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Supplementary Figure S1. Survival analysis in extreme quartiles of RAI2 expression in lung colon and ovarian cancer data sets.

Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology. Objective: To evaluate the long-term clinical effectiveness of a novel group-based outpatient physical therapy (PT) following total knee replacement (TKR). Methods: In this 2-center, unblinded, superiority, randomized controlled trial, 180 patients on a waiting list for primary TKR due to osteoarthritis were randomized to a 6 session group-based outpatient PT intervention and usual care (n = 89) or usual care alone (n = 91). The primary outcome was patient-reported functional ability measured by the Lower Extremity Functional Scale at 12 months postoperative. Secondary outcomes included knee symptoms, depression, anxiety, and satisfaction. Questionnaires were completed preoperatively and at 3, 6, and 12 months postoperatively. Results: The mean difference in function between groups was 4.47 (95% confidence interval [95% CI] 0.20, 8.75; P = 0.04) at 12 months postoperative, favoring the intervention. The mean difference in function between groups decreased over time, from 8.1 points at 3 months (95% CI 3.8, 12.4; P < 0.001) to 5.4 (95% CI 1.1, 9.8; P = 0.015) at 6 months postoperative. There were no clinically relevant differences in any secondary outcomes between groups, although patients in the intervention group were more likely to be satisfied with their PT. No serious adverse events related to the intervention were reported. Conclusion: Supplementing usual care with this group-based outpatient PT intervention led to improvements in function at 12 months after TKR, although the magnitude of the difference was below the minimum clinically important difference of 9 points. However, patient satisfaction was higher in the intervention group, and there was some evidence of clinically relevant improvements in function at 3 months.

Background: Prosthetic implants used in total hip replacements (THR) have a range of bearing surface combinations (metal-on-polyethylene, ceramic-on-polyethylene, ceramic-on-ceramic, and metal-on-metal), head sizes (small [

Objectives: To assess the feasibility of a multi-site randomised controlled trial to evaluate the effect of functional electrical stimulation on bradykinesia in people with Parkinson’s disease. Design: A two-arm assessor blinded randomised controlled trial with an 18 weeks intervention period and 4 weeks post-intervention follow-up. Setting: Two UK hospitals; a therapy outpatient department in a district general hospital and a specialist neuroscience centre. Participants: A total of 64 participants with idiopathic Parkinson’s disease and slow gait −1. Interventions: Functional electrical stimulation delivered to the common peroneal nerve while walking in addition to standard care compared with standard care alone. Main measures: Feasibility aims included the determination of sample size, recruitment and retention rates, acceptability of the protocol and confirmation of the primary outcome measure. The outcome measures were 10 m walking speed, Unified Parkinson’s Disease Rating Scale (UPDRS), Mini Balance Evaluation Systems Test, Parkinson’s Disease Questionnaire-39, EuroQol 5-dimension 5-level, New Freezing of Gait questionnaire, Falls Efficacy Score International and falls diary. Participants opinion on the study design and relevance of outcome measures were evaluated using an embedded qualitative study. Results: There was a mean difference between groups of 0.14 ms−1 (CI 0.03, 0.26) at week 18 in favour of the treatment group, which was maintained at week 22, 0.10 ms−1 (CI –0.05, 0.25). There was a mean difference in UPDRS motor examination score of –3.65 (CI –4.35, 0.54) at week 18 which was lost at week 22 –0.91 (CI –2.19, 2.26). Conclusion: The study design and intervention were feasible and supportive for a definitive trial. While both the study protocol and intervention were acceptable, recommendations for modifications are made.

IntroductionSubstantial variation in the delivery of hip fracture care, and patient outcomes persists between hospitals, despite established UK national standards and guidelines. Patients’ outcomes are partly explained by patient-level risk factors, but it is hypothesised that organisational-level factors account for the persistence of unwarranted variation in outcomes. The mixed-methods REducing unwarranted variation in the Delivery of high qUality hip fraCture services in England and Wales (REDUCE) study, aims to determine key organisational factors to target to improve patient care.Methods and analysisQuantitative analysis will assess the outcomes of patients treated at 172 hospitals in England and Wales (2016–2019) using National Hip Fracture Database data combined with English Hospital Episodes Statistics; Patient Episode Database for Wales; Civil Registration (deaths) and multiple organisational-level audits to characterise each service provider. Statistical analyses will identify which organisational factors explain variation in patient outcomes, and typify care pathways with high-quality consistent patient outcomes. Documentary analysis of 20 anonymised British Orthopaedic Association hospital-initiated peer-review reports, and qualitative interviews with staff from four diverse UK hospitals providing hip fracture care, will identify barriers and facilitators to care delivery. The COVID-19 pandemic has posed a major challenge to the resilience of services and interviews will explore strategies used to adapt and innovate. This system-wide understanding will inform the development, in partnership with key national stakeholders, of an ‘Implementation Toolkit’ to inform and improve commissioning and delivery of hip fracture services.Ethics and disseminationThis study was approved: quantitative study by London, City and East Research Ethics Committee (20/LO/0101); and qualitative study by Faculty of Health Sciences University of Bristol Research Ethics Committee (Ref: 108284), National Health Service (NHS) Health Research Authority (20/HRA/71) and each NHS Trust provided Research and Development approval. Findings will be disseminated through scientific conferences, peer-reviewed journals and online workshops.

ObjectivesTo estimate the relationship between patient characteristics and referral decisions made by musculoskeletal hubs, and to assess the possible impact of an evidence-based referral tool.DesignRetrospective analysis of medical records and decision tree model evaluating policy changes using local and national data.SettingOne musculoskeletal interface clinic (hub) in England.Participants922 adults aged ≥50 years referred by general practitioners with symptoms of knee or hip osteoarthritis.InterventionsWe assessed the current frequency and determinants of referrals from one hub and the change in referrals that would occur at this centre and nationally if evidence-based thresholds for referral (Oxford Knee and Hip Scores, OKS/OHS) were introduced.Main outcome measureOKS/OHS, referrals for surgical assessment, referrals for arthroplasty, costs and quality-adjusted life years.ResultsOf 110 patients with knee symptoms attending face-to-face hub consultations, 49 (45%) were referred for surgical assessment; the mean OKS for these 49 patients was 18 (range: 1–41). Of 101 hip patients, 36 (36%) were referred for surgical assessment (mean OHS: 21, range: 5–44). No patients referred for surgical assessment were above previously reported economic thresholds for OKS (43) or OHS (45). Setting thresholds of OKS ≤31 and OHS ≤35 might have resulted in an additional 22 knee referrals and 26 hip referrals in our cohort. Extrapolating hub results across England suggests a possible increase in referrals nationally, of around 13 000 additional knee replacements and 4500 additional hip replacements each year.ConclusionsMusculoskeletal hubs currently consider OKS/OHS and other factors when making decisions about referral to secondary care for joint replacement. Those referred typically have low OHS/OKS, and introducing evidence-based OKS/OHS thresholds would prevent few inappropriate (high-functioning, low-pain) referrals. However, our findings suggest that some patients not currently referred could benefit from arthroplasty based on OKS/OHS. More research is required to explore other important patient characteristics currently influencing hub decisions.

Background: Pulmonary arterial hypertension (PAH) is an uncommon condition with progressive heart failure and premature death. Treatment costs up to £120,000 per patient per year, and the psychological burden of PAH is substantial. Mindfulness-based stress reduction (MBSR) is an intervention with the potential to reduce this burden, but to date, it has not been applied to people with pulmonary hypertension. We wished to determine whether a trial of MBSR for people with PAH would be feasible.Methods: A customised gentle MBSR programme of eight sessions was developed for people with physical disability due to PAH, and they were randomised to group-based MBSR or treatment as usual. The completeness of outcome measures including Beck Anxiety Index, Beck Depression Inventory and standard physical assessment at 3 months after randomisation were recorded. Health care utilisation was measured. Attendance at the sessions and the costs involved in delivering the intervention were assessed. Semi-structured interviews were conducted to explore the acceptability of the MBSR intervention and when appropriate the reasons for trial non-participation.Results: Fifty-two patients were recruited, but only 34 were randomised due to patients finding it difficult to travel to sessions. Twenty-two completed all questionnaires and attended all clinics, both routine and additional in order to collect outcomes measures. The MSBR sessions were delivered in Bristol, Cardiff and London, costing, on average, between £2234 (Cardiff) and £4128 (London) per patient to deliver. Attendance at each session averaged between two patients in Bristol and Cardiff and three in London. For those receiving treatment as usual, clinician blinding was achievable. Interviews revealed that people who attended MBSR found it interesting and helpful in managing their symptoms and minimising the psychological component of their disease.Conclusions: We found that attendance at group MBSR was poor in people with chronic PAH within the context of a trial. Achieving better MBSR intervention attendance or use of an Internet-based programme might maximise the benefit of MBSR.

In metazoans, epithelial architecture provides a context that dynamically modulates most if not all epithelial cell responses to intrinsic and extrinsic signals, including growth or survival signalling and transforming oncogene action. Three-dimensional (3D) epithelial culture systems provide tractable models to interrogate the function of human genetic determinants in establishment of context-dependency. We performed an arrayed genetic shRNA screen in mammary epithelial 3D cultures to identify new determinants of epithelial architecture, finding that the key phenotype impacting shRNAs altered not only the data population average but even more noticeably the population distribution. The broad distributions were attributable to sporadic gene silencing actions by shRNA in unselected populations. We employed Maximum Mean Discrepancy concept to capture similar population distribution patterns and demonstrate here the feasibility of the test in identifying an impact of shRNA in populations of 3D structures. Integration of the clustered morphometric data with protein-protein interactions data enabled hypothesis generation of novel biological pathways underlying similar 3D phenotype alterations. The results present a new strategy for 3D phenotype-driven pathway analysis, which is expected to accelerate discovery of context-dependent gene functions in epithelial biology and tumorigenesis.

Introduction/Background Ovarian cancer is the leading cause of death from gynaecological cancer, with more than 7000 new cases registered in the UK in 2014. Standard treatment includes surgical resection of all macroscopic tumour, followed by chemotherapy. Surgery can be extensive and associated with substantial blood loss which is conventionally replaced with a donor blood transfusion. While often necessary and lifesaving, the use of donor blood is associated with increased risks of complications and adverse surgical outcomes. Intraoperative cell salvage (ICS) is a blood conservation strategy in which red cells collected from blood lost during surgery are returned to the patient thus minimising the use of donor blood. The aim of this feasibility study was to assess whether ICS is a safe alternative to blood transfusion and if a larger, fully powered trial can successfully be planned and delivered. Methodology This is a randomised, controlled multi-centre feasibility trial conducted in four UK acute NHS hospitals over 12 months. Adult women requiring primary or interval surgery for suspected ovarian cancer were eligible for the trial if CT scan evidence supported FIGO stage III/IV ovarian or primary peritoneal cancer. Participants were randomised 1:1 ratio to receive either intra-operative cell salvage (ICS) reinfusion or donor blood transfusion intra-operatively,with stratification by study site. Results 173 women were approached, and 59 took part. In the ICS group, 16 (62%) of the 26 participants received ICS reinfusion. In the donor blood group, 14 of the 29 (48%) received donor blood. Twenty-two (40%) participants (9 ICS, 13 control) experienced infections, mainly wound, urinary tract or chest. Six participants died (2 ICS, 4 control) were all due to disease progression. Conclusion We have demonstrated that ICS is safe and acceptable alternative to blood transfusion in ovarian cancer surgery. Further larger randomised trial is needed to determine the long term outcomes. Disclosure Nothing to disclose.

BackgroundDisfigurement (visible difference) from wide-ranging congenital or acquired conditions, injuries, or treatments can negatively impact adolescents’ psychological well-being, education and health behaviours. Alongside medical interventions, appearance-specific cognitive behavioural and social skills training to manage stigma and appearance anxiety may improve psychosocial outcomes. YP Face IT (YPF), is a Web-based seven session self-help program plus booster quiz, utilising cognitive behavioural and social skills training for young people (YP) struggling with a visible difference. Co-designed by adolescents and psychologists, it includes interactive multimedia and automated reminders to complete sessions/homework. Adolescents access YPF via a health professional who determines its suitability and remotely monitors clients’ usage.ObjectiveTo establish the feasibility of evaluating YPF for 12-17 year olds self-reporting appearance-related distress and/or bullying associated with a visible difference.MethodsRandomized controlled trial with nested qualitative and economic study evaluating YPF compared with usual care (UC). Feasibility outcomes included: viability of recruiting via general practitioner (GP) practices (face to face and via patient databases) and charity advertisements; intervention acceptability and adherence; feasibility of study and data collection methods; and health professionals’ ability to monitor users’ online data for safeguarding issues. Primary psychosocial self-reported outcomes collected online at baseline, 13, 26, and 52 weeks were as follows: appearance satisfaction (Appearance Subscale from Mendleson et al’s (2001) Body Esteem Scale); social anxiety (La Greca’s (1999) Social Anxiety Scale for Adolescents). Secondary outcomes were; self-esteem; romantic concerns; perceived stigmatization; social skills and healthcare usage. Participants were randomised using remote Web-based allocation.ResultsThirteen charities advertised the study yielding 11 recruits, 13 primary care practices sent 687 invitations to patients on their databases with a known visible difference yielding 17 recruits (2.5% response rate), 4 recruits came from GP consultations. Recruitment was challenging, therefore four additional practices mass-mailed 3,306 generic invitations to all 12-17 year old patients yielding a further 15 participants (0.5% response rate). Forty-seven YP with a range of socioeconomic backgrounds and conditions were randomised (26% male, 91% white, mean age 14 years (SD 1.7)); 23 to YPF, 24 to UC). At 52 weeks, 16 (70%) in the intervention and 20 (83%) in UC groups completed assessments. There were no intervention-related adverse events; most found YPF acceptable with three withdrawing because they judged it was for higher-level concerns; 12 (52%) completed seven sessions. The study design was acceptable and feasible, with multiple recruitment strategies. Preliminary findings indicate no changes from baseline in outcome measures among the UC group and positive changes in appearance satisfaction and fear of negative evaluation among the YPF group when factoring in baseline scores and intervention adherence.ConclusionsYPF is novel, safe and potentially helpful. Its full psychosocial benefits should be evaluated in a large-scale RCT, which would be feasible with wide-ranging recruitment strategies.Trial RegistrationISRCTN registry ISRCTN40650639; http://www.isrctn.com/ISRCTN40650639

IntroductionPeople often experience distress following stroke due to fundamental challenges to their identity.ObjectivesTo evaluate (1) the acceptability of ‘HeART of Stroke’ (HoS), a community-based arts and health group intervention, to increase psychological well-being; and (2) the feasibility of a definitive randomised controlled trial (RCT).DesignTwo-centre, 24-month, parallel-arm RCT with qualitative and economic components. Randomisation was stratified by centre and stroke severity. Participant blinding was not possible. Outcome assessment blinding was attempted.SettingCommunity.ParticipantsCommunity-dwelling adults ≤2 years poststroke recruited via hospital clinical teams/databases or community stroke/rehabilitation teams.InterventionsArtist-facilitated arts and health group intervention (HoS) (ten 2-hour sessions over 14 weeks) plus usual care (UC) versus UC.OutcomesThe outcomes were self-reported measures of well-being, mood, capability, health-related quality of life, self-esteem and self-concept (baseline and 5 months postrandomisation). Key feasibility parameters were gathered, data collection methods were piloted, and participant interviews (n=24) explored the acceptability of the intervention and study processes.ResultsDespite a low recruitment rate (14%; 95% CI 11% to 18%), 88% of the recruitment target was met, with 29 participants randomised to HoS and 27 to UC (57% male; mean (SD) age=70 (12.1) years; time since stroke=9 (6.1) months). Follow-up data were available for 47 of 56 (84%; 95% CI 72% to 91%). Completion rates for a study-specific resource use questionnaire were 79% and 68% (National Health Service and societal perspectives). Five people declined HoS postrandomisation; of the remaining 24 who attended, 83% attended ≥6 sessions. Preliminary effect sizes for candidate primary outcomes were in the direction of benefit for the HoS arm. Participants found study processes acceptable. The intervention cost an estimated £456 per person and was well-received (no intervention-related serious adverse events were reported).ConclusionsFindings from this first community-based study of an arts and health intervention for people poststroke suggest a definitive RCT is feasible. Recruitment methods will be revised.Trial registration numberISRCTN99728983.

Background Postpartum haemorrhage remains a major cause of maternal mortality and morbidity worldwide. Active management of the third stage of labour reduces the risk of postpartum haemorrhage. Oxytocin and oxytocin/ergometrine are commonly used in the UK, with oxytocin/ergometrine being more effective at preventing moderate, but not severe, blood loss. Many guidelines specifically recommend using oxytocin for all vaginal births, as it is associated with fewer adverse events. However, a survey conducted by the Southmead Hospital Maternity Research Team revealed that 71.4% of UK obstetric units still routinely use oxytocin/ergometrine. Carbetocin is a newer medication that may be as effective but has fewer side effects. No studies have directly compared all three medications. Methods The IMox study aims to determine the most effective, acceptable and cost-effective drug for primary prevention of postpartum haemorrhage following vaginal birth. The IMox study is a prospective, multi-centre, double-blind, randomised trial directly comparing oxytocin, oxytocin/ergometrine and carbetocin given intramuscularly for the prevention of postpartum haemorrhage in the third stage of labour. The primary effectiveness outcome is the use of an additional uterotonic drug. Secondary effectiveness outcomes reflect maternal morbidity and mortality within the immediate postpartum period. Participant questionnaires and subjective reporting of side effects will be used to evaluate maternal acceptability. Maternal quality of life utilities will be collected antenatally, and on days 1 and 14 after birth to enable a cost-effectiveness assessment of each studied drug. Participants will be pregnant women planning a vaginal birth in six hospitals in England. Participants will be approached and invited to provide consent to participate from 20 weeks gestation until in established labour. A complete sample of 5712 participants (1904 per arm) providing data for the primary outcome will allow for a robust determination of efficacy between all three study drugs. Data will be collected until participants are discharged from the hospital and on postnatal days 1 and 14 regardless of location. All analyses will be on a modified intention-to-treat basis, and additionally repeated on a per protocol basis. Data collection commenced in Feburary 2015 and was completed in August 2018. Discussion This study is the first to directly compare oxytocin, oxytocin/ergometrine and carbetocin in the same population for the prevention of postpartum haemorrhage following vaginal birth. Furthermore, this study will be the first to directly compute health economic outcomes from such a three-way comparison. This study is limited to using short-term outcomes, and so will not provide evidence for important outcomes such as long-term maternal psychological well-being and time to next conception. Trial registration ClinicalTrials.gov, NCT02216383. Registered on 18 August 2014. EudraCT, 2014-001948-37. Registered on 23 September 2014. ISRCTN, ISRCTN10232550. Retrospectively registered on 6 March 2018). Electronic supplementary material The online version of this article (10.1186/s13063-018-3109-2) contains supplementary material, which is available to authorized users.

IntroductionKnee replacements are highly successful for many people, but if a knee replacement fails, revision surgery is generally required. Surgeons and patients may choose from a range of implant components and combinations that make up knee replacement constructs, all with potential implications for how long a knee replacement will last. To inform surgeon and patient decisions, a comprehensive synthesis of data from randomised controlled trials is needed to evaluate the effects of different knee replacement implants on overall construct survival. Due to limited follow-up in trials, joint registry analyses are also needed to assess the long-term survival of constructs. Finally, economic modelling can identify cost-effective knee replacement constructs for different patient groups.Methods and analysisIn this protocol, we describe systematic reviews and network meta-analyses to synthesise evidence on the effectiveness of knee replacement constructs used in total and unicompartmental knee replacement and analyses of two national joint registries to assess long-term outcomes. Knee replacement constructs are defined by bearing materials and mobility, constraint, fixation and patella resurfacing. For men and women in different age groups, we will compare the lifetime cost-effectiveness of knee replacement constructs.Ethics and disseminationSystematic reviews are secondary analyses of published data with no ethical approval required. We will design a common joint registry analysis plan and provide registry representatives with information for submission to research or ethics committees. The project has been assessed by the National Health Service (NHS) REC committee and does not require ethical review.Study findings will be disseminated to clinicians, researchers and administrators through open access articles, presentations and websites. Specific UK-based groups will be informed of results including National Institute for Health Research and National Institute for Health and Care Excellence, as well as international orthopaedic associations and charities. Effective dissemination to patients will be guided by our patient–public involvement group and include written lay summaries and infographics.PROSPERO registration numberCRD42019134059 and CRD42019138015.

RhoA regulates actin cytoskeleton but recent evidence suggest a role for this conserved Rho GTPase also in other cellular processes, including transcriptional control of cell proliferation and survival. Interestingy, loss of RhoA is synthetic lethal with oncogenic Myc, a master transcription factor that turns on anabolic metabolism to promote cell growth in many cancers. We show evidence indicating that the synthetic lethal interaction between RhoA loss and Myc arises from deficiency in glutamine utilization, resulting from impaired co-regulation of glutaminase expression and anaplerosis by Myc and RhoA – serum response factor (SRF) pathway. The results suggest metabolic coordination between Myc and RhoA/SRF in sustaining cancer cell viability and indicate RhoA/SRF as a potential vulnerability in cancer cells for therapeutic targeting.

OBJECTIVE:To evaluate the feasibility of conducting a randomized controlled trial comparing group-based outpatient physiotherapy with usual care in patients following total knee replacement.DESIGN:A feasibility study for a randomized controlled trial.SETTING:One secondary-care hospital orthopaedic centre, Bristol, UK.PARTICIPANTS:A total of 46 participants undergoing primary total knee replacement.INTERVENTIONS:The intervention group were offered six group-based exercise sessions after surgery. The usual care group received standard postoperative care. Participants were not blinded to group allocation.OUTCOME MEASURES:Feasibility was assessed by recruitment, reasons for non-participation, attendance, and completion rates of study questionnaires that included the Lower Extremity Functional Scale and Knee Injury and Osteoarthritis Outcome Score.RESULTS:Recruitment rate was 37%. Five patients withdrew or were no longer eligible to participate. Intervention attendance was high (73%) and 84% of group participants reported they were 'very satisfied' with the exercises. Return of study questionnaires at six months was lower in the usual care (75%) than in the intervention group (100%). Mean (standard deviation) Lower Extremity Functional Scale scores at six months were 45.0 (20.8) in the usual care and 57.8 (15.2) in the intervention groups.CONCLUSION:Recruitment and retention of participants in this feasibility study was good. Group-based physiotherapy was acceptable to participants. Questionnaire return rates were lower in the usual care group, but might be enhanced by telephone follow-up. The Lower Extremity Functional Scale had high responsiveness and completion rates. Using this outcome measure, 256 participants would be required in a full-scale randomized controlled trial.

Background: Excessive drinking leads to poor absorption of nutrients and homeless problem-drinkers often have nutritionally inadequate diets. Depletion of nutrients such as vitamin B1 can lead to cognitive impairment, which can hinder efforts to reduce drinking or engage with services. This review aimed to assess effectiveness of interventions designed to prevent or treat malnutrition in homeless problem-drinkers.Methods: We systematically searched nine electronic databases and 13 grey literature sources for studies evaluating interventions to improve nutrition in homeless populations, without regional or language restrictions. Screening for inclusion was done in duplicate. One reviewer extracted data and assessed risk of bias, and another checked the extractions. Primary outcomes were nutrition status/deficiency, liver damage, and cognitive function. Secondary outcomes included abstinence, comorbidities, resource use, acceptability and engagement with intervention. Results were synthesised narratively.Results: We included 25 studies (2 Randomised Controlled Trials; 15 uncontrolled before and after; 7 surveys; 1 case-control). Nine studies evaluated educational and support interventions, five food provision, and three supplement provision. Eight studies evaluated a combination of these interventions. No two interventions were the same, and all studies were at high risk of bias. Nutritional status (intake/ deficiency) were reported in 11 studies and liver function in one. Fruit and vegetable intake improved with some education and support interventions (n=4 studies) but not others (n=2). Vitamin supplements appeared to improve vitamin deficiency levels in the blood (n=2). Free or subsidised meals (n=4) and food packs (n=1) did not always fulfil dietary needs, but were usually considered acceptable by users. Some multicomponent interventions improved nutrition (n=3) but acceptability varied (n=3). No study reported cost effectiveness.Conclusions: The evidence for any one intervention for improving malnutrition in homeless problem-drinkers was based on single studies at high risk of bias. Various food and supplement provision interventions appear effective in changing nutritional status in single studies. Educational and multicomponent interventions show improved nutritional behaviour in some studies but not others. Further better quality evidence is required before these interventions can be recommended for implementation. Any future studies should seek the end user input in their design and conduct.Registration: Registered with PROSPERO: CRD42015024247 (http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015024247)

Differentiated epithelial structure communicates with individual constituent epithelial cells to suppress their proliferation activity. However, the pathways linking epithelial structure to cessation of the cell proliferation machinery or to unscheduled proliferation in the context of tumorigenesis are not well defined. Here we demonstrate the strong impact of compromised epithelial integrity on normal and oncogenic Myc-driven proliferation in three-dimensional mammary epithelial organoid culture. Systematic silencing of 34 human homologs of Drosophila genes, with previously established functions in control of epithelial integrity, demonstrates a role for human genes of apico-basal polarity, Wnt and Hippo pathways and actin dynamics in regulation of the size, integrity and cell proliferation in organoids. Perturbation of these pathways leads to diverse functional interactions with Myc: manifested as a RhoA-dependent synthetic lethality and Par6-dependent effects on the cell cycle. Furthermore, we show a role for Par6G as a negative regulator of the phosphatidylinositol 3'-kinase/phosphoinositide-dependent protein kinase 1/Akt pathway and epithelial cell proliferation and evidence for frequent inactivation of Par6G gene in epithelial cancers. The findings demonstrate that determinants of epithelial structure regulate the cell proliferation activity via conserved and cancer-relevant regulatory circuitries, which are important for epithelial cell cycle restriction and may provide new targets for therapeutic intervention.

Regulatory pathways that drive early hematogenous dissemination of tumor cells are insufficiently defined. Here, we used the presence of disseminated tumor cells (DTC) in the bone marrow to define patients with early disseminated breast cancer and identified low retinoic acid–induced 2 (RAI2) expression to be significantly associated with DTC status. Low RAI2 expression was also shown to be an independent poor prognostic factor in 10 different cancer datasets. Depletion of RAI2 protein in luminal breast cancer cell lines resulted in dedifferentiation marked by downregulation of ERα, FOXA1, and GATA3, together with increased invasiveness and activation of AKT signaling. Functional analysis of the previously uncharacterized RAI2 protein revealed molecular interaction with CtBP transcriptional regulators and an overlapping function in controlling the expression of a number of key target genes involved in breast cancer. These results suggest that RAI2 is a new metastasis-associated protein that sustains differentiation of luminal breast epithelial cells. Significance: We identified downregulation of RAI2 as a novel metastasis-associated genetic alteration especially associated with early occurring bone metastasis in ERα-positive breast tumors. We specified the role of the RAI2 protein to function as a transcriptional regulator that controls the expression of several key regulators of breast epithelial integrity and cancer. Cancer Discov; 5(5); 506–19. ©2015 AACR. See related commentary by Esposito and Kang, p. 466 This article is highlighted in the In This Issue feature, p. 453

ObjectivesEvaluation of a pilot study of an online consultation system in primary care. We describe who used the system, when and why, and the National Health Service costs associated with its use.Design15-month observational study.SettingPrimary care practices in South West England.Results36 General practices covering 396 828 patients took part in the pilot. The online consultation website was viewed 35 981 times over the pilot period (mean 9.11 visits per 1000 patients per month). 7472 patients went on to complete an ‘e-consultation’ (mean 2.00 online consultations per 1000 patients per month). E-consultations were mainly performed on weekdays and during normal working hours. Patient records (n=485) were abstracted for eight practices and showed that women were more likely to use e-consultations than men (64.7% vs 35.3%) and users had a median age of 39 years (IQR 30–50). The most common reason for an e-consultation was an administrative request (eg, test results, letters and repeat prescriptions (22.5%)) followed by infections/immunological issues (14.4%). The majority of patients (65.2%) received a response within 2 days. The most common outcome was a face-to-face (38%) or telephone consultation (32%). The former were more often needed for patients consulting about new conditions (OR 1.56, 95% CI 1.05 to 2.27, p=0.049). The average cost of a practice’s response to an e-consultation was £36.28, primarily triage time and resulting face-to-face/telephone consultations needed.ConclusionsUse of e-consultations is very low, particularly at weekends. Unless this can be improved, any impact on staff workload and patient waiting times is likely to be negligible. It is possible that use of e-consultations increases primary care workload and costs. Online consultation systems could be developed to improve efficiency both for staff and patients. These findings have implications for software developers as well as primary care services and policy-makers who are considering investing in online consultation systems.

Intervenção social. - ISSN 0874-1611. - N. 49/50 (2017). - p. 67-83. Neste artigo pretende-se debater as virtualidades das histórias de vida, enquanto instrumento de pesquisa, tomando como exemplo uma investigação já concluída. Uma investigação cujo principal objetivo foi o de analisar um projeto de intervenção que se propôs inverter trajetórias de desinvestimento na qualificação escolar de jovens cuja socialização ocorreu em contextos fortemente restritivos de oportunidades. Partindo das reflexões produzidas na referida investigação, procurar-se-á discutir como se pode tirar partido das histórias de vida não só para aprofundar a compreensão dos processos sociais que empurram numerosos jovens para as margens da sociedade, mas também para neles desencadear a tomada de consciência de que podem distanciar-se, em alguma medida, dos seus habitus2 originais e, de certo modo, provocar a alteração do seu “destino” social.

Elevated MYC levels sensitize tumor cells to apoptosis but the therapeutic potential of this mechanism remains unclear. We find, in a model of MYC-driven breast cancer, that pharmacological activation of AMPK dramatically synergizes with BCL-2/BCL-XL inhibitors to activate MYC-dependent apoptosis. We demonstrate the translational potential of an AMPK and BCL- 2/BCL-XL co-targeting strategy in ex vivo and in vivo models of MYC-high breast cancer. Metformin combined with either navitoclax or venetoclax efficiently inhibits tumor growth, confers survival benefits and induces tumor infiltration by immune cells. However, withdrawal of the drugs allowed tumor re- growth with presentation of PD1+/CD8+ T cell infiltrates, suggesting immune escape. A two-step treatment regimen, beginning with neoadjuvant metformin+venetoclax to induce apoptosis and followed by tumor resection and adjuvant metformin+venetoclax+anti-PD1 treatment to overcome immune escape, led to durable antitumor responses even after drug withdrawal. We demonstrate that pharmacological reactivation of MYC-dependent apoptosis is a powerful antitumor strategy involving both tumor cell depletion and immunosurveillance. Citation Format: Heidi M. Haikala, Johanna M. Anttila, Mariel Savelius, Elsa Marques, Tiina Raatikainen, Mette Ilander, Henna Hakanen, Johanna Mattson, Paivi Heikkila, Marjut Leidenius, Heikki Joensuu, Satu Mustjoki, Panu Kovanen, Martin Eilers, Joel D. Leverson, Juha T. Klefström. Pharmacological reactivation of MYC-dependent apoptosis cooperates with anti-PD1 immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-189.

The original version of this Article contained an error in Fig. 7. In panel b, the survival curves were shifted relative to the y axis. This error has been corrected in both the PDF and HTML versions of the Article.

For the last decade, stringent monitoring of waiting time performance targets provided English hospitals with incentives to reduce official waiting times for elective surgery. It is less clear whether the total amount of time patients waited in secondary care, from first referral to outpatient clinic until treatment, has also fallen. We used Hospital Episode Statistics inpatient data for patients undergoing total joint replacement during a period of active monitoring of targets (between 2006/7 and 2008/9) and linked it to outpatient data to reconstruct patients' pathway in the 3 years before surgery and provide alternative measurements of waiting times. Our findings suggest that although official waiting times decreased drastically in our study period, total waiting time in secondary care has not declined. Patients with shorter official waits spent a longer time in a ‘work-up’ period prior to inclusion in the official waiting list, and socio-economic inequities persisted in waiting times for joint replacement. We found no evidence that target policies achieved efficiency gains during our study period. Copyright © 2013 John Wiley & Sons, Ltd.

Objectives Economic evaluations alongside randomized controlled trials that collect data using patient-completed questionnaires are prone to missing data. Our objective was to determine whether giving patients a resource use log (RUL) at baseline would improve the odds of completing questions in a follow-up resource use questionnaire (RUQ) and to identify patients' views on RUL's usefulness and acceptability. Methods The RUL study was a randomized controlled trial and qualitative study nested within a larger randomized controlled trial (the Arthroplasty Pain Experience Study trial). Eighty-five patients were randomized at baseline to receive or not receive an RUL. At 3-month follow-up, all participants received a postal RUQ. We created dummy variables for 13 resource use categories indicating whether complete information had been given for each category. We compared the completion rates between arms by using descriptive statistics and logistic regression. We explored patients' experience of using the RUL by interviewing a different subsample of Arthroplasty Pain Experience Study patients (n = 24) at 2- to 4-week follow-up. Results At 3 months, 74 of the 85 (87% in each arm) patients returned the RUQ. Patients in the RUL arm were 3.5 times more likely to complete the National Health Service community-based services category ( P = 0.08). The RUL was positively received by patients and was generally seen as a useful memory aid. Conclusions The RUL is a useful and acceptable tool in reducing the amount of missing data for some types of resource use.

Introduction A significant number of adolescents suffer extensive and enduring difficulties such as social anxiety, body image dissatisfaction, low self-esteem and bullying as a result of conditions or injuries that affect their appearance (eg, craniofacial and skin conditions, treatment side effects and scarring). Evidence-based psychosocial interventions to meet their specific needs are currently lacking. YP Face IT, developed by the UK's Centre for Appearance Research in collaboration with clinical experts and young people, is an innovative online psychosocial intervention designed to offer this group immediate support, advice and coping strategies. It has been endorsed by young people, their parents/carers, GPs, clinical psychologists and health professionals working with those affected by appearance-related conditions. Methods and analysis Young people aged 12–17 with an appearance-altering condition/injury that self-identify as experiencing appearance-related distress, teasing or bullying will be invited to participate via GP practices and UK charities. Consenting participants will be randomised to the intervention (YP Face IT) or the treatment as usual (TAU) control group. Outcome measures will be completed by young people and their parents/carers at baseline, 13, 26 and 52 weeks. Primary outcome measures will be the Body Esteem Scale and the Social Anxiety Scale for Adolescents. Participants will complete other health-related outcome measures and resource use questionnaires for health economic analysis. We will assess recruitment rates, acceptability of the YP Face IT programme, adherence and retention to treatment, questionnaire completion rates, variation of TAU in Primary Care and the feasibility of GP practice staff supervising young people's use of YP Face IT. Ethics and dissemination This feasibility trial protocol (V.1, 3 March 2014), received a favourable ethical opinion from the NRES Committee South West-Frenchay (reference number 14/SW/0058). Findings will be disseminated through academic peer-reviewed publications, conferences and to participating GP practices and charities supporting those with conditions affecting appearance. Trial registration number [ISRCTN40650639][1]; Pre-results. [1]: http://www.isrctn.com/search?q=yp+face+it

BackgroundTotal hip replacements (THRs) and total knee replacements (TKRs) are common elective procedures. In the REsearch STudies into the ORthopaedic Experience (RESTORE) programme, we explored the care and experiences of patients with osteoarthritis after being listed for THR and TKR up to the time when an optimal outcome should be expected.ObjectiveTo undertake a programme of research studies to work towards improving patient outcomes after THR and TKR.MethodsWe used methodologies appropriate to research questions: systematic reviews, qualitative studies, randomised controlled trials (RCTs), feasibility studies, cohort studies and a survey. Research was supported by patient and public involvement.ResultsSystematic review of longitudinal studies showed that moderate to severe long-term pain affects about 7–23% of patients after THR and 10–34% after TKR. In our cohort study, 10% of patients with hip replacement and 30% with knee replacement showed no clinically or statistically significant functional improvement. In our review of pain assessment few research studies used measures to capture the incidence, character and impact of long-term pain. Qualitative studies highlighted the importance of support by health and social professionals for patients at different stages of the joint replacement pathway. Our review of longitudinal studies suggested that patients with poorer psychological health, physical function or pain before surgery had poorer long-term outcomes and may benefit from pre-surgical interventions. However, uptake of a pre-operative pain management intervention was low. Although evidence relating to patient outcomes was limited, comorbidities are common and may lead to an increased risk of adverse events, suggesting the possible value of optimising pre-operative management. The evidence base on clinical effectiveness of pre-surgical interventions, occupational therapy and physiotherapy-based rehabilitation relied on small RCTs but suggested short-term benefit. Our feasibility studies showed that definitive trials of occupational therapy before surgery and post-discharge group-based physiotherapy exercise are feasible and acceptable to patients. Randomised trial results and systematic review suggest that patients with THR should receive local anaesthetic infiltration for the management of long-term pain, but in patients receiving TKR it may not provide additional benefit to femoral nerve block. From a NHS and Personal Social Services perspective, local anaesthetic infiltration was a cost-effective treatment in primary THR. In qualitative interviews, patients and health-care professionals recognised the importance of participating in the RCTs. To support future interventions and their evaluation, we conducted a study comparing outcome measures and analysed the RCTs as cohort studies. Analyses highlighted the importance of different methods in treating and assessing hip and knee osteoarthritis. There was an inverse association between radiographic severity of osteoarthritis and pain and function in patients waiting for TKR but no association in THR. Different pain characteristics predicted long-term pain in THR and TKR. Outcomes after joint replacement should be assessed with a patient-reported outcome and a functional test.ConclusionsThe RESTORE programme provides important information to guide the development of interventions to improve long-term outcomes for patients with osteoarthritis receiving THR and TKR. Issues relating to their evaluation and the assessment of patient outcomes are highlighted. Potential interventions at key times in the patient pathway were identified and deserve further study, ultimately in the context of a complex intervention.Study registrationCurrent Controlled Trials ISRCTN52305381.FundingThis project was funded by the NIHR Programme Grants for Applied Research programme and will be published in full inProgramme Grants for Applied Research; Vol. 4, No. 12. See the NIHR Journals Library website for further project information.

Primary total knee replacement is a common operation that is performed to provide pain relief and restore functional ability. Inpatient physiotherapy is routinely provided after surgery to enhance recovery prior to hospital discharge. However, international variation exists in the provision of outpatient physiotherapy after hospital discharge. While evidence indicates that outpatient physiotherapy can improve short-term function, the longer term benefits are unknown. The aim of this randomised controlled trial is to evaluate the long-term clinical effectiveness and cost-effectiveness of a 6-week group-based outpatient physiotherapy intervention following knee replacement. Two hundred and fifty-six patients waiting for knee replacement because of osteoarthritis will be recruited from two orthopaedic centres. Participants randomised to the usual-care group (n = 128) will be given a booklet about exercise and referred for physiotherapy if deemed appropriate by the clinical care team. The intervention group (n = 128) will receive the same usual care and additionally be invited to attend a group-based outpatient physiotherapy class starting 6 weeks after surgery. The 1-hour class will be run on a weekly basis over 6 weeks and will involve task-orientated and individualised exercises. The primary outcome will be the Lower Extremity Functional Scale at 12 months post-operative. Secondary outcomes include: quality of life, knee pain and function, depression, anxiety and satisfaction. Data collection will be by questionnaire prior to surgery and 3, 6 and 12 months after surgery and will include a resource-use questionnaire to enable a trial-based economic evaluation. Trial participation and satisfaction with the classes will be evaluated through structured telephone interviews. The primary statistical and economic analyses will be conducted on an intention-to-treat basis with and without imputation of missing data. The primary economic result will estimate the incremental cost per quality-adjusted life year gained from this intervention from a National Health Services (NHS) and personal social services perspective. This research aims to benefit patients and the NHS by providing evidence on the long-term effectiveness and cost-effectiveness of outpatient physiotherapy after knee replacement. If the intervention is found to be effective and cost-effective, implementation into clinical practice could lead to improvement in patients’ outcomes and improved health care resource efficiency. ISRCTN32087234 , registered on 11 February 2015.

Methods 85 patients undergoing joint replacement were randomised to receive or not receive an RUL at hospital discharge. A postal RUQ was then administered to participants at 3-months after surgery. A blinded researcher extracted primary care resource use data in relation to the patient’s joint replacement from GP records from hospital discharge until completion of the 3-month RUQ. Data from both sources were coded into use of resource and number of contacts and two binary variables indicating perfect recall were calculated. For each resource use category, descriptive statistics were calculated by data source and trial arm, and adjusted odds ratios were estimated.

Amphetamines exert their persistent addictive effects by activating brain's reward pathways, perhaps through the release of dopamine in the nucleus accumbens (and/or in other places). On the other hand, there is a relationship between dopamine and all behavioural aspects that involve motor activity and it has been demonstrated that exercise leads to an increase in the synthesis and release of dopamine, stimulates neuroplasticity and promotes feelings of well-being. Moreover, exercise and drugs of abuse activate overlapping neural systems. Thus, our aim was to study the influence of chronic exercise in the mechanism of addiction using an amphetamine-induced conditioned-place-preference in rats.Adult male Sprague-Dawley rats were randomly separated in groups with and without chronic exercise. Chronic exercise consisted in a 8 week treadmill running program, with increasing intensity. The conditioned place preference test was performed in both groups using a procedure and apparatus previously established. A 2 mg.kg(-1) amphetamine or saline solution was administered intraperitonially according to the schedule of the conditioned place preference. Before conditioning none of the animals showed preference for a specific compartment of the apparatus. The used amphetamine dose in the conditioning phase was able to produce a marked preference towards the drug-associated compartment in the group without exercise. In the animals with exercise a significant preference by the compartment associated with saline was observed. These results lead us to conclude that a previous practice of regular physical activity may help preventing amphetamine addiction in the conditions used in this test.

IntroductionOvarian cancer is the leading cause of death from gynaecological cancer, with more than 7000 new cases registered in the UK in 2014. In patients suitable for surgery, the National Institute of Health and Care Excellence guidance for treatment recommends surgical resection of all macroscopic tumour, followed by chemotherapy. The surgical procedure can be extensive and associated with substantial blood loss which is conventionally replaced with a donor blood transfusion. While often necessary and lifesaving, the use of donor blood is associated with increased risks of complications and adverse surgical outcomes. Intraoperative cell salvage (ICS) is a blood conservation strategy in which red cells collected from blood lost during surgery are returned to the patient thus minimising the use of donor blood. This is the protocol for a feasibility randomised controlled trial with an embedded qualitative study and feasibility economic evaluation. If feasible, a later definitive trial will test the effectiveness and cost-effectiveness of ICS reinfusion versus donor blood transfusion in ovarian cancer surgery.Methods and analysisSixty adult women scheduled for primary or interval ovarian cancer surgery at participating UK National Health Service Trusts will be recruited and individually randomised in a 1:1 ratio to receive ICS reinfusion or donor blood (as required) during surgery. Participants will be followed up by telephone at 30 days postoperatively for adverse events monitoring and by postal questionnaire at 6 weeks and 3 monthly thereafter, to capture quality of life and resource use data. Qualitative interviews will capture participants’ and clinicians’ experiences of the study.Ethics and disseminationThis study has been granted ethical approval by the South West–Exeter Research Ethics Committee (ref: 16/SW/0256). Results will be disseminated via peer-reviewed publications and will inform the design of a larger trial.Trial registration numberISRCTN19517317.

Methamphetamine (METH) is a powerful psychostimulant whose noxious effects depend largely on the pattern of abuse. METH-induced glutamate release may overactivate N-methyl-d-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (NMDAR and AMPAR, respectively) causing excitotoxicity. In the brain, these receptors are also known for their essential role in mediating memory consolidation. Therefore, we assessed glial fibrillary acidic protein (GFAP) expression as a marker for astrogliosis and neurodegeneration by using Fluoro-Jade C (F-J C) staining. Moreover, we investigated the effect of two METH regimens on NMDAR NR1 and NR2A and on AMPAR GluR2 subunit expression in the rat striatum and frontal cortex 24 h after drug treatment. Adult Sprague-Dawley rats were injected subcutaneously (s.c.) on six consecutive days with saline (control and acute groups) or with an increasing dose of METH (10, 15, 15, 20, 20, 25 mg/kg/day; ED group). On the seventh day, both METH groups were given a "bolus" of 30 mg/kg METH, whereas controls received saline. We evaluated the expression levels of GFAP by both Western blot and immunohistochemical assays and concluded that there was no difference from control levels. In addition, neither drug regimen resulted in neurodegeneration within 24 h of last METH administration. In the frontal cortex of the acute group, NR1 expression level was decreased, and both NR2A and GluR2 were increased. Also, in the striatum of the acute group, the expression level of GluR2 was significantly increased, and both GluR2 and NR2A levels were augmented in the striatum of the ED group. Taken together, these results suggest a protective mechanism by decreasing permeability and/or functionality of AMPAR and NMDAR to counteract METH-induced glutamate overflow in the brain. Moreover, these results may explain, in part, the mnemonic deficits and psychotic behavior associated with METH abuse.

The glutamate-glutamine cycle between neurons and glia is tightly related to excitatory glutamatergic and inhibitory GABAergic regulation in brain. The role of this neuron-astrocyte cross-talk on the neurotoxicity induced by amphetamines is not understood. Also, the impact of neurotoxic doses of amphetamines on the balance between glutamatergic and GABAergic circuits is largely unknown. The aim of this work was to assess the acute effect of a neurotoxic regimen of amphetamine (AMPH) on glutamine (GLN, an astrocytic marker) levels and on glutamine/glutamate (an index for glutamate-glutamine cycle) and GABA/glutamate ratios in rat brain. Sprague-Dawley rats were sacrificed 4 and 24 h after a single-dose regimen of AMPH (30 mg/kg, i.p.), and the caudate-putamen (CPu), frontal cortex (FC), and hippocampus (Hp) were dissected for analysis of glutamate (GLU), gamma-aminobutyric acid (GABA), and GLN. The total content of these amino acids was measured using a microbore HPLC electrochemical detector. Although AMPH did not change GLU levels, it increased both GLN content and GLN/GLU ratio (160-469%) at 4 h, but not at 24 h, in all regions after injection. Striatal GABA levels and GABA/GLU ratio were increased (46 and 100%, respectively) at 24 h. In hippocampus the GABA/GLU increase (60%) occurred as early as 4 h after treatment. To the contrary, AMPH exerted no effect in GABA/GLU balance in frontal cortex. These data strongly suggest that this neurotoxic AMPH regimen provoked an early increase in the glutamate-glutamine cycle between neurons and glia. This increase may ultimately lead to an upregulation of the inhibitory system as a compensatory response.

The aim of this study was to verify the effect of chronic exercise on the striatal dopamine (DA) outflow induced by low and high single doses of amphetamine (AMPH), and verify the existence of an exercise protective role on neurodegeneration. Adult male Sprague-Dawley rats were randomly separated into six groups: chronic exercise, saline; chronic exercise, 5 mg kg(-1) AMPH; chronic exercise, 30 mg kg(-1) AMPH; without exercise, saline; without exercise, 5 mg kg(-1) AMPH; without exercise, 30 mg kg(-1) AMPH. Chronic exercise consisted of an 8-week running program on a treadmill, with increasing intensity. Animals were anesthetized, placed into a stereotaxic frame and an intracerebral guide cannula implanted into the caudate-putamen. When indicated, microdialysis was performed. Dialysate samples were collected during 30-min intervals for 6 h, before and after the intraperitonial administration of AMPH or saline solution. HPLC with electrochemical detection was used to quantify DA. Chronic exercise did not significantly change the extracellular DA basal values. Regarding the maximal DA levels in the dialysates, in the rats treated with 5 mg kg(-1) AMPH, there was no significant difference between groups with and without chronic exercise; on the contrary, in animals treated with 30 mg kg(-1) AMPH, the DA release was lower in the group with chronic exercise. Moreover, the maintenance of higher levels of DA along time in the training group suggests a diminished reuptake of DA. By using the Fluoro-Jade C staining technique, we did not find neuronal death in any of the groups. In conclusion, these results suggest that chronic exercise leads to a diminished release and reuptake of DA after administration of a high dose of AMPH, whereas neither chronic exercise nor AMPH seems to induce neurodegeneration.

Methamphetamine (METH) is a powerful psychostimulant that increases glutamate (Glu) levels in the mammalian brain and it is currently known that hippocampi are particularly susceptible to METH. Moreover, it is well established that the overactivation of N-methyl-d-aspartate (NMDA) and AMPA ionotropic Glu receptors causes excitotoxicity. In the present study, we investigated the effect of acute (30 mg/kg) versus escalating dose (ED) administration of METH on NMDA receptor 1, NMDA receptor 2 and glutamate receptor 2 (GluR2) subunit expression in the hippocampus and on memory. Adult Sprague-Dawley rats were injected s.c. during six consecutive days with saline (control and acute groups) or with a growing dose of METH (10, 15, 15, 20, 20, 25 mg/kg/day; ED group). On the 7th day, both METH groups were injected with a 'bolus' of 30 mg/kg METH whereas controls received saline. Western blot analysis showed an increase of GluR2 and NR2A expression levels and no alterations on NR1 subunit in the acute group. On the other hand, in the ED group, GluR2 and NR2A expression levels were unaltered and there was a decrease on NR1 levels. Moreover, we did not observe neurodegeneration with both administration paradigms, as assessed by Fluoro-Jade C staining, but we did observe a strong astrogliosis in the acute administration group by using both immunohistochemistry and Western blot analysis. The impact of METH on working memory was evaluated using the Y maze test and revealed significant mnemonic deficit in the rats acutely treated with the drug. Overall, our results suggest a protection mechanism under conditions of METH administration by decreasing permeability and/or functionality of NMDA and AMPA receptors, which has implications on memory. So, the participation of the glutamatergic system should be considered as an important pharmacological target to design new strategies to prevent or diminish the harmful effect of drug consumption.

BACKGROUND: Prosthetic hip implants have many combinations of bearing surface materials, sizes, and fixation techniques, which can determine the quality of life of patients after primary total hip replacement (THR) and the likelihood of needing revision surgery. When an implant fails, patients require revision THR, which is distressing to the patient and expensive for the health care payer. Primary THR is one of the most common elective procedures performed worldwide, with over 300,000 performed annually in the USA and over 80,000 in England and Wales. It is important to review all available randomised controlled trial (RCT) evidence to determine which implant bearing surface materials, size, and fixation technique are most effective for patients.METHODS/DESIGN: This is a protocol for a systematic review and meta-analysis of RCTs comparing outcomes of hip implant bearing surfaces, size, and fixation techniques used in THR. Implant combinations compared in the literature include four bearing surface combinations (metal-on-polyethylene, metal-on-metal, ceramic-on-polyethylene, and ceramic-on-ceramic); two femoral head sizes (large vs small heads); and four fixation techniques (uncemented, cemented, hybrid, and reverse hybrids). The primary outcome will be revision surgery. We will also collect data on patient characteristics, mortality, quality of life, and other outcomes. In network meta-analysis, we will estimate the relative effectiveness of every implant bearing surface, head size (large vs small), and fixation permutation, using evidence where implants have been compared directly in an RCT and indirectly through common comparators in different RCTs.DISCUSSION: There has been much debate about materials used for prosthetic implants in THR. Different combinations of prosthetic materials, sizes, and fixation, can vary widely in cost and fail at different rates for different patient groups. Given the number of THRs performed yearly, and the increasing use of expensive implants, it is important to review evidence to inform surgeons, patients, and health care providers of optimal implant bearing combinations for given patient characteristics. This review will inform a cost-effectiveness model that will include evidence from other sources, to determine the most effective and cost-effective implant bearing combination for patients.SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015019435.

Background Problem alcohol drinking in homeless and vulnerably housed people can lead to malnutrition, which is associated with complications such as alcohol-related brain damage. Homeless alcohol drinkers are likely to have worse health outcomes and different nutritional needs compared with housed alcohol-drinking persons. It is not clear whether interventions to improve nutritional status in this population have been effective. The purpose of this review is to assess the effectiveness and cost-effectiveness of interventions for preventing or correcting micronutrient deficiencies and other forms of malnutrition and related comorbidities in this population. Methods/design A systematic search for studies of a nutrition-based intervention applied in the homeless or vulnerably housed population with problem drinking will be conducted. The following electronic databases will be systematically searched for relevant studies: MEDLINE, EMBASE, Web of Science, PsycINFO, CAB abstracts, CINAHL, Cochrane Public Health Group Register and Cochrane Drugs and Alcohol Group Register. Screening of identified abstracts for relevance and assessment of papers for inclusion will be done in duplicate. One reviewer will extract data from the studies and assess quality, and this will be checked by another reviewer. Discrepancies will be resolved by consensus. The primary outcomes are (mal)nutrition status or micronutrient deficiencies or change in (mal)nutrition status or micronutrient deficiencies, measures of liver damage and cognitive function. Secondary outcomes include comorbidities, quality of life and functional scales, resources used to deliver treatment, uptake/acceptability of the intervention and engagement with treatment services. Results will be analysed descriptively, and, if appropriate, meta-analyses will be performed. Discussion The results of this review should help to inform the development of effective interventions that can be implemented in the community to improve the health of homeless people who are problem drinkers. Systematic review registration PROSPERO CRD42015024247 Electronic supplementary material The online version of this article (doi:10.1186/s13643-015-0114-3) contains supplementary material, which is available to authorized users.

The regulatory networks of cell polarization and polarity effector proteins have been subjects of feverish interest in the field of cell and developmental biology but many advances in the polarity research may have flown unnoticed past the radar of mainstream cancer biologist. However, recent findings suggesting important cell cycle gatekeeping functions for polarity proteins may change that. For example, PAR6 proteins interact with classical cancer driver signaling pathways, including MAPK and PI3K and moreover, PAR6 (PARD6) genes are frequently altered in various cancers. Mammalian genomes harbor three different PARD6 genes. Recent studies in breast cancer have suggested that different PARD6 genes are not only important players but may play even opposite roles during tumorigenesis. Par-6 is one of the partitioning-defective (par) genes identified by Kemphues et al in a landmark genetic screen, which discovered genes important for the first, asymmetric embryonic cell division in C.elegans [1]. In the invertebrate oocytes, most Par proteins are segregated to two opposite poles of the cells - the anterior cell cortex is occupied by Par-3 and Par-6, which interact with each other via PSD95/Dlg/ZO1 (PDZ) domains. In epithelial cells of diverse species, including humans, the PAR3/PAR6 defines the apical region and co-localizes with tight junctions. A current view is that PAR6 is a multimodular scaffold protein, which together with PAR3 forms a loose or non-constitutive complex with atypical protein kinase C (aPKC) and CDC42. This PAR3-PAR6-aPKC/CDC42 or ‘PAR complex’ has a principal role in most if not all process where cellular asymmetry is important, for example asymmetric cell division, apico-basal and anterio-posterior polarity, axon specification and directional migration [2, 3]. The evolution's kitchen has added an extra degree of complexity to the polarizing systems in large and long-lived animals by multiplying the single Par-6 gene in invertebrates to three separate PARD6 genes in mammals: PARD6A, PARD6B and PARD6G. In humans and mice, all PARD6 genes reside in different chromosomes yet they are very similar, with > 70% sequence similarity. Nevertheless, many PAR6 studies do not clearly indicate which of the three proteins was studied and not surprisingly, the picture of individualistic functions of PAR6 proteins has remained incomplete. Recent findings in breast cancer research have suggested intriguing differences between the PARD6 genes. PARD6B locus resides in a chromosomal region that is frequently amplified and overexpressed in breast cancer [4]. In cell culture, PAR6A-aPKC activity is important for HER2/ErbB2-dependent disruption of organized epithelial structure [5]. Moreover, elevated PARD6A or PARD6B expression signals together with aPKC (PKCɩ) and CDC42 to stimulate MAPK signaling and cell proliferation, without affecting the apico-basal polarity [4]. Thus, the genetic and functional evidence suggest a gain-of function i.e. oncogenic mode of activity for PARD6B in breast cancer. Contrary to the earlier findings, our shRNA screen identified both PAR6B and PAR6G as critical suppressors of cell proliferation [6]. The study was designed to identify genes important for epithelial cell cycle restriction in three-dimensional mammary epithelial organoid culture. MCF10A cells undergo morphogenesis to form quiescent acinar structures in basement membrane gels. The neighborhood suppression of proliferation is tight in matured structures, able to resist even the cell autonomous proliferation signals from oncogenic Myc. The tumor suppressor gene LKB1 has been earlier identified as a key proliferation gatekeeper in mature MCF10A organoids [7]. LKB1 is a human homolog of par-4 (one of the Kemphues genes) and therefore, it was thrilling to discover similar cell cycle gatekeeping functions in other PARD genes [6]. Loss of PAR6G could alone prevent the epithelial cell cycle restriction, whereas loss of PAR6B needed cooperation with oncogenic Myc to trigger the cell cycle re-entry in quiescent MCF10A structures. Loss of PAR6B or PAR6G diminished the phosphorylation of PKCz, which indicates decreased PAR complex activity and the gene deficiencies enabled growth factor-independent cell cycle progression in monolayer culture. The PAR6B or PAR6G-deficiency induced cell cycle deregulation associated with strong AKT phosphorylation on T308, which residue is used for AKT phosphoactivation by PI3K/PDK1 pathway. Therefore, PAR6 activity appears to be important for repressive regulation of PI3K/PDK1/AKT-dependent proliferation signaling [6]. Should we interpret these findings so that any shift in PAR6 activity, up or down, predisposes to uncontrolled cell proliferation and tumorigenesis? The question was addressed by investigating cancer genomes for the type of mutations affecting different PARD6 genes. Consistent with the suggested oncogenic role of PAR6B, chromosomal gains, amplifications and overexpression dominated the landscape of PARD6B mutations. The surprising finding was that PARD6G landscape was etched with typical loss of function mutations: chromosomal losses, deletions and loss of heterozygosity. Thus, PARD6B and PARD6G genes display essentially opposite mutational landscape in tumors. We posit that while a change in any individual PAR6 protein has the capacity to bring PAR6 activity up- or downwards in the cells to instigate specific cell proliferation pathways, for some reason the tumorigenic processes seem to favor gains for PARD6B and losses for PARD6G (Fig.​(Fig.1).1). The differences could arise from cell type-specific expression, subcellular compartmentalization of the protein or even from different context-dependent functions of PAR6 proteins in tissues, which will eventually determine in which way an expression-altered PAR6 protein best serves the process of tumorigenesis. Future studies will be needed to better clarify the roles of individual PAR6 genes in tumor development – which surely will be an exciting research area offering perspectives to evolutionary biology and oncology alike. Figure 1 PAR6 proteins play opposite roles in tumorigenesis

Introduction Over 152 000 people in the UK have strokes annually and a third experience residual disability. Low mood also affects a third of stroke survivors; yet psychological support is poor. While Arts for Health interventions have been shown to improve well-being in people with mild-to-moderate depression post-stroke, their role in helping people regain sense of self, well-being and confidence has yet to be evaluated. The main aim of this study is to explore the feasibility of conducting a pragmatic multicentre randomised controlled trial to assess the effectiveness and cost-effectiveness of an Arts for Health group intervention (‘HeART of Stroke’ (HoS)) for stroke survivors. HoS is a 10-session artist-facilitated group intervention held in the community over 14 weeks. It offers a non-judgemental, supportive environment for people to explore sense of self, potentially enhancing well-being and confidence. Methods and analysis Sixty-four people, up to 2 years post-stroke, recruited via secondary care research staff or community stroke/rehabilitation teams in two UK centres will be randomised to either HoS plus usual care or usual care only. Self-reported outcomes, measured at baseline and approximately 5 months postrandomisation, will include stroke-related, well-being, mood, self-esteem, quality of life and process measures. Analyses will focus on estimating key feasibility parameters (eg, rates of recruitment, retention, intervention attendance). We will develop outcome and resource use data collection methods to inform an effectiveness and cost-effectiveness analysis in the future trial. Interviews, with a sample of participants, will explore the acceptability of the intervention and study processes, as well as experiences of the HoS group. Ethics and dissemination National Health Service (NHS), Research and Development and University ethical approvals have been obtained. Two peer-reviewed journal publications are planned plus one service user led publication. Findings will be disseminated at key national conferences, local stakeholder events and via institutional websites. This paper presents independent research funded by the National Institute for Health Research (NIHR) under its Research for Patient Benefit (RfPB) Programme (Grant Reference Number PB-PG-0212-27054).

Background The Arthroplasty Pain Experience (APEX) studies are two randomised controlled trials in primary total hip (THR) and total knee replacement (TKR) at a large UK orthopaedics centre. APEX investigated the effect of local anaesthetic wound infiltration (LAI), administered before wound closure, in addition to standard analgesia, on pain severity at 12 months. This article reports results of the within-trial economic evaluations. Methods Cost-effectiveness was assessed from the health and social care payer perspective in relation to quality adjusted life years (QALYs) and the primary clinical outcome, the WOMAC Pain score at 12-months follow-up. Resource use was collected from hospital records and patient-completed postal questionnaires, and valued using unit cost estimates from local NHS Trust finance department and national tariffs. Missing data were addressed using multiple imputation chained equations. Costs and outcomes were compared per trial arm and plotted in cost-effectiveness planes. If no arm was dominant (i.e., more effective and less expensive than the other), incremental cost-effectiveness ratios were estimated. The economic results were bootstrapped incremental net monetary benefit statistics (INMB) and cost-effectiveness acceptability curves. One-way deterministic sensitivity analyses explored any methodological uncertainty. Results In both the THR and TKR trials, LAI was the dominant treatment: cost-saving and more effective than standard care, in relation to QALYs and WOMAC Pain. Using the £20,000 per QALY threshold, in THR, the INMB was £1,125 (95 % BCI, £183 to £2,067) and the probability of being cost-effective was over 98 %. In TKR, the INMB was £264 (95 % BCI, −£710 to £1,238), but there was only 62 % probability of being cost-effective. When considering an NHS perspective only, LAI was no longer dominant in THR, but still highly cost-effective, with an INMB of £961 (95 % BCI, £50 to £1,873). Conclusions Administering LAI is a cost-effective treatment option in THR and TKR surgeries. The evidence, because of larger QALY gain, is stronger for THR. In TKR, there is more uncertainty around the economic result, and smaller QALY gains. Results, however, point to LAI being cheaper than standard analgesia, which includes a femoral nerve block. Trial registration ISRCTN96095682, 29/04/2010. Electronic supplementary material The online version of this article (doi:10.1186/s12916-015-0389-1) contains supplementary material, which is available to authorized users.