump inhibitor (PPI) prescription rates. Results There were 4613 confirmed CDI cases, with an incidence (95% CI) of 1.44 (1.40–1.48) per 1000 registered patients. Unadjusted analysis showed that an increased risk of total CDI incidence was associated with higher total antibiotic prescribing [relative risk (RR) (95% CI) = 1.338 (1.170–1.529) per 1000 items per 1000 specific therapeutic group age-sex related GP prescribing units (STAR-PU)] and that high-risk antibiotic classes were positively associated with total CDI incidence. Location, age ≥65 years and diabetes were associated with increased risk of CDI. After adjusting for confounders, prescribing of clindamycin showed a positive association with total CDI incidence [RR (95% CI) = 1.079 (1.001–1.162) log items per 1000 registered patients]. Conclusions An increased risk of CDI is demonstrated at a primary care practice population level, reflecting their antibiotic prescribing rates, particularly clindamycin, and population demographics

Neuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitors.

Myelin regeneration can occur spontaneously in demyelinating diseases such as multiple sclerosis (MS). However, the underlying mechanisms and causes of its frequent failure remain incompletely understood. Here we show, using an in-vivo remyelination model, that demyelinated axons are electrically active and generate de novo synapses with recruited oligodendrocyte progenitor cells (OPCs), which, early after lesion induction, sense neuronal activity by expressing AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)/kainate receptors. Blocking neuronal activity, axonal vesicular release or AMPA receptors in demyelinated lesions results in reduced remyelination. In the absence of neuronal activity there is a ∼6-fold increase in OPC number within the lesions and a reduced proportion of differentiated oligodendrocytes. These findings reveal that neuronal activity and release of glutamate instruct OPCs to differentiate into new myelinating oligodendrocytes that recover lost function. Co-localization of OPCs with the presynaptic protein VGluT2 in MS lesions implies that this mechanism may provide novel targets to therapeutically enhance remyelination.This work was supported by the Medical Research Council (R.T.K, R.J.M.F and H.O.B.G. G0701476; K.V. and R.T.K 1233560), Wellcome Trust (R.T.K. and K.A.E. 091543/Z/10/Z), Marie Curie training programme Axregen EC FP7 ITN (I.L. and R.T.K 214003), and core support grant from the Wellcome Trust and MRC to the Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ncomms951

Short-term Succinic Acid Treatment Mitigates Cerebellar Mitochondrial OXPHOS Dysfunction, Neurodegeneration and Ataxia in a Purkinje-specific Spinocerebellar Ataxia Type 1 (SCA1) Mouse Model

Mitochondrial dysfunction plays a significant role in neurodegenerative disease including ataxias and other movement disorders, particularly those marked by progressive degeneration in the cerebellum. In this study, we investigate the role of mitochondrial oxidative phosphorylation (OXPHOS) deficits in cerebellar tissue of a Purkinje cell-driven spinocerebellar ataxia type 1 (SCA1) mouse. Using RNA sequencing transcriptomics, OXPHOS complex assembly analysis and oxygen consumption assays, we report that in the presence of mutant polyglutamine-expanded ataxin-1, SCA1 mice display deficits in cerebellar OXPHOS complex I (NADH-coenzyme Q oxidoreductase). Complex I genes are upregulated at the time of symptom onset and upregulation persists into late stage disease; yet, functional assembly of complex I macromolecules are diminished and oxygen respiration through complex I is reduced. Acute treatment of postsymptomatic SCA1 mice with succinic acid, a complex II (succinate dehydrogenase) electron donor to bypass complex I dysfunction, ameliorated cerebellar OXPHOS dysfunction, reduced cerebellar pathology and improved motor behavior. Thus, exploration of mitochondrial dysfunction and its role in neurodegenerative ataxias, and warrants further investigation

A Reappraisal of Children’s ‘Potential’

What does it mean for a child to fulfil his or her potential? This article explores the contexts and implications of the much-used concept of potential in educational discourses. We claim that many of the popular, political and educational uses of the term in relation to childhood have a problematic blind spot: interpersonality, and the necessary coexistence for the concept to be receivable of all children’s ‘potentials’. Rather than advocating abandoning the term—a futile gesture given its emotive force—we argue that the concept of children’s potential must be profoundly rethought to be workable as a philosophical notion in education. In an era marked by the unspoken assumption that ‘unlimited potential’ is always a good thing, we argue that it might be necessary to think about the limitations of the notion of individual potential; namely, the moment when it comes into contact with other people’s projects. We propose a conceptualisation of potential as the negotiated, situated, ever-changing creation of a group of individuals, in a process marked by conflict, and which remains essentially difficult.This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s11217-016-9508-

Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell-mediated deletion

This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).This work was funded by the Medical Research Council (Clinical Research Training Fellowship to DP and grant G0801213 to M.K. Maini)

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Genetic variation within genes associated with mitochondrial function is significantly associated with later age at onset of Parkinson disease and contributes to disease risk

Mitochondrial dysfunction has been implicated in the aetiology of monogenic Parkinson’s disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here we comprehensively assessed the role of mitochondrial function associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. First, we identified that a proportion of the “missing heritability” of the PD can be explained by common variation within genes implicated in mitochondrial disease (primary gene list) and mitochondrial function (secondary gene list). Next we calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. Most significantly we further report that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomisation, which showed that 14 of these mitochondrial function associated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD