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Stem and progenitor cells are characterized by their ability to self-renew and produce differentiated progeny. A fine balance between these processes is achieved through controlled asymmetric divisions and is necessary to generate cellular diversity during development and to maintain adult tissue homeostasis. Disruption of this balance may result in premature depletion of the stem/progenitor cell pool, or abnormal growth. In many tissues, including the brain, dysregulated asymmetric divisions are associated with cancer. Whether there is a causal relationship between asymmetric cell division defects and cancer initiation is as yet not known. Here, we review the cellular and molecular mechanisms that regulate asymmetric cell divisions in the neural lineage and discuss the potential connections between this regulatory machinery and cancer.

Hashizume et al . report a new therapeutic strategy for treating pediatric gliomas with mutations in the H3F3A gene by inhibiting histone demethylation. Pediatric brainstem gliomas often harbor oncogenic K27M mutation of histone H3.3. Here we show that GSKJ4 pharmacologic inhibition of K27 demethylase JMJD3 increases cellular H3K27 methylation in K27M tumor cells and demonstrate potent antitumor activity both in vitro against K27M cells and in vivo against K27M xenografts. Our results demonstrate that increasing H3K27 methylation by inhibiting K27 demethylase is a valid therapeutic strategy for treating K27M-expressing brainstem glioma.

Defective asymmetric cell divisions of stem and progenitor cells are associated with tumorigenesis by a largely unknown mechanism. A signalling axis involving Snail, microRNA-146a and Numb is now shown to regulate the switch between symmetric and asymmetric cell division in colorectal cancer stem cells.

The Consolidated Standards of Reporting Trials extension for the stepped-wedge cluster randomized trial (SW-CRT) is a recently published reporting guideline for SW-CRTs. We assess the quality of reporting of a recent sample of SW-CRTs. Quality of reporting was asssessed according to the 26 items in the new guideline using a novel crowd sourcing methodology conducted independently and in duplicate, with random assignment, by 50 reviewers. We assessed reliability of the quality assessments, proposing this as a novel way to assess robustness of items in reporting guidelines. Several items were well reported. Some items were very poorly reported, including several items that have unique requirements for the SW-CRT, such as the rationale for use of the design, description of the design, identification and recruitment of participants within clusters, and concealment of cluster allocation (not reported in more than 50% of the reports). Agreement across items was moderate (median percentage agreement was 76% [IQR 64 to 86]). Agreement was low for several items including the description of the trial design and why trial ended or stopped for example. When reporting SW-CRTs, authors should pay particular attention to ensure clear reporting on the exact format of the design with justification, as well as how clusters and individuals were identified for inclusion in the study, and whether this was done before or after randomization of the clusters, which are crucial for risk of bias assessments. Some items, including why the trial ended, might either not be relevant to SW-CRTs or might be unclearly described in the statement. •The stepped-wedge cluster randomized trial (SW-CRT) is a novel cluster randomized trial variant that is increasingly being used.•The design has many methodological complexities, which increase its risk of bias.•This article reports a baseline assessment of the quality of reporting according to this new guideline using a novel crowdsourcing methodology.•This review has been produced with involvement with many of the leading experts in this study design.•We are in the position of being ahead of the curve with great potential to improve reporting of this innovative design by revealing where quality is currently lacking before its widespread use.

Within the central nervous system (CNS), the hypothalamus senses and integrates information on the nutrient state of the body. However, the molecular mechanisms translating nutrient sensing into changes in gene expression and, ultimately, nutrient intake remain unclear. A crucial function for the cyclic AMP‐response element binding protein (CREB) co‐activator CREB‐regulated transcription co‐activator 2 (CRTC2) in maintaining glucose homeostasis has been shown in the liver. Here, we report CRTC2 expression in distinct areas of the CNS, including hypothalamic neurons. We show that hypothalamic CRTC2 phosphorylation and subcellular localization is altered by nutrient state. Specifically, glucose regulates hypothalamic CRTC2 activity via AMP‐activated protein kinase (AMPK)‐mediated phosphorylation of CRTC2. Hypothalamic AMPK controls the expression of the cAMP response element (CRE) gene, insulin receptor substrate 2 ( Irs2 ), by regulating CRTC2 occupancy of the Irs2 promoter. Indeed, CRTC2 is required for the appropriate expression of specific hypothalamic CRE genes. Our data identify CRTC2 as a new hypothalamic AMPK target and highlight a role for CRTC2 in the mechanisms linking hypothalamic glucose sensing with CRE gene regulation. The hypothalamus senses and regulates the metabolic state of the body. Lerner et al identify a role for the CREB co‐activator CRTC2 (CREB‐regulated transcription co‐activator 2) that acts as a link between hypothalamic nutrient‐sensing and appropriate gene regulation.

ObjectivesThis feasibility study and process evaluation assessed the likely success of a definitive trial of intramedullary fixation with locked retrograde nails versus extramedullary fixation with fixed angle plates for fractures of the distal femur.Design & settingA multicentre, parallel, two-arm, randomised controlled feasibility study with an embedded process evaluation was conducted at seven NHS hospitals in England. Treatment was randomly allocated in 1:1 ratio, stratified by centre and chronic cognitive impairment. Participants, but not surgeons or research staff, were blinded to the allocation.ParticipantsPatients 18 years and older with a fracture of the distal femur, who their surgeon believed would benefit from internal fixation, were eligible to take part.Participants were allocated to receive either a retrograde intramedullary nail or an anatomical locking plate.OutcomesThe primary outcomes for this feasibility study were the recruitment rate and completion rate of the EQ-5D-5L at 4 months post-randomisation. Baseline characteristics, disability rating index, quality of life scores, measurements of social support and self-efficacy, resource use and radiographic assessments were also collected. The views of patients and staff were collected during interviews.ResultsRecruitment and data completion were lower than expected. 23 of 82 eligible patients were recruited (nail, 11; plate, 12). The recruitment rate was estimated as 0.42 (95% CI 0.27 to 0.62) participants per centre-month. Data completeness of the EQ-5D-5L at 4 months was 61 per cent (95% CI 43% to 83%). The process evaluation demonstrated that the main barriers to recruitment were variation in treatment pathways across centres, lack of surgeon equipoise and confidence in using both interventions and newly formed research cultures that lacked cohesion.ConclusionsA modified trial design, with embedded recruitment support intervention, comparing functional outcome in cognitively intact adults who have sustained a fragility fracture of the distal femur is feasible.Ethics approvalThe Wales Research Ethics Committee 5 approved the study (ref: 16/WA/0225).Trial registration number ISRCTN92089567; Pre-results.

IntroductionHip fracture is a serious injury in adults, especially those aged over 60 years. The most common type of hip fracture (displaced intracapsular) is treated for the majority of patients with a partial hip replacement (hemiarthroplasty). The hemiarthroplasty implant can be fixed to the bone with or without bone cement. Cement is the current recommended technique but recently some risks have been identified, which could potentially be avoided by using uncemented implants. Controversy, therefore, remains about which type of hemiarthroplasty offers patients the best outcomes.This is the protocol for a multicentre randomised controlled trial comparing cemented hemiarthroplasty versus uncemented hemiarthroplasty for patients 60 years and over with a displaced intracapsular hip fracture.Methods and analysisMulticentre (a minimum of seven UK hospitals), multisurgeon, parallel group, two-arm, superiority, randomised controlled trial. Patients aged 60 years and older with a displaced intracapsular hip fracture treated with hemiarthroplasty surgery are eligible. Participants will be randomly allocated on a 1:1 basis to either a cemented hemiarthroplasty or a modern hydroxyapatite coated uncemented hemiarthroplasty. Otherwise all care will be in accordance with the National Institute for Health and Care Excellence guidance. A minimum of 1128 patients will be recruited to obtain 90% power to detect a 0.075-point difference in the primary endpoint: health-related quality of life (EuroQol 5 dimensions 5 levels) at 4 months postinjury. The treatment effect will be estimated using a two-sided t-test adjusted for age, gender and cognitive impairment based on an intention-to-treat analysis. Secondary outcomes include mortality, complications including revision surgery and cause, mobility status, residential status, health-related quality of life at 1 and 12 months and health resource use. A within-trial economic analysis will be conducted.Ethics, dissemination and fundingWales Research Ethics Committee 5 approved the feasibility phase on 2 December 2016 (16/WA/0351) and the definitive trial on 22 November 2017 (17/WA/0383). This study is sponsored by the University of Oxford and funded by the National Institute for Health Research, Research for Patient Benefit (PB-PG-0215–36043 and PB-PG-1216–20021). A manuscript for a peer-reviewed journal will be prepared and the results shared with patients via local mechanisms at participating centres.Trial registration number ISRCTN18393176

BackgroundSouth Asian ancestry populations are underrepresented in genomic studies and therapeutics trials. British South Asians suffer from multi-morbidity leading to polypharmacy. Our objective was to elucidate British South Asian ancestry community perspectives on pharmacogenomic implementation and sharing pharmacogenomic clinical data for research.MethodsFour focus groups were conducted (9–12 participants in each). Two groups were mixed gender, while one group was male only and one was female only. Simultaneous interpretation was available to participants in Urdu and Bengali. Focus groups were recorded and abridged transcription and thematic analysis were undertaken.ResultsThere were 42 participants, 64% female. 26% were born in the UK or Europe. 52% were born in Bangladesh and 17% in Pakistan. 36% reported university level education.Implementation of pharmacogenomics was perceived to be beneficial to individuals but pose a risk of overburdening resource limited systems. Pharmacogenomic research was perceived to be beneficial to the community, with concerns about data privacy and misuse. Data sharing was desirable if the researchers did not have a financial stake, and benefits would be shared.Trust was the key condition for the acceptability of both clinical implementation and research. Trust was linked with medication compliance. Education, outreach, and communication facilitate trust.Conclusions (Significance and Impact of the Study)Pharmacogenomics implementation with appropriate education and communication has the potential to enhance trust and contribute to increased medication compliance. Trust drives data sharing, which would enable enhanced representation in research. Representation in scientific evidence base could cyclically enhance trust and compliance.

This study assessed the contribution of five genes previously known to be involved in cholestatic liver disease in British Bangladeshi and Pakistani people. Five genes ( ABCB4 , ABCB11 , ATP8B1 , NR1H4 , TJP2 ) were interrogated by exome sequencing data of 5236 volunteers. Included were non-synonymous or loss of function (LoF) variants with a minor allele frequency < 5%. Variants were filtered, and annotated to perform rare variant burden analysis, protein structure, and modelling analysis in-silico . Out of 314 non-synonymous variants, 180 fulfilled the inclusion criteria and were mostly heterozygous unless specified. 90 were novel and of those variants, 22 were considered likely pathogenic and 9 pathogenic. We identified variants in volunteers with gallstone disease (n = 31), intrahepatic cholestasis of pregnancy (ICP, n = 16), cholangiocarcinoma and cirrhosis (n = 2). Fourteen novel LoF variants were identified: 7 frameshift, 5 introduction of premature stop codon and 2 splice acceptor variants. The rare variant burden was significantly increased in ABCB11 . Protein modelling demonstrated variants that appeared to likely cause significant structural alterations. This study highlights the significant genetic burden contributing to cholestatic liver disease. Novel likely pathogenic and pathogenic variants were identified addressing the underrepresentation of diverse ancestry groups in genomic research.

Background Qualitative research has been used to explore patients’ and healthcare professionals’ experiences of surgical randomised controlled trials (RCTs). From this research, reasons why patients accept or decline participation and barriers to engaging clinicians in trials have been identified. In a trauma setting, recruitment to surgical trials can be particularly difficult as patients may require urgent treatment and their ability to consider their options, ask questions and reach a decision may be hindered by the impact of their injury. Little research, however, has explored patients’ and healthcare professionals’ experiences of surgical RCTs in a trauma setting. This study aimed to understand patients’ and staff’s experiences of an orthopaedic trauma trial. Methods We carried out semi-structured interviews with 11 patients and 24 staff (10 surgeons and 14 research associates) participating in a UK multi-centre feasibility trial comparing intramedullary nails versus distal locking plates for fractures of the distal femur (TrAFFix). Interviews explored patients’ experience of TrAFFix and their reason for participating and staffs' experience of recruiting to TrAFFix and trauma trials more generally. Interviews were audio recorded and transcribed verbatim. Transcripts were analysed using thematic analysis. Results Three themes were identified. These were i) navigating research with patients after orthopaedic trauma, ii) knowing that it is the right decision and iii) making it work. These themes reflect: i) how research associates supported and guided patients through the consent process enabling them to participate, ii) the difficulty in engaging surgeons in a trial when individual equipoise and experience of the interventions are low despite the presence of community equipoise and iii) the way in which research teams worked together and encouraged the development of a research culture within the clinical teams in order to facilitate recruitment. Conclusions Our findings highlight the pivotal role of research associates (RAs) in facilitating trial recruitment. RAs supported patients to enable them to make a decision about participation and assisted in developing a research culture within the team by promoting studies and communicating research to clinical staff. Our findings also reinforce surgeons’ difficulty with equipoise and suggest that accepting community equipoise could facilitate recruitment.