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Purpose:OBI-3424 is a highly selective prodrug that is converted by aldo-keto reductase family 1 member C3 (AKR1C3) to a potent DNA-alkylating agent. OBI-3424 has entered clinical testing for hepatocellular carcinoma and castrate-resistant prostate cancer, and it represents a potentially novel treatment for acute lymphoblastic leukemia (ALL).Experimental Design:We assessed AKR1C3 expression by RNA-Seq and immunoblotting, and evaluated the in vitro cytotoxicity of OBI-3424. We investigated the pharmacokinetics of OBI-3424 in mice and nonhuman primates, and assessed the in vivo efficacy of OBI-3424 against a large panel of patient-derived xenografts (PDX).Results:AKR1C3 mRNA expression was significantly higher in primary T-lineage ALL (T-ALL; n = 264) than B-lineage ALL (B-ALL; n = 1,740; P < 0.0001), and OBI-3424 exerted potent cytotoxicity against T-ALL cell lines and PDXs. In vivo, OBI-3424 significantly prolonged the event-free survival (EFS) of nine of nine ALL PDXs by 17.1–77.8 days (treated/control values 2.5–14.0), and disease regression was observed in eight of nine PDXs. A significant reduction (P < 0.0001) in bone marrow infiltration at day 28 was observed in four of six evaluable T-ALL PDXs. The importance of AKR1C3 in the in vivo response to OBI-3424 was verified using a B-ALL PDX that had been lentivirally transduced to stably overexpress AKR1C3. OBI-3424 combined with nelarabine resulted in prolongation of mouse EFS compared with each single agent alone in two T-ALL PDXs.Conclusions:OBI-3424 exerted profound in vivo efficacy against T-ALL PDXs derived predominantly from aggressive and fatal disease, and therefore may represent a novel treatment for aggressive and chemoresistant T-ALL in an AKR1C3 biomarker-driven clinical trial.

Research suggests that for every suicide as many as hundreds of people are left behind to bear the loss, referred to in the literature as suicide survivors. Part of survivors’ difficulty in process...

Descriptions of how to foster and accomplish interprofessional collaboration (IPC) in practice across different healthcare settings are needed. This paper examines the transformation of a normative interstitial lung disease (ILD) clinic to an IPC delivering person-centric care across an outpatient specialty clinic and the community. It describes how the IPC was started; the actions undertaken to do this; and the processes supporting it within the outpatient clinic, and between it and its community-based partners. Qualitative research methods (participants-as-co-researchers, unstructured interviews, thematic content analysis) were used with the two physicians founding the IPC to understand this transformation process; this is supplemented with preliminary findings of interviews with patients/carers (N = 30) attending the outpatient clinic. Analysis suggests the power of IPC to improve patients' quality of life and death, reduce acute care use and hospitalization, and realize patient preferences for location of death. Despite this, the ILD IPC encounters resistance from larger institutional and political forces.

For many, the COVID-19 pandemic is the overwhelming, ever-present reality of dying—of loved ones, close family members, dear friends, colleagues, or patients. Fear, avoidance of or lack of time for...

As Canada prepared to host the 2010 Vancouver Winter Olympic Games, a sporting spectacle whose central ideological purpose historically has been the promotion of peace and international goodwill, its government continued its controversial war in Afghanistan where Canadian Armed Forces had been engaged since 2001 and whose presence there was increasingly becoming mired under allegations of complicity in the torture of Afghan detainees. Drawing on Judith Butler’s post-9/11 work on framing and the differential rendering of some (but not all) lives as both precarious and grievable, we critically examine what came to be the intersection of the 2010 Games and the government of Canada’s attempts to neutralize the detainee-transfer crisis that was set to engulf the country’s political and military leaders. Both the 2010 Winter Olympic Games and Canada’s Olympic Torch resolution would be politically manoeuvred to address this crisis as part of the government’s broader framing strategies associated with its enduring detainee crisis and war in Afghanistan.

A traditional Native Hawaiian text, the Kumulipo, provides the basis for re-thinking well-being in the Hawaiian context and the relationship between Native Hawaiian cultural practices and Western l...

Suicide rates are on the rise and subsequently more people, also known as suicide survivors, are left to grieve these types of losses. Yet, there has been limited examination and understand...

Background The threat of antimicrobial resistance has led to intensified efforts to reduce antibiotic utilisation, but serious bacterial infections are increasing in frequency. Objectives To estimate the risks of serious bacterial infections in association with lower antibiotic prescribing and understand stakeholder views with respect to safe antibiotic reduction. Design Mixed-methods research was undertaken, including a qualitative interview study of patient and prescriber views that informed a cohort study and a decision-analytic model, using primary care electronic health records. These three work packages were used to design an application (app) for primary care prescribers. Data sources The Clinical Practice Research Datalink. Setting This took place in UK general practices. Participants A total of 706 general practices with 66.2 million person-years of follow-up from 2002 to 2017 and antibiotic utilisation evaluated for 671,830 registered patients. The qualitative study included 31 patients and 30 health-care professionals from primary care. Main outcome measures Sepsis and localised bacterial infections. Results Patients were concerned about antimicrobial resistance and the side effects, as well as the benefits, of antibiotic treatment. Prescribers viewed the onset of sepsis as the most concerning potential outcome of reduced antibiotic prescribing. More than 40% of antibiotic prescriptions in primary care had no coded indication recorded across both Vision® and EMIS® practice systems. Antibiotic prescribing rates varied widely between general practices, but there was no evidence that serious bacterial infections were less frequent at higher prescribing practices (adjusted rate ratio for 20% increase in prescribing 1.03, 95% confidence interval 1.00 to 1.06; p = 0.074). The probability of sepsis was lower if an antibiotic was prescribed at an infection consultation, and the number of antibiotic prescriptions required to prevent one episode of sepsis (i.e. the number needed to treat) decreased with age. For those aged 0–4 years, the number needed to treat was 29,773 (95% uncertainty interval 18,458 to 71,091) in boys and 27,014 (95% uncertainty interval 16,739 to 65,709) in girls. For those aged > 85 years, the number needed to treat was 262 (95% uncertainty interval 236 to 293) in men and 385 (95% uncertainty interval 352 to 421) in women. Frailty was associated with a greater risk of sepsis and a smaller number needed to treat. For severely frail patients aged 55–64 years, the number needed to treat was 247 (95% uncertainty interval 156 to 459) for men and 343 (95% uncertainty interval 234 to 556) for women. At all ages, the probability of sepsis was greatest for urinary tract infection, followed by skin infection and respiratory tract infection. The numbers needed to treat were generally smaller for the period 2014–17, when sepsis was diagnosed more frequently. The results are available using an app that we developed to provide primary care prescribers with stratified risk estimates during infection consultations. Limitations Analyses were based on non-randomised comparisons. Infection episodes and antibiotic prescribing are poorly documented in primary care. Conclusions Antibiotic treatment is generally associated with lower risks, but the most serious bacterial infections remain infrequent even without antibiotic treatment. This research identifies risk strata in which antibiotic prescribing can be more safely reduced. Future work The software developed from this research may be further developed and investigated for antimicrobial stewardship effect. Funding This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 9, No. 9. See the NIHR Journals Library website for further project information.

As we reflect on the leisure science canon, we use this occasion to ponder how our scholarship has engaged with communities with alternative worldviews compared with the Euro-North American...

Background Uptake of health checks for cardiovascular risk assessment in primary care in England is lower than anticipated. The question-behavior effect (QBE) may offer a simple, scalable intervention to increase health check uptake. Purpose The present study aimed to evaluate the effectiveness of enhanced invitation methods employing the QBE, with or without a financial incentive to return the questionnaire, at increasing uptake of health checks. Methods We conducted a three-arm randomized trial including all patients at 18 general practices in two London boroughs, who were invited for health checks from July 2013 to December 2014. Participants were randomized to three trial arms: (i) Standard health check invitation letter only; (ii) QBE questionnaire followed by standard invitation letter; or (iii) QBE questionnaire with offer of a financial incentive to return the questionnaire, followed by standard invitation letter. In intention to treat analysis, the primary outcome of completion of health check within 6 months of invitation, was evaluated using a p value of .0167 for significance. Results 12,459 participants were randomized. Health check uptake was evaluated for 12,052 (97%) with outcome data collected. Health check uptake within 6 months of invitation was: standard invitation, 590 / 4,095 (14.41%); QBE questionnaire, 630 / 3,988 (15.80%); QBE questionnaire and financial incentive, 629 / 3,969 (15.85%). Difference following QBE questionnaire, 1.43% (95% confidence interval −0.12 to 2.97%, p = .070); following QBE questionnaire and financial incentive, 1.52% (−0.03 to 3.07%, p = .054). Conclusions Uptake of health checks following a standard invitation was low and not significantly increased through enhanced invitation methods using the QBE., In a large randomized controlled trial, enhanced invitation methods based on the question-behavior effect did not increase uptake of health checks

© 2019 Elsevier Inc. Inhibition of the Menin (MEN1) and MLL (MLL1, KMT2A) interaction is a potential therapeutic strategy for MLL-rearranged (MLL-r) leukemia. Structure-based design yielded the potent, highly selective, and orally bioavailable small-molecule inhibitor VTP50469. Cell lines carrying MLL rearrangements were selectively responsive to VTP50469. VTP50469 displaced Menin from protein complexes and inhibited chromatin occupancy of MLL at select genes. Loss of MLL binding led to changes in gene expression, differentiation, and apoptosis. Patient-derived xenograft (PDX) models derived from patients with either MLL-r acute myeloid leukemia or MLL-r acute lymphoblastic leukemia (ALL) showed dramatic reductions of leukemia burden when treated with VTP50469. Multiple mice engrafted with MLL-r ALL remained disease free for more than 1 year after treatment. These data support rapid translation of this approach to clinical trials.

Purpose: OBI-3424 is a highly selective prodrug that is converted by aldo-keto reductase family 1 member C3 (AKR1C3) to a potent DNA-alkylating agent. OBI-3424 has entered clinical testing for hepatocellular carcinoma and castrate-resistant prostate cancer, and it represents a potentially novel treatment for acute lymphoblastic leukemia (ALL). Experimental Design: We assessed AKR1C3 expression by RNA-Seq and immunoblotting, and evaluated the in vitro cytotoxicity of OBI-3424. We investigated the pharmacokinetics of OBI-3424 in mice and nonhuman primates, and assessed the in vivo efficacy of OBI-3424 against a large panel of patient-derived xenografts (PDX). Results: AKR1C3 mRNA expression was significantly higher in primary T-lineage ALL (T-ALL; n = 264) than B-lineage ALL (B-ALL; n = 1,740; P < 0.0001), and OBI-3424 exerted potent cytotoxicity against T-ALL cell lines and PDXs. In vivo, OBI-3424 significantly prolonged the event-free survival (EFS) of nine of nine ALL PDXs by 17.1–77.8 days (treated/control values 2.5–14.0), and disease regression was observed in eight of nine PDXs. A significant reduction (P < 0.0001) in bone marrow infiltration at day 28 was observed in four of six evaluable T-ALL PDXs. The importance of AKR1C3 in the in vivo response to OBI-3424 was verified using a B-ALL PDX that had been lentivirally transduced to stably overexpress AKR1C3. OBI-3424 combined with nelarabine resulted in prolongation of mouse EFS compared with each single agent alone in two T-ALL PDXs. Conclusions: OBI-3424 exerted profound in vivo efficacy against T-ALL PDXs derived predominantly from aggressive and fatal disease, and therefore may represent a novel treatment for aggressive and chemoresistant T-ALL in an AKR1C3 biomarker-driven clinical trial.

While considerable scholarly research has examined online media’s function as a public sphere forum, surprisingly little analysis has extended to examining the public’s actual deliberations of the covered issue(s). Recognizing this gap, this discussion conceives online news comments in response to a CBCNews ( Canadian Broadcasting Corporation online news) article reporting the release of Active Healthy Kids Canada’s 2010 Report Card on Physical Activity for Children and Youth as such a forum. Children’s physical (in)activity habits have become a central focus of various realms (e.g. medical, government, public health, educational and media), which have increasingly framed them as a pressing societal concern. And while the discursive effects of such representations have been subject to critical cultural analysis, not examined to date is the public’s understanding of this issue. The online comments posted in response to the CBCNews article are thus used as an occasion to examine some of the Canadian public’s sense-making of this “problem” in terms of the discourses they invoked in their deliberations.

Oral anticoagulation (OAC) is used to prevent stroke in patients with atrial fibrillation or heart valve disorders. However, OAC may cause haemorrhagic stroke. We completed a randomized trial of stroke secondary prevention 1, using primary care electronic health records (EHRs) collected into the UK Clinical Practice Research Datalink (CPRD). A small proportion of participants were prescribed warfarin following a haemorrhagic stroke diagnosis. The present research aimed to explain this observation. Participants were selected from all 11 391 patients with prevalent stroke, from 106 family practices in England and Scotland, included in the trial 1. Patients were included if they had a record of haemorrhagic stroke before the trial and were treated with warfarin during the trial. Family physicians were sent a postal questionnaire asking respondents about the nature of the stroke suffered by the patient and indications for warfarin therapy. Type of stroke was coded using the International Classification of Diseases 10th Revision 2. Warfarin accounts for 99% of OAC prescriptions in the CPRD. The project was approved by an external scientific and ethical review committee (ISAC protocol 08_083A2). GPs consented to their practice's participation. Fully anonymized data were used and no patient consent was sought. There were 134 (1.2%) participants with EHRs documenting previous haemorrhagic stroke who were prescribed warfarin during the trial. The index stroke event was coded into the EHR as a sub-arachnoid haemorrhage for 25 (24%) of cases and as intracerebral haemorrhage (ICH) for 78 (76%) of cases. There were 40 (47%) women and the mean age was 75 years (range 40 to 94 years). Questionnaire responses were obtained for 103 (77%) patients with sufficient information to confirm the type of stroke obtained for 86 (64%) (Figure 1). Figure 1 Flow chart showing physician-reported data for confirmed stroke type and indication for OAC therapy in 103 participants with electronic records for haemorrhagic stroke Questionnaire responses revealed that there were 41 (48%) patients with a physician-confirmed diagnosis of cerebral infarction (n = 39) or other non-haemorrhagic stroke (n = 2). The diagnosis was confirmed by imaging reports recorded for 36 (88%) of patients. There were five patients with a code for ischaemic stroke recorded after the initial haemorrhagic stroke but only two of these were within 1 year of the index stroke, possibly representing a clarification of the initial diagnosis. Indications for OAC in this group of participants included atrial fibrillation (n = 27), disease of pre-cerebral and cerebral arteries (n = 4), venous thromboembolism and other and not known (n = 10). There were 45 patients with a physician-confirmed diagnosis of haemorrhagic stroke including sub-arachnoid haemorrhage (n = 17) and ICH (n = 28). The diagnosis was supported by imaging results for 38 (84%) patients. Indications for OAC therapy included atrial fibrillation (n = 20), venous thrombosis (n = 10), pulmonary embolism (n = 5), aortic valve replacement (n = 3), percutaneous coronary intervention, vasculitis and not known (n = 7). We conclude that in the EHRs of a large population of stroke patients, there may be appreciable numbers with a diagnosis of haemorrhagic stroke who are treated with OAC therapy. We reported previously on the clinical coding of stroke in EHRs 3 and the potential for misclassification of stroke diagnoses. The present results should not be considered to evaluate the overall reliability of stroke coding in EHRs, because the sample was one in which data discrepancies were expected. In about half of patients, the stroke event was mis-coded as a haemorrhagic stroke when the physician-reported diagnosis for the same event date was one of cerebral infarction. Misclassification might sometimes result from haemorrhagic transformation, which is not necessarily a contra-indication to OAC therapy. Physicians may draw on sources of data from outside the EHR. Nevertheless, it is concerning that appreciable numbers of stroke patients are prescribed OAC therapy with incorrect diagnostic information coded into their EHRs, with potential medico-legal implications. Improved information sharing between providers would be of benefit to physicians. A second group comprises patients with a confirmed diagnosis of haemorrhagic stroke who were treated with OAC therapy for co-existing thromboembolic disorders. This highlights the difficult balance of risks and benefits that may sometimes be required in clinical practice. However, the use of OAC therapy in patients with previous ICH remains controversial 4. Improved evidence and decision support are required for these high risk patients.

In the Hawaiian Kingdom of the nineteenth century, Mōʻī David Kalākaua employed social and cultural policies and “spectacles of display” to sustain the sovereignty of the lāhui. At first glance, these policies suggest that Hawaiian social and cultural practices easily cohere with Western leisure theoretical concepts. Drawing on Jonathan Z. Smith’s comparative approach, we present strategies for maieutic listening to Kanaka ʻŌiwi scholarship and voices and a rectification of leisure theory while maintaining an ambiguity around the commonality between Kanaka ʻŌiwi social and cultural practices and Western leisure theory.

Objective: To identify general practitioner (GP) viewsand understanding on the use of delayed prescribing in primary care.Design: Qualitative semistructured telephone interviewstudy.Setting: Primary care general practices in England.Participants: 32 GPs from identified high-prescribingand low-prescribing general practices in England.Method: Semistructured telephone interviews wereconducted with GPs identified from practices withinclinical commissioning groups with the highest andlowest prescribing rates in England. A thematicanalysis of the data was conducted to generate themes.Results: All GPs had a good understanding ofrespiratory tract infection (RTI) management and howthe delayed prescribing approach could be used inprimary care. However, GPs highlighted factors thatwere influential as to whether delayed prescribing wassuccessfully carried out during the consultation. Theseincluded the increase in evidence of antimicrobialresistance, and GPs’ prior experiences of using delayedprescribing during the consultation. The patient–practitioner relationship could also influence treatmentoutcomes for RTI, and a lack of an agreed prescribingstrategy within and between practices was consideredto be of significance to GPs. Participants expressedthat a lack of feedback on prescribing data at anindividual and practice level made it difficult to know ifdelayed prescribing strategies were successful inreducing unnecessary consumption. GPs agreed thatcoherent and uniform training and guidelines would beof some benefit to ensure consistent prescribingthroughout the UK.Conclusions: Delayed prescribing is encouraged inprimary care, but is not always implementedsuccessfully. Greater uniformity within and betweenpractices in the UK is needed to operationalise delayedprescribing, as well as providing feedback on theuptake of antibiotics. Finally, GPs may need furtherguidance on how to answer the concerns of patientswithout interpreting these questions as a demand forantibiotics, as well as educating the patient aboutantimicrobial resistance and supporting a goodpatient–practitioner relationship.

BACKGROUND: To evaluate the effect of NHS Health Checks on cardiovascular risk factor detection and inequalities.METHODS: Matched cohort study in the Clinical Practice Research Datalink, including participants who received a health check in England between 1 April 2010 and 31 March 2013, together with matched control participants, with linked deprivation scores.RESULTS: There were 91 618 eligible participants who received a health check, of whom 75 123 (82%) were matched with 182 245 controls. After the health check, 90% of men and 92% of women had complete data for blood pressure, total cholesterol, smoking and body mass index; a net 51% increase (P < 0.001) over controls. After the check, gender and deprivation inequalities in recording of all risk factors were lower than for controls. Net increase in risk factor detection was greater for hypercholesterolaemia (men +33%; women +32%) than for obesity (men +8%; women +4%) and hypertension in men only (+5%) (all P < 0.001). Detection of smoking was 5% lower in health check participants than controls (P < 0.001). Over 4 years, statins were prescribed to 11% of health -check participants and 7.6% controls (hazard ratio 1.58, 95% confidence interval 1.53-1.63, P < 0.001).CONCLUSION: NHS Health Checks are associated with increased detection of hypercholesterolaemia, and to a lesser extent obesity and hypertension, but smokers may be under-represented.

INTRODUCTION: Respiratory tract infections (RTIs) account for about 60% of antibiotics prescribed in primary care. This study aims to test the effectiveness, in a cluster randomised controlled trial, of electronically delivered, multicomponent interventions to reduce unnecessary antibiotic prescribing when patients consult for RTIs in primary care. The research will specifically evaluate the effectiveness of feeding back electronic health records (EHRs) data to general practices.METHODS AND ANALYSIS: 2-arm cluster randomised trial using the EHRs of the Clinical Practice Research Datalink (CPRD). General practices in England, Scotland, Wales and Northern Ireland are being recruited and the general population of all ages represents the target population. Control trial arm practices will continue with usual care. Practices in the intervention arm will receive complex multicomponent interventions, delivered remotely to information systems, including (1) feedback of each practice's antibiotic prescribing through monthly antibiotic prescribing reports estimated from CPRD data; (2) delivery of educational and decision support tools; (3) a webinar to explain and promote effective usage of the intervention. The intervention will continue for 12 months. Outcomes will be evaluated from CPRD EHRs. The primary outcome will be the number of antibiotic prescriptions for RTIs per 1000 patient years. Secondary outcomes will be: the RTI consultation rate; the proportion of consultations for RTI with an antibiotic prescribed; subgroups of age; different categories of RTI and quartiles of intervention usage. There will be more than 80% power to detect an absolute reduction in antibiotic prescription for RTI of 12 per 1000 registered patient years. Total healthcare usage will be estimated from CPRD data and compared between trial arms.ETHICS AND DISSEMINATION: Trial protocol was approved by the National Research Ethics Service Committee (14/LO/1730). The pragmatic design of the trial will enable subsequent translation of effective interventions at scale in order to achieve population impact.TRIAL REGISTRATION NUMBER: ISRCTN95232781; Pre-results.

Saturating the Canadian landscape are media and health industry discourses representing childhood physical ‘(in)activity’ and ‘obesity’ as being at ‘epidemic’ proportion. Increasingly identified as a focus of concern within such representations is the school setting, simultaneously positioned both as a cause of and a key institutional site for redressing these ‘pathologies’. Drawing on qualitative research carried out at a Canadian elementary school, this discussion offers a Foucaultian governmental analysis of one school's navigation of this gauntlet of accountability to improve children's health. Specifically, the school-wide fitness-based initiative known as ‘Thrash yourself Thursdays’, whose objective is the production of ‘healthy’ students, is examined to understand the power relations enacted through it, and how the target of this practice (i.e. the children) negotiated such efforts to shape their bodily conduct. This in turn, offers a unique contribution to the governmental literature, which is mor...

Objectives To evaluate the effectiveness and safety at population scale of electronically delivered prescribing feedback and decision support interventions at reducing antibiotic prescribing for self limiting respiratory tract infections. Design Open label, two arm, cluster randomised controlled trial. Setting UK general practices in the Clinical Practice Research Datalink, randomised between 11 November 2015 and 9 August 2016, with final follow-up on 9 August 2017. Participants 79 general practices (582 675 patient years) randomised (1:1) to antimicrobial stewardship (AMS) intervention or usual care. Interventions AMS intervention comprised a brief training webinar, automated monthly feedback reports of antibiotic prescribing, and electronic decision support tools to inform appropriate prescribing over 12 months. Intervention components were delivered electronically, supported by a local practice champion nominated for the trial. Main outcome measures Primary outcome was the rate of antibiotic prescriptions for respiratory tract infections from electronic health records. Serious bacterial complications were evaluated for safety. Analysis was by Poisson regression with general practice as a random effect, adjusting for covariates. Prespecified subgroup analyses by age group were reported. Results The trial included 41 AMS practices (323 155 patient years) and 38 usual care practices (259 520 patient years). Unadjusted and adjusted rate ratios for antibiotic prescribing were 0.89 (95% confidence interval 0.68 to 1.16) and 0.88 (0.78 to 0.99, P=0.04), respectively, with prescribing rates of 98.7 per 1000 patient years for AMS (31 907 prescriptions) and 107.6 per 1000 patient years for usual care (27 923 prescriptions). Antibiotic prescribing was reduced most in adults aged 15-84 years (adjusted rate ratio 0.84, 95% confidence interval 0.75 to 0.95), with one antibiotic prescription per year avoided for every 62 patients (95% confidence interval 40 to 200). There was no evidence of effect for children younger than 15 years (adjusted rate ratio 0.96, 95% confidence interval 0.82 to 1.12) or people aged 85 years and older (0.97, 0.79 to 1.18); there was also no evidence of an increase in serious bacterial complications (0.92, 0.74 to 1.13). Conclusions Electronically delivered interventions, integrated into practice workflow, result in moderate reductions of antibiotic prescribing for respiratory tract infections in adults, which are likely to be of importance for public health. Antibiotic prescribing to very young or old patients requires further evaluation. Trial registration ISRCTN95232781.

Considerable public discourse is devoted to the topics of childhood (in)activity and obesity in Canada, which are commonly marked by phrases such as “public health threat,” “crisis,” and “unprecedented levels of sedentary behaviour.” The intent of this discussion, by way of a governmentally informed socio-historical discourse analysis, is to interrogate critically both the contemporary public discourses of childhood (in)activity that represent it as a “new” and “unprecedented” crisis facing the individual and the nation, and the effects produced through such a representation. Historical documents, including a 1978 article from The Canadian magazine that examined the poor fitness level of Canadian children, are used comparatively to assess the merit of such claims. Far from being new or unprecedented, the contemporary “crisis” of childhood (in)activity and obesity displays continuities with the past. Physical activity, thus, is a central technology of health governance within the contemporary Canadian landscape. Abstract: Le debat public portant sur l’obesite et la sedentarite des enfants au Canada fait couler beaucoup d’encre. Les expressions « menace pour la sante publique », « crise » et « niveaux de sedentarite sans precedent » sont monnaie courante. Le but de cette etude, par le biais d’une analyse sur le debat sociohistorique menee par le gouvernement, est d’interroger de facon critique les debats publics contemporains sur la sedentarite des enfants qui la representent comme une crise « nouvelle » et « sans precedent » qui touche l’individu et la nation, ainsi que les effets de ce type de representation. Des documents historiques, y compris un article de 1978 tire du magazine The Canadian , qui analysait la mauvaise condition physique des enfants canadiens, sont utilises de facon comparative pour evaluer le bien-fonde de ces affirmations. Loin d’etre nouvelle ou sans precedent, la « crise » contemporaine de l’obesite et de la sedentarite des enfants presente une certaine continuite avec le passe. L’activite physique est une technique essentielle de la gouvernance de la sante au sein du paysage canadien contemporain.

A number of scholars have noted the increased social currency that a risk vocabulary has come to assume in late modernity. This vocabulary has been deployed in discourses o physical inactivity and obesity, wherein children have increasingly been identified as an at-risk population leading a sedentary lifestyle, which is culturally represented as a primary risk factor for obesity and ultimately ill health. This article explores the usefulness of Foucault’s governmental perspective in problematizing the function served and effects produced by a risk vocabulary within discourses and practices directed at intervening in the childhood inactivity and obesity epidemics with a specific focus on the Canadian context.

People with schizophrenia typically experience auditory hallucinations or delusions during acute episodes. Although effective drug treatments are available, many have intractable symptoms that do not recover between acute episodes. One proposed alternative to drug treatments is transcranial magnetic stimulation (TMS). To date, many research trials to assess effectiveness of TMS for people with symptoms of schizophrenia have been conducted worldwide. However, there is a lack of consensus on whether TMS should be recommended to be adopted in routine clinical practice. We conducted a systematic review of the literature for all relevant randomized controlled trials (RCTs) comparing TMS with sham or standard treatment. Forty-one trials (1473 participants) survived eligibility criteria and had extractable data. We found significant differences in favor of temporoparietal TMS compared with sham TMS for global state (7 RCTs, n = 224, MD: -0.5, 95% CI: -0.76 to -0.23) and for positive symptoms measured on the Positive and Negative Syndrome Scale (5 RCTs, n = 127, MD: -6.09, 95% CI: -10.95 to -1.22). However, we also found that the quality of trial reporting was frequently suboptimal and the risks of bias were strong or unascertainable for many trial aspects; this led to many results being graded as very low-quality evidence. On that basis, we were unable to definitively support or refute the routine use of TMS in clinical practice. Future definitive trials of TMS with rigorous processes and high-quality reporting are needed.

Background People with schizophrenia often experience symptoms which fail to fully respond to antipsychotic medication. Transcranial magnetic stimulation (TMS) has been proposed as a new treatment for people with schizophrenia, especially those who experience persistent auditory hallucinations. Objectives To estimate the effects of TMS alone, compared with sham TMS or with 'standard management' and any other comparison interventions in reducing psychotic symptoms associated with schizophrenia. Search methods We searched the Cochrane Schizophrenia Group Trials Register (June 2006, June 2008, April 2013). This register is compiled by methodical searches of MEDLINE, EMBASE, BIOSIS, CINAHL, Dissertation abstracts, LILACS, PSYNDEX, PsycINFO, RUSSMED, and Sociofile, and is supplemented with handsearching of relevant journals and numerous conference proceedings. Selection criteria We included all randomised controlled trials recruiting at least five participants and comparing TMS with sham TMS or any other treatment for people with schizophrenia. Data collection and analysis We extracted data independently. For dichotomous data we calculated relative risks (RRs) and their 95% confidence intervals (CIs). For continuous data, we calculated mean differences (MD) and 95% CI. We used a fixed-effect model. We assessed overall quality of the evidence using the GRADE approach. Main results We included 41 studies with 1473 participants in the review. We found significant differences in favour of temporoparietal TMS compared to sham TMS for global state measured on the CGI scale (7 RCTs, n = 224, MD -0.5, 95% CI -0.76 to -0.23, very low-quality evidence) and positive symptoms measured on the PANSS scale (5 RCTs, n = 127, MD -6.09, 95% CI -10.95 to -1.22, very low-quality evidence). Participants experienced significantly more headaches in the temporoparietal TMS group (10 RCTs, n = 392, RR 2.65, 95% CI 1.56 to 4.50, very low-quality evidence). However, no more participants left the study early from the TMS group than from the sham group (very low-quality evidence). Cognitive state was assessed using 39 different measures, and all were equivocal (very low-quality evidence). We included only two trials which compared temporoparietal TMS with standard treatment. In both trials the participants received first- and second-generation antipsychotic medication in both treatment groups, therefore TMS was used an adjunctive therapy to medication. We found no significant differences in the number of participants that showed clinical improvement in global state (1 RCT, n = 100, RR 1.19, 95% CI 0.91 to 1.57) or left the study early (2 RCTs, n = 140, RR 0.33, 95% CI 0.08 to 1.46) (both very low-quality evidence). No studies reported on global state score, mental state, cognitive state and adverse effects. For prefrontal TMS compared to sham TMS, global state was measured on three different scales, all of which presented equivocal results (very low quality evidence). We could not pool data for mental state on the PANSS scale due to high heterogeneity. Cognitive state was assessed using 19 different measures, with 15/19 being equivocal (very low-quality evidence). Prefrontal TMS caused more headaches (6 RCTs, n = 164, RR 2.77, 95% CI 1.22 to 6.26, very low-quality evidence) but there was no difference in the number of participants leaving the study early (very low-quality evidence). No studies reported data for clinical improvement. We found a significant difference in favour of prefrontal theta burst stimulation TMS compared to sham TMS for mental state on the PANNS scale (3 RCTs, n = 108, MD -5.71, 95% CI -9.32 to -2.10, very low evidence). We found no difference for clinical improvement, cognitive state, number of headaches, and leaving the study early (very low-quality evidence). None of the included studies reported satisfaction with care. Authors' conclusions Based on this review, there is insufficient evidence to support or refute the use of TMS to treat symptoms of schizophrenia. Although some evidence suggests that TMS, and in particular temporoparietal TMS, may improve certain symptoms (such as auditory hallucinations and positive symptoms of schizophrenia) compared to sham TMS, the results were not robust enough to be unequivocal across the assessment measures used. There was insufficient evidence to suggest any added benefit with TMS used as an adjunctive therapy to antipsychotic medication. The overall quality of evidence was graded as very low due to risk of bias, and this was accompanied by an imprecision in estimates due to the relatively small number of participants in the studies. Thus, consideration is required in improving the quality of trial processes, as well as the quality of reporting of ongoing and future TMS trials, so as to facilitate accurate future judgements in assessing risk of bias. Differences in TMS techniques in relation to stimulation intensity, stimulation length, brain areas stimulated and variations in the design of sham TMS all contributed to the heterogeneity of study findings and limited the interpretation and applicability of the results. In addition, the trials assessed their outcomes with a variety of scales, and usable data were limited. Therefore, to better evaluate the treatment effects of TMS in people with schizophrenia, we favour the use of standardised treatment protocols and outcome measures.

ObjectivePostoperative mediastinitis after median sternotomy is associated with disability and mortality. The aim of this study was to identify risk factors for mortality 1 year after postoperative mediastinitis diagnosis.MethodsPostoperative mediastinitis was defined as an organ-space infection involving the mediastinum and necessitating debridement. A total of 183 cases of postoperative mediastinitis were prospectively identified from infection control databases. By using univariate and multivariate analysis, clinical risk factors for 1-year mortality were identified.ResultsOf 183 patients, 36 (19.7%) died within 3 months of the initial operation. Overall, 51 (33%) died during the study period (the median time to death from the date of diagnosis was 37 days [interquartile range, 11,139 days]). In multivariate analysis, independent predictors of 1-year mortality were a greater than 3-day delay in sternal closure after debridement (hazard ratio, 6.27; P < .001), age greater than 65 years (hazard ratio, 2.29; P = .015), serum creatinine level greater than 2 mg/dL before debridement (hazard ratio, 2.52; P = .019), stay in an intensive care unit before sternal debridement (hazard ratio, 5.56; P < .001), and postoperative mediastinitis due to methicillin-resistant Staphylococcus aureus (hazard ratio, 2.13; P = .02). Treatment with antibiotics with in vitro activity against the infecting pathogen within 7 days of initial debridement was associated with a decreased risk for mortality (hazard ratio, 0.40; P = .03).ConclusionsOur data suggest that, to improve long-term survival, patients with postoperative mediastinitis should undergo sternal closure within 72 hours after sternal debridement and should receive effective antimicrobial therapy based on operative culture results.

The benefits of single‐gender experiences for females have been discussed in a variety of contexts, including education, sport and outdoor recreation. In both the discourses of female‐run outdoor adventure travel programs providing such experiences, and the leisure studies and outdoor education literatures, claims are made about the distinct social environment created on such trips and the positive outcomes for females undertaking them. Absent from these discourses is reference to empirical research exploring women's perceptions of such experiences, thereby allowing one to evaluate the merit of such claims. In what would initially appear to be an observation in a completely different vein, there is also a relative dearth of scholarly examinations within leisure and recreational studies of women's lived‐body experiences of their physicalities through active outdoor recreation, and the potentially empowering effects of them. This paper seeks to draw out the connections between these seemingly disparate obse...

ObjectiveTo explore the experience and perceptions of illness, the decision to consult a general practitioner and the use of self-management approaches for chronic or recurrent sinusitis.DesignQualitative semistructured interview study.SettingUK primary care.Participants32 participants who had been participating in the ‘SNIFS’ (Steam inhalation and Nasal Irrigation For recurrent Sinusitis) trial in the South of England.MethodThematic analysis of semistructured telephone interviews.ResultsParticipants often reported dramatic impact on both activities and their quality of life. Participants were aware of both antibiotic side effects and resistance, but if they had previously been prescribed antibiotics, many patients believed that they would be necessary for the future treatment of sinusitis. Participants used self-help treatments for short and limited periods of time only. In the context of the trial, steam inhalation used for recurrent sinusitis was described as acceptable but is seen as having limited effectiveness. Nasal irrigation was viewed as acceptable and beneficial by more patients. However, some participants reported that they would not use the treatment again due to the uncomfortable side effects they experienced, which outweighed any symptom relief, which may have resulted had they continued.ConclusionsSteam inhalation is acceptable but seen as having limited effectiveness. Nasal irrigation is generally acceptable and beneficial for symptoms, but detailed information on the correct procedure and potential benefits of persisting may increase acceptability and adherence in those patients who find it uncomfortable.Trial registration numberISRCTN 88204146.

Background This study aimed to evaluate the yield of the NHS Health Checks programme. Methods A cohort study, conducted in the Clinical Practice Research Datalink in England. Electronic health records were analysed for patients aged 40–74 receiving an NHS Health Check between 2010 and 2013. Results There were 65 324 men and 75 032 women receiving a health check. For every 1000 men assessed, there were 205 smokers (95% confidence interval 195–215), 355 (340–369) with hypertension (140/90mmHg) and 633 (607–658) with elevated cholesterol (5 mmol/l). Among 1000 women, there were 161 (151–171) smokers, 247 (238–257) with hypertension and 668 (646–689) with elevated cholesterol. In the 12 months following the check, statins were prescribed to 18% of men and 21% of women with 20% cardiovascular risk and antihypertensive drugs to 11% of men and 16% of women with 20% cardiovascular risk. Slight reductions in risk factor values were observed in the minority of participants with follow-up values recorded in the 15 months following the check. Conclusions A universal primary prevention programme identifies substantial risk factor burden in a population without known cardiovascular disease. Research is needed to monitor interventions, and intermediate- and long-term outcomes, in those identified at high risk.

Background: NHS Health Checks is a new program for primary prevention of heart disease, stroke, diabetes, chronic kidney disease, and vascular dementia in adults aged 40 to 74 years in England. Individuals without existing cardiovascular disease or diabetes are invited for a Health Check every 5 years. Uptake among those invited is lower than anticipated. Method: The project is a three-arm randomized controlled trial to test the hypothesis that enhanced invitation methods, using the Question-Behaviour Effect (QBE), will increase uptake of NHS Health Checks compared with a standard invitation. Participants comprise individuals eligible for an NHS Health Check registered in two London boroughs. Participants are randomized into one of three arms. Group A receives the standard NHS Health Check invitation letter, information sheet, and reminder letter at 12 weeks for nonattenders. Group B receives a QBE questionnaire 1 week before receiving the standard invitation, information sheet, and reminder letter where appropriate. Group C is the same as Group B, but participants are offered a £5 retail voucher if they return the questionnaire. Participants are randomized in equal proportions, stratified by general practice. The primary outcome is uptake of NHS Health Checks 6 months after invitation from electronic health records. We will estimate the incremental health service cost per additional completed Health Check for trial groups B and C versus trial arm A, as well as evaluating the impact of the QBE questionnaire, and questionnaire plus voucher, on the socioeconomic inequality in uptake of Health Checks. The trial includes a nested comparison of two methods for implementing allocation, one implemented manually at general practices and the other implemented automatically through the information systems used to generate invitations for the Health Check. Discussion: The research will provide evidence on whether asking individuals to complete a preliminary questionnaire, by using the QBE, is effective in increasing uptake of Health Checks and whether an incentive alters questionnaire return rates as well as uptake of Health Checks. The trial interventions can be readily translated into routine service delivery if they are shown to be cost-effective. Trial registration: Current Controlled Trials ISRCTN42856343. Date registered: 21.03.2013.

Background and Purpose— The aim of this study was to evaluate whether the remote introduction of electronic decision support tools into family practices improves risk factor control after first stroke. This study also aimed to develop methods to implement cluster randomized trials in stroke using electronic health records. Methods— Family practices were recruited from the UK Clinical Practice Research Datalink and allocated to intervention and control trial arms by minimization. Remotely installed, electronic decision support tools promoted intensified secondary prevention for 12 months with last measure of systolic blood pressure as the primary outcome. Outcome data from electronic health records were analyzed using marginal models. Results— There were 106 Clinical Practice Research Datalink family practices allocated (intervention, 53; control, 53), with 11 391 (control, 5516; intervention, 5875) participants with acute stroke ever diagnosed. Participants at trial practices had similar characteristics as 47 887 patients with stroke at nontrial practices. During the intervention period, blood pressure values were recorded in the electronic health records for 90% and cholesterol values for 84% of participants. After intervention, the latest mean systolic blood pressure was 131.7 (SD, 16.8) mm Hg in the control trial arm and 131.4 (16.7) mm Hg in the intervention trial arm, and adjusted mean difference was −0.56 mm Hg (95% confidence interval, −1.38 to 0.26; P =0.183). The financial cost of the trial was approximately US $22 per participant, or US $2400 per family practice allocated. Conclusions— Large pragmatic intervention studies may be implemented at low cost by using electronic health records. The intervention used in this trial was not found to be effective, and further research is needed to develop more effective intervention strategies. Clinical Trial Registration— URL: http://www.controlled-trials.com . Current Controlled Trials identifier: ISRCTN35701810.

This paper builds upon an earlier exploratory discussion about the term physicality that called for conceptual clarity regarding our theoretical understanding and use of it within the context of women’s lives. In light of fieldwork conducted, physicality is suggested to be the complex interplay of body perception, agency, and self-perception. This article focuses on examining one feature of this construct by assessing the relevance of body perception to two groups of women’s experiences of their physicalities through two differently gendered activities: aerobics and wilderness canoe-tripping. Pivotal to this has been qualitatively understanding the lived-body as experienced and understood by the women. In-depth interviews and participant observation were used to explore the meaning and significance these women derived from experiencing their bodies/themselves through these activities. Of specific interest was understanding the effects of these experiences in terms of shaping their understandings of their physicalities particularly beyond that of appearance. Central to this has been apprehending the physically and socially empowering effects of these experiences, especially at the level of their identity. Through the data analysis, body perception was found to be relevant to the women’s physical activity involvement in two distinct ways: as a factor initiating activity involvement and as a perception emerging through the experience. In turn, these differing perceptions of the body were found to impact diversely upon their physicalities, either broadening them or contributing to alternative ways of understanding them.

Background Patients frequently experience sleep problems and present to primary care. However, information is limited regarding the management strategies that GPs employ. Aim To gain an understanding of current GP management strategies for insomnia. Design and setting A postal questionnaire survey and qualitative interviews with GPs in the south of England. Method A postal survey of 296 GPs and qualitative interviews were carried out with 23 of the GPs. Results The survey response rate was 56% (166/296). GPs look for signs of depression and anxiety in patients and if present treat these first. ‘Sleep hygiene’ advice is provided by 88% (147/166) of GPs but often seems insufficient and they feel under pressure to prescribe. Benzodiazepines and Z drugs are prescribed, often reluctantly, for short periods, because of known problems with dependence and tolerance. Many GPs prescribe low-dose amitriptyline for insomnia although it is not licensed for this indication. For insomnia 95% (157/166) of survey responders ‘ever prescribe’ amitriptyline, with 31% (52/166) stating they do so commonly. Most GPs perceived amitriptyline to be effective and a longer-term option for those with ongoing sleep problems. GPs report a lack of knowledge and confidence in the provision and use of psychological therapies, such as cognitive behavioural therapy (CBT), in the management of insomnia. Conclusion GPs often find ‘sleep hygiene’ advice is insufficient for managing insomnia and report frequently prescribing medication, including amitriptyline (off licence), which is often based on perceived patient pressure for a prescription. Patients are rarely offered psychological therapies such as CBT for insomnia, despite evidence suggesting its potential effectiveness.

Background The study aimed to conduct a process evaluation for a cluster randomised trial of a computer-delivered, point-of-care intervention to reduce antibiotic prescribing in primary care. The study aimed to evaluate both the intervention and implementation of the trial. Methods The intervention comprised a set of electronic educational and decision support tools that were remotely installed and activated during consultations with patients with acute respiratory infections over a 12 month intervention period. A mixed method evaluation was conducted with 103 general practitioners (GPs) who participated in the trial. Semi-structured telephone interviews were conducted with 20 GPs who had been in the intervention group of the trial and 4 members of the implementation staff. Questionnaires, consisting of both intervention evaluation and theory-based measures, were self-administered to 83 GPs (56 control group and 27 intervention group). Results Interviews suggested that a key factor influencing GPs’ use of the intervention appeared to be their awareness of the implementation of the system into their practice. GPs who were aware of the implementation of the intervention reported feeling confident in using it if they chose to and understood the purpose of the intervention screens. However, GPs who were unaware that the intervention would be appearing often reported feeling confused when they saw the messages appear on the screen and not fully understanding what they were for or how they could be used. Intervention evaluation questionnaires indicated that GPs were satisfied with the usability of the prompts, and theory-based measures revealed that intervention group GPs reported higher levels of self-efficacy in managing RTI patients according to recommended guidelines compared to GPs in the control group. Conclusions Remote installation of a computer-delivered intervention for use at the point-of-care was feasible and acceptable. Additional measures to promote awareness of the intervention may be required to promote health care professionals’ utilisation of the intervention and these might sometimes compromise the pragmatic intention of a trial. Trial registration ISRCTN47558792 (registered on 17 March 2010).

BackgroundAntibiotics are still prescribed to most patients attending primary care with acute sore throat, despite evidence that there is modest benefit overall from antibiotics. Targeting antibiotics using either clinical scoring methods or rapid antigen detection tests (RADTs) could help. However, there is debate about which groups of streptococci are important (particularly Lancefield groups C and G), and uncertainty about the variables that most clearly predict the presence of streptococci.ObjectiveThis study aimed to compare clinical scores or RADTs with delayed antibiotic prescribing.DesignThe study comprised a RADT in vitro study; two diagnostic cohorts to develop streptococcal scores (score 1; score 2); and, finally, an open pragmatic randomised controlled trial with nested qualitative and cost-effectiveness studies.SettingThe setting was UK primary care general practices.ParticipantsParticipants were patients aged ≥ 3 years with acute sore throat.InterventionsAn internet program randomised patients to targeted antibiotic use according to (1) delayed antibiotics (control group), (2) clinical score or (3) RADT used according to clinical score.Main outcome measuresThe main outcome measures were self-reported antibiotic use and symptom duration and severity on seven-point Likert scales (primary outcome: mean sore throat/difficulty swallowing score in the first 2–4 days).ResultsThe IMI TestPack Plus Strep A (Inverness Medical, Bedford, UK) was sensitive, specific and easy to use. Lancefield group A/C/G streptococci were found in 40% of cohort 2 and 34% of cohort 1. A five-point score predicting the presence of A/C/G streptococci [FeverPAIN: Fever; Purulence; Attend rapidly (≤ 3 days); severe Inflammation; and No cough or coryza] had moderate predictive value (bootstrapped estimates of area under receiver operating characteristic curve: 0.73 cohort 1, 0.71 cohort 2) and identified a substantial number of participants at low risk of streptococcal infection. In total, 38% of cohort 1 and 36% of cohort 2 scored ≤ 1 for FeverPAIN, associated with streptococcal percentages of 13% and 18%, respectively. In an adaptive trial design, the preliminary score (score 1;n = 1129) was replaced by FeverPAIN (n = 631). For score 1, there were no significant differences between groups. For FeverPAIN, symptom severity was documented in 80% of patients, and was lower in the clinical score group than in the delayed prescribing group (–0.33; 95% confidence interval –0.64 to –0.02;p = 0.039; equivalent to one in three rating sore throat a slight rather than moderately bad problem), and a similar reduction was observed for the RADT group (–0.30; –0.61 to 0.00;p = 0.053). Moderately bad or worse symptoms resolved significantly faster (30%) in the clinical score group (hazard ratio 1.30; 1.03 to 1.63) but not the RADT group (1.11; 0.88 to 1.40). In the delayed group, 75/164 (46%) used antibiotics, and 29% fewer used antibiotics in the clinical score group (risk ratio 0.71; 0.50 to 0.95;p = 0.018) and 27% fewer in the RADT group (0.73; 0.52 to 0.98;p = 0.033). No significant differences in complications or reconsultations were found. The clinical score group dominated both other groups for both the cost/quality-adjusted life-years and cost/change in symptom severity analyses, being both less costly and more effective, and cost-effectiveness acceptability curves indicated the clinical score to be the most likely to be cost-effective from an NHS perspective. Patients were positive about RADTs. Health professionals’ concerns about test validity, the time the test took and medicalising self-limiting illness lessened after using the tests. For both RADTs and clinical scores, there were tensions with established clinical experience.ConclusionsTargeting antibiotics using a clinical score (FeverPAIN) efficiently improves symptoms and reduces antibiotic use. RADTs used in combination with FeverPAIN provide no clear advantages over FeverPAIN alone, and RADTs are unlikely to be incorporated into practice until health professionals’ concerns are met and they have experience of using them. Clinical scores also face barriers related to clinicians’ perceptions of their utility in the face of experience. This study has demonstrated the limitation of using one data set to develop a clinical score. FeverPAIN, derived from two data sets, appears to be valid and its use improves outcomes, but diagnostic studies to confirm the validity of FeverPAIN in other data sets and settings are needed. Experienced clinicians need to identify barriers to the use of clinical scoring methods. Implementation studies that address perceived barriers in the use of FeverPAIN are needed.Trial registrationCurrent Controlled Trials ISRCTN32027234.Source of fundingThis project was funded by the NIHR Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 18, No. 6. See the NIHR Journals Library website for further project information.