British South Asian ancestry participants views of pharmacogenomics clinical implementation and research: a thematic analysis.

BACKGROUND: South 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. METHODS: Four 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. RESULTS: There 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.

Moulded cast compared with K-wire fixation after manipulation of an acute dorsally displaced distal radius fracture: the DRAFFT 2 RCT.

BACKGROUND: Patients with a displaced fracture of the distal radius are frequently offered surgical fixation. Manipulation of the fracture and moulded plaster casting is an alternative treatment that avoids metal implants, but evidence of its effectiveness is lacking. OBJECTIVE: To compare functional outcomes, quality-of-life outcomes, complications and resource use among patients with a dorsally displaced fracture of the distal radius treated with manipulation and surgical fixation with Kirschner wires (K-wires) and those treated with manipulation and moulded cast. DESIGN: Pragmatic, superiority, multicentre, randomised controlled trial with a health economic evaluation. SETTING: A total of 36 orthopaedic trauma centres in the UK NHS. PARTICIPANTS: Patients (aged ≥ 16 years) treated for an acute dorsally displaced fracture of the distal radius were potentially eligible. Patients were excluded if their injury had occurred > 2 weeks previously, if the fracture was open, if it extended > 3 cm from the radiocarpal joint or if it required open reduction, or if the participant was unable to complete questionnaires. INTERVENTIONS: Participants were randomly assigned in theatre (1 : 1) to receive a moulded cast (i.e. the cast group) or surgical fixation with K-wires (i.e. the K-wire group) after fracture manipulation. MAIN OUTCOME MEASURES: The primary outcome measure was the Patient-Rated Wrist Evaluation score at 12 months, analysed on an intention-to-treat basis. Health-related quality of life was recorded using the EuroQol-5 Dimensions, five-level version, and resource use was recorded from a health and personal social care perspective. RESULTS: Between January 2017 and March 2019, 500 participants (mean age 60 years, 83% women) were randomly allocated to receive a moulded cast (n = 255) or surgical fixation with K-wire (n = 245) following a manipulation of their fracture. A total of 395 (80%) participants were included in the primary analysis at 12 months. There was no difference in the Patient-Rated Wrist Evaluation score at 1 year post randomisation [cast group: n = 200, mean score 21.2 (standard deviation 23.1); K-wire group: n = 195, mean score 20.7 (standard deviation 22.3); adjusted mean difference -0.34 (95% confidence interval -4.33 to 3.66); p = 0.87]. A total of 33 (13%) participants in the cast group required surgical fixation for loss of fracture position in the first 6 weeks, compared with one participant in the K-wire group (odds ratio 0.02, 95% confidence interval 0.001 to 0.10). The base-case cost-effectiveness analysis showed that manipulation and surgical fixation with K-wires had a higher mean cost than manipulation and a moulded cast, despite similar mean effectiveness. The use of K-wires is unlikely to be cost-effective, and sensitivity analyses found this result to be robust. LIMITATIONS: Because the interventions were identifiable, neither patients nor clinicians could be blind to their treatment. CONCLUSIONS: Surgical fixation with K-wires was not found to be superior to moulded casting following manipulation of a dorsally displaced fracture of the distal radius, as measured by Patient-Rated Wrist Evaluation score. However, one in eight participants treated in a moulded cast required surgery for loss of fracture reduction in the first 6 weeks. After a successful closed reduction, clinicians may consider a moulded cast as a safe and cost-effective alternative to surgical fixation with K-wires. FUTURE WORK: Further research should focus on optimal techniques for immobilisation and manipulation of this type of fracture, including optimal analgesia, and for rehabilitation of the patient after immobilisation. TRIAL REGISTRATION: This trial is registered as ISRCTN11980540 and UKCRN Portfolio 208830. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 11. See the NIHR Journals Library website for further project information.

Many patients with a wrist fracture can be treated with a simple cast or splint. However, if the broken bones have moved out of position, patients are frequently offered a manipulation of the fracture to restore the position of the broken bones. The bones may then be held in place with metal implants while they heal. A moulded plaster cast, shaped to support the bones, is an alternative treatment that avoids metal implants, but there is little research to suggest which treatment is better. The Distal Radius Acute Fracture Fixation Trial 2 (DRAFFT 2) study compared surgical fixation with metal wires with a moulded cast for patients with a broken wrist. Half of the patients underwent surgical fixation and half were given the moulded cast. The decision about which treatment patients were given was made by chance using a computer to ensure a fair comparison. The patients in both groups described their own wrist function and quality of life in the first year after their treatment and these descriptions were compared. A total of 500 patients took part at 36 NHS hospitals in the UK. The patients treated with a moulded cast reported very similar wrist function and quality of life to that of the patients treated with surgical fixation. However, one in eight patients treated with the moulded cast later required surgery because their broken bones had fallen back out of position. This study showed that a moulded cast is as good as, but costs less than, surgical fixation for patients with a broken wrist in terms of wrist function. However, a small proportion of the patients treated with a moulded cast may require later surgery if the broken bones cannot be held in position by the cast alone.

Complications following hip fracture: Results from the World Hip Trauma Evaluation cohort study.

INTRODUCTION: Hip fractures are common in people over 60 years of age, and are associated with significant disability, morbidity and mortality. The aim of this study was to record the incidence of complications in the first 120 days following hip fracture. METHODS: The World Hip Trauma Evaluation (WHiTE) study is a multicentre, prospective cohort study conducted in National Health Service (NHS) hospitals in England and Wales. Participants are 60 years and older who received operative treatment for a hip fracture. We report the incidence of complications recorded by hospital staff until discharge from hospital and by participants at 120-days post-surgery. RESULTS: An analysis of 8673 consecutive participants enrolled in the WHiTE study revealed the following risks of complications within the first 120 days: signs of wound infection (3.1%); dislocation (0.5%); failure of fixation (0.6%); peri­prosthetic fracture (0.3%); overall revision surgery (0.9%); blood loss requiring transfusion (6.1%); chest infection (6.3%); urinary tract infection (5.0%); deep vein thrombosis/pulmonary embolus (1.8%); cerebrovascular accident (0.6%); acute coronary syndrome/myocardial infarction (0.6%); acute kidney injury (1.3%). CONCLUSION: The rates of complications reported here provide a reference range against which future studies might be assessed. Registration: ISRCTN63982700.

Randomised controlled trial comparing hydroxyapatite coated uncemented hemiarthroplasty with cemented hemiarthroplasty for the treatment of displaced intracapsular hip fractures: a protocol for the WHITE 5 study.

INTRODUCTION: Hip 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 ANALYSIS: Multicentre (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 FUNDING: Wales 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.

Prescribing and adherence to bone protection medications following hip fracture in the United Kingdom: results from the World Hip Trauma Evaluation (WHiTE) cohort study.

AIMS: Bone health assessment and the prescription of medication for secondary fracture prevention have become an integral part of the acute management of patients with hip fracture. However, there is little evidence regarding compliance with prescription guidelines and subsequent adherence to medication in this patient group. PATIENTS AND METHODS: The World Hip Trauma Evaluation (WHiTE) is a multicentre, prospective cohort of hip fracture patients in NHS hospitals in England and Wales. Patients aged 60 years and older who received operative treatment for a hip fracture were eligible for inclusion in WHiTE. The prescription of bone protection medications was recorded from participants' discharge summaries, and participant-reported use of bone protection medications was recorded at 120 days following surgery. RESULTS: Of 5456 recruited patients with baseline data, 2853 patients (52%) were prescribed bone protection medication at discharge, of which oral bisphosphonates were the most common, 4109 patients (75%) were prescribed vitamin D or calcium, and 606 patients (11%) were not prescribed anything. Of those prescribed a bone protection medication, only 932 patients (33%) reported still taking their medication 120 days later. CONCLUSION: These data provide a reference for current prescription and adherence rates. Adherence with oral medication remains poor in patients with hip fracture. Cite this article: Bone Joint J 2019;101-B:1402-1407.

Retrograde intramedullary nail fixation compared with fixed-angle plate fixation for fracture of the distal femur: the TrAFFix feasibility RCT.

BACKGROUND: Fractures of the distal femur are an increasingly common injury; the optimal management of these injuries remains controversial. The two interventions used in UK practice are intramedullary fixation, with a locked retrograde nail, and extramedullary fixation, with a fixed angle plate. OBJECTIVES: This study assessed the feasibility of a definitive trial and included a process evaluation to understand the generalisability and likely success of a future trial. DESIGN: A multicentre, parallel, two-arm, randomised controlled feasibility trial with an embedded process evaluation. Treatment with a plate or nail was allocated in a 1 : 1 ratio, stratified by centre and chronic cognitive impairment. Surgeons were not blinded, but participants were not told their allocation. SETTING: Seven NHS hospitals. PARTICIPANTS: Patients aged ≥ 18 years with a fracture of the distal femur who the attending surgeon believed would benefit from internal fixation were potentially eligible. Patients were excluded if they had a loose arthroplasty requiring revision or a femoral deformity or arthroplasty that precluded nail fixation. The sample was recruited between 29 September 2016 and 31 August 2017. Consent was obtained from the patient or appropriate consultee before enrolment. INTERVENTIONS: Patients were randomised to receive fixation of their distal femur fracture with either a proximally and distally locked retrograde nail that spanned the diaphysis of the femur or an anatomical distal femoral locking plate with at least one locked screw distal to the fracture. Reduction and supplemental fixation were at the surgeon's discretion. OUTCOMES: The primary outcome measures for this study were the recruitment rate and the completion rate of the EuroQol-5 Dimensions, five-level version (EQ-5D-5L), at 6 weeks and 4 months. Additional measurements included baseline characteristics, measures of social support and self-efficacy, disability rating index, dementia quality-of-life measures and a radiographical assessment of any malunion. Participants' and staff views were obtained, at interview, for the process evaluation. RESULTS: The process evaluation showed that surgeon-related factors, principally confidence with both technologies and a lack of individual equipoise, were key barriers to recruitment. A total of 23 participants were randomised and analysed (nail, n = 11; plate, n = 12). The recruitment rate was estimated as 0.42 [95% confidence interval (CI) 0.27 to 0.62] participants per centre per month, lower than the prespecified feasibility threshold of 1.0 participants per centre per month. Data completeness of the EQ-5D-5L was estimated at 65% (95% CI 43% to 83%). CONCLUSIONS: This feasibility study has challenged many of the assumptions that underpinned the development of proposed definitive trial protocol. A modified protocol is proposed that would be feasible given the recruitment rate observed here, which is equal to that reported in the similar FixDT trial [Health Technology Assessment (HTA) 11/136/04: Costa ML, Achten J, Hennings S, Boota N, Griffin J, Petrou S, et al. Intramedullary nail fixation versus locking plate fixation for adults with a fracture of the distal tibia: the UK FixDT RCT. Health Technol Assess 2018;22(25)], which delivered to target and budget. FUTURE WORK: A definitive trial with a modified design is recommended, including an internal pilot to confirm initial recruitment rate assumptions. REGISTRATION: Current Controlled Trials ISRCTN92089567. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 51. See the NIHR Journals Library website for further project information. Funding was also supported by the NIHR Oxford Biomedical Research Centre.

Breaks of the lower end of the thigh bone are increasingly common injuries. Two operations are used to treat these injuries: a rod placed along the centre of the bone or a plate attached to the edge of the bone. It is not clear which is better. We report the results from a study that will help develop the design of a definitive study to test which operation produces the best outcomes for patients. Adult patients with a break at the end of the thigh bone treated in one of seven hospitals were eligible to take part in the study. Participants were treated with one of two operations; the choice was made by chance using a computer program. Participants' basic information and pre-injury health status were recorded and participants were followed up at 6 and 16 weeks. We assessed the rate at which participants agreed to take part in the study and the number who completed follow-up. A value-for-money analysis was performed to determine how to plan this element of a future study. Staff and patients were interviewed about the study processes and the context of the treatments and hospitals to understand how the treatments work and the practicalities of delivering the study. Lower than expected numbers of participants took part in the study; 173 patients were considered for the study, but only 23 agreed to participate. The main reason was that several of the participating surgeons felt strongly that one or the other operation was superior. The rate of follow-up was similar to that of other studies using these treatments. Therefore, the proposed definitive trial is unlikely to be successful if designed in the same way as this feasibility study. Several important considerations that informed the planning of this study were found not to hold true. We believe a modified study could be delivered and could answer this important research question.

Intramedullary nails versus distal locking plates for fracture of the distal femur: results from the Trial of Acute Femoral Fracture Fixation (TrAFFix) randomised feasibility study and process evaluation.

OBJECTIVES: This 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 & SETTING: A 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. PARTICIPANTS: Patients 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. OUTCOMES: The 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. RESULTS: Recruitment 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. CONCLUSIONS: A 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 APPROVAL: The Wales Research Ethics Committee 5 approved the study (ref: 16/WA/0225). TRIAL REGISTRATION NUMBER: ISRCTN92089567; Pre-results.

Targeting a Plk1-Controlled Polarity Checkpoint in Therapy-Resistant Glioblastoma-Propagating Cells.

The treatment of glioblastoma (GBM) remains challenging in part due to the presence of stem-like tumor-propagating cells that are resistant to standard therapies consisting of radiation and temozolomide. Among the novel and targeted agents under evaluation for the treatment of GBM are BRAF/MAPK inhibitors, but their effects on tumor-propagating cells are unclear. Here, we characterized the behaviors of CD133(+) tumor-propagating cells isolated from primary GBM cell lines. We show that CD133(+) cells exhibited decreased sensitivity to the antiproliferative effects of BRAF/MAPK inhibition compared to CD133(-) cells. Furthermore, CD133(+) cells exhibited an extended G2-M phase and increased polarized asymmetric cell divisions. At the molecular level, we observed that polo-like kinase (PLK) 1 activity was elevated in CD133(+) cells, prompting our investigation of BRAF/PLK1 combination treatment effects in an orthotopic GBM xenograft model. Combined inhibition of BRAF and PLK1 resulted in significantly greater antiproliferative and proapoptotic effects beyond those achieved by monotherapy (P < 0.05). We propose that PLK1 activity controls a polarity checkpoint and compensates for BRAF/MAPK inhibition in CD133(+) cells, suggesting the need for concurrent PLK1 inhibition to improve antitumor activity against a therapy-resistant cell compartment.

Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma.

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.

A microRNA-operated switch of asymmetric-to-symmetric cancer stem cell divisions.

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.

Asymmetric cell division of stem and progenitor cells during homeostasis and cancer.

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.

A role for the CREB co-activator CRTC2 in the hypothalamic mechanisms linking glucose sensing with gene regulation.

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.