Redesigning interstitial lung disease clinic care through interprofessional collaboration.

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.

What makes a good antibody-drug conjugate?

Introduction: Antibody-Drug Conjugates (ADCs) are becoming increasingly important weapons in the fight against cancer, as evidenced by the growing number of approved products. The complex nature of an ADC means that there is a vast array of choices to consider in the design of such drugs.Areas covered: We provide an overview of developments in each facet of ADC structure: the antibody, linker, and payload. Looking at the current clinical landscape, we discuss trends that have led to the evolution of ADC design.Expert opinion:Following a history of setbacks and high discontinuation rates, the understanding of the ADC field has grown. If developers can obtain a firm grasp of the structure-function relationship of their molecule, we expect the advances in ADC design to translate to improved clinical success. Moreover, the breadth of ADC applications will continue to expand to target new indications with novel targets and payloads.

A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia.

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.

OBI-3424, a Novel AKR1C3-Activated Prodrug, Exhibits Potent Efficacy against Preclinical Models of T-ALL.

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.

Electronically delivered interventions to reduce antibiotic prescribing for respiratory infections in primary care: cluster RCT using electronic health records and cohort study.

BACKGROUND: Unnecessary prescribing of antibiotics in primary care is contributing to the emergence of antimicrobial drug resistance. OBJECTIVES: To develop and evaluate a multicomponent intervention for antimicrobial stewardship in primary care, and to evaluate the safety of reducing antibiotic prescribing for self-limiting respiratory infections (RTIs). INTERVENTIONS: A multicomponent intervention, developed as part of this study, including a webinar, monthly reports of general practice-specific data for antibiotic prescribing and decision support tools to inform appropriate antibiotic prescribing. DESIGN: A parallel-group, cluster randomised controlled trial. SETTING: The trial was conducted in 79 general practices in the UK Clinical Practice Research Datalink (CPRD). PARTICIPANTS: All registered patients were included. MAIN OUTCOME MEASURES: The primary outcome was the rate of antibiotic prescriptions for self-limiting RTIs over the 12-month intervention period. COHORT STUDY: A separate population-based cohort study was conducted in 610 CPRD general practices that were not exposed to the trial interventions. Data were analysed to evaluate safety outcomes for registered patients with 45.5 million person-years of follow-up from 2005 to 2014. RESULTS: There were 41 intervention trial arm practices (323,155 patient-years) and 38 control trial arm practices (259,520 patient-years). There were 98.7 antibiotic prescriptions for RTIs per 1000 patient-years in the intervention trial arm (31,907 antibiotic prescriptions) and 107.6 per 1000 patient-years in the control arm (27,923 antibiotic prescriptions) [adjusted antibiotic-prescribing rate ratio (RR) 0.88, 95% confidence interval (CI) 0.78 to 0.99; p = 0.040]. There was no evidence of effect in children aged < 15 years (RR 0.96, 95% CI 0.82 to 1.12) or adults aged ≥ 85 years (RR 0.97, 95% CI 0.79 to 1.18). Antibiotic prescribing was reduced in adults aged between 15 and 84 years (RR 0.84, 95% CI 0.75 to 0.95), that is, one antibiotic prescription was avoided for every 62 patients (95% CI 40 to 200 patients) aged 15-84 years per year. Analysis of trial data for 12 safety outcomes, including pneumonia and peritonsillar abscess, showed no evidence that these outcomes might be increased as a result of the intervention. The analysis of data from non-trial practices showed that if a general practice with an average list size of 7000 patients reduces the proportion of RTI consultations with antibiotics prescribed by 10%, then 1.1 (95% CI 0.6 to 1.5) more cases of pneumonia per year and 0.9 (95% CI 0.5 to 1.3) more cases of peritonsillar abscesses per decade may be observed. There was no evidence that mastoiditis, empyema, meningitis, intracranial abscess or Lemierre syndrome were more frequent at low-prescribing practices. LIMITATIONS: The research was based on electronic health records that may not always provide complete data. The number of practices included in the trial was smaller than initially intended. CONCLUSIONS: This study found evidence that, overall, general practice antibiotic prescribing for RTIs was reduced by this electronically delivered intervention. Antibiotic prescribing rates were reduced for adults aged 15-84 years, but not for children or the senior elderly. FUTURE WORK: Strategies for antimicrobial stewardship should employ stratified interventions that are tailored to specific age groups. Further research into the safety of reduced antibiotic prescribing is also needed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN95232781. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 11. See the NIHR Journals Library website for further project information.

The overuse of antibiotics to treat infections is contributing to the rise of antibiotic resistance in bacteria. A trial was carried out to evaluate whether or not interventions delivered through general practice computer systems may be used to reduce antibiotic prescribing for self-limiting respiratory tract infections (RTIs). The study was carried out in 79 UK general practices. The study tested the effect of a webinar to introduce the trial interventions, which included monthly feedback reports of data for respiratory consultations and antibiotic prescriptions, as well as computer-delivered decision support tools. These interventions were specially developed for this study and were pre-tested with general practitioners and practice nurses. Over the 12-month intervention period, the antibiotic-prescribing rate was about 12% lower in the intervention trial arm than in the control arm. There was no effect of intervention in children aged < 15 years or adults aged ≥ 85 years, but antibiotic prescribing was reduced by about 16% in adults aged between 15 and 84 years. Assuming this was caused by the intervention, one antibiotic prescription was avoided per year for every 62 patients aged between 15 and 84 years and registered with a trial practice. The study found no evidence that the intervention might increase the risk of 12 bacterial infections. In addition, a follow-up study of 610 UK general practices not included in the trial was conducted. The study found that if a general practice with an average list size of 7000 patients reduces the proportion of RTI consultations with antibiotics prescribed by 10%, then it may be possible to observe about one more case of pneumonia per year and one more case of peritonsillar abscess per decade, but no increase in other infections is likely. It can be concluded that electronically delivered interventions, including feedback of antibiotic-prescribing data for specific indications, may have the potential to reduce unnecessary antibiotic prescribing; however, antimicrobial stewardship interventions need to be tailored to particular age groups.

Effectiveness and safety of electronically delivered prescribing feedback and decision support on antibiotic use for respiratory illness in primary care: REDUCE cluster randomised trial.

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.

Implementing multiple health behaviour change interventions for cardiovascular risk reduction in primary care: a qualitative study.

BACKGROUND: The implementation of multiple health behaviour change interventions for cardiovascular risk reduction in primary care is suboptimal. This study aimed to identify barriers and facilitators to implementing multiple health behaviour change interventions for cardiovascular disease (CVD) risk reduction in primary care. METHODS: Qualitative study using semi-structured interviews informed by the Theoretical Domains Framework. Interviews were conducted with a purposive sample of healthcare professionals working in the implementation of the NHS Health Check programme in London. Data were analysed using the Framework method. RESULTS: Thirty participants were recruited including ten general practitioners, ten practice nurses, seven healthcare assistants and three practice managers from 23 practices. Qualitative analysis identified three main themes: healthcare professionals' conceptualising health behaviour change; delivering multiple health behaviour change interventions in primary care; and delivering the health check programme. Healthcare professionals generally recognised the importance of health behaviour change for CVD risk reduction but were more sceptical about the potential for successful intervention through primary care. Participants identified the difficulty of sustained behaviour change for patients, the lack of evidence for effective interventions and limited access to appropriate resources in primary care as barriers. Discussing changing multiple health behaviours was perceived to be overwhelming for patients and difficult to implement for healthcare professionals with current primary care resources. The health check programme consists of several components that are difficult to fully complete in limited time. CONCLUSIONS: Advancing the prevention agenda will require strategies to support the delivery of behaviour change interventions in primary care. Greater emphasis needs to be given to promoting behaviour change through supportive environmental context. Further research is needed to evaluate current external lifestyle services to improve the intervention outcomes.

Automated recruitment and randomisation for an efficient randomised controlled trial in primary care.

BACKGROUND/AIMS: Use of electronic health records and information technology to deliver more efficient clinical trials is attracting the attention of research funders and researchers. We report on methodological issues and data quality for a comparison of 'automated' and manual (or 'in-practice') methods for recruitment and randomisation in a large randomised controlled trial, with individual patient allocation in primary care. METHODS: We conducted a three-arm randomised controlled trial in primary care to evaluate interventions to improve the uptake of invited NHS health checks for cardiovascular risk assessment. Eligible participants were identified using a borough-wide health check management information system. An in-practice recruitment and randomisation method used at 12 general practices required the research team to complete monthly visits to each general practice. For the fully automated method, employed for six general practices, randomisation of eligible participants was performed automatically and remotely using a bespoke algorithm embedded in the health check management information system. RESULTS: There were 8588 and 4093 participants recruited for the manual and automated methods, respectively. The in-practice method was ready for implementation 3 months sooner than the automated method and the in-practice method allowed for full control and documentation of the randomisation procedure. However the in-practice approach was labour intensive and the requirement for participant records to be stored locally resulted in the loss of data for 10 practice months. No records for participants allocated using the automated method were lost. A fixed-effects meta-analysis showed that effect estimates for the primary outcome were consistent for the two allocation methods. CONCLUSIONS: This trial demonstrated the feasibility of automated recruitment and randomisation methods into a randomised controlled trial performed in primary care. Future research should explore the application of these techniques in other clinical contexts and health care settings. TRIAL REGISTRATION: Current Controlled Trials, ID: ISRCTN42856343 . Registered on 21 March 2013.

Enhanced Invitations Using the Question-Behavior Effect and Financial Incentives to Promote Health Check Uptake in Primary Care.

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.

Cardiovascular risk at health checks performed opportunistically or following an invitation letter. Cohort study.

Background: A population-based programme of health checks has been established in England. Participants receive postal invitations through a population-based call-recall system but health check providers may also offer health checks opportunistically. We compared cardiovascular risk scores for 'invited' and 'opportunistic' health checks. Methods: Cohort study of all health checks completed at 18 general practices from July 2013 to June 2015. For each general practice, cardiovascular (CVD) risk scores were compared by source of check and pooled using meta-analysis. Effect estimates were compared by gender, age-group, ethnicity and fifths of deprivation. Results: There were 6184 health checks recorded (2280 invited and 3904 opportunistic) with CVD risk scores recorded for 5359 (87%) participants. There were 17.0% of invited checks and 22.2% of opportunistic health checks with CVD risk score ≥10%; a relative increment of 28% (95% confidence interval: 14-44%, P < 0.001). In the most deprived quintile, 15.3% of invited checks and 22.4% of opportunistic checks were associated with elevated CVD risk (adjusted odds ratio: 1.94, 1.37-2.74, P  < 0.001). Conclusions: Respondents at health checks performed opportunistically are at higher risk of cardiovascular disease than those participating in response to a standard invitation letter, potentially reducing the effect of uptake inequalities.

'Well, it literally stops me from having a life when it's really bad': a nested qualitative interview study of patient views on the use of self-management treatments for the management of recurrent sinusitis (SNIFS trial).

OBJECTIVE: To 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. DESIGN: Qualitative semistructured interview study. SETTING: UK primary care. PARTICIPANTS: 32 participants who had been participating in the 'SNIFS' (Steam inhalation and Nasal Irrigation For recurrent Sinusitis) trial in the South of England. METHOD: Thematic analysis of semistructured telephone interviews. RESULTS: Participants 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. CONCLUSIONS: Steam 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 NUMBER: ISRCTN 88204146.

Qualitative interview study of antibiotics and self-management strategies for respiratory infections in primary care.

OBJECTIVE: To explore perceptions of illness, the decisions to consult and the acceptability of delayed antibiotic prescriptions and self-help treatments for respiratory tract infections (RTIs). DESIGN: Qualitative semistructured interview study. SETTING: UK primary care. PARTICIPANTS: 20 adult patients who had been participating in the 'PIPS' (Pragmatic Ibuprofen Paracetamol and Steam) trial in the South of England. METHOD: Semistructured telephone interviews were conducted with participants to explore their experiences and views on various treatments for RTI. RESULTS: Participants had concerns about symptoms that were not clinically serious and were mostly unaware of the natural history of RTIs, but were aware of the limitations of antibiotics and did not expect them with every consultation. Most viewed delayed prescriptions positively and had no strong preference over which technique is used to deliver the delayed antibiotic, but some patients received mixed messages, such as being told their infection was viral then being given an antibiotic, or were sceptical about the rationale. Participants disliked self-help treatments that involved taking medication and were particularly concerned about painkillers in combination. Steam inhalation was viewed as only moderately helpful for mild symptoms. CONCLUSION: Delayed prescribing is acceptable no matter how the delay is operationalised, but explanation of the rationale is needed and care taken to minimise mixed messages about the severity of illnesses and causation by viruses or bacteria. Better access is needed to good natural history information, and the signs and symptoms requiring or not requiring general practitioner advice. Significant concerns about paracetamol, ibuprofen and steam inhalation are likely to need careful exploration in the consultation.

Multiple health behaviour change interventions for primary prevention of cardiovascular disease in primary care: systematic review and meta-analysis.

BACKGROUND: It is uncertain whether multiple health behaviour change (MHBC) interventions are effective for the primary prevention of cardiovascular disease (CVD) in primary care. A systematic review and a meta-analysis were performed to evaluate the effectiveness of MHBC interventions on CVD risk and CVD risk factors; the study also evaluated associations of theoretical frameworks and intervention components with intervention effectiveness. METHODS: The search included randomised controlled trials of MHBC interventions aimed at reducing CVD risk in primary prevention population up to 2017. Theoretical frameworks and intervention components were evaluated using standardised methods. Meta-analysis with stratification and meta-regression were used to evaluate intervention effects. RESULTS: We identified 31 trials (36 484 participants) with a minimum duration of 12 months follow-up. Pooled net change in systolic blood pressure (16 trials) was -1.86 (95% CI -3.17 to -0.55; p=0.01) mm Hg; diastolic blood pressure (15 trials), -1.53 (-2.43 to -0.62; p=0.001) mm Hg; body mass index (14 trials), -0.13 (-0.26 to -0.01; p=0.04) kg/m2; serum total cholesterol (14 trials), -0.13 (-0.19 to -0.07; p<0.001) mmol/L. There was no significant association between interventions with a reported theoretical basis and improved intervention outcomes. No association was observed between intervention intensity (number of sessions and intervention duration) and intervention outcomes. There was significant heterogeneity for some risk factor analyses, leading to uncertain validity of some pooled net changes. CONCLUSIONS: MHBC interventions delivered to CVD-free participants in primary care did not appear to have quantitatively important effects on CVD risk factors. Better reporting of interventions' rationale, content and delivery is essential to understanding their effectiveness.

Enhanced invitation methods and uptake of health checks in primary care: randomised controlled trial and cohort study using electronic health records.

BACKGROUND: A national programme of health checks to identify risk of cardiovascular disease (CVD) is being rolled out but is encountering difficulties because of low uptake. OBJECTIVE: To evaluate the effectiveness of an enhanced invitation method using the question-behaviour effect (QBE), with or without the offer of a financial incentive to return the QBE questionnaire, at increasing the uptake of health checks. The research went on to evaluate the reasons for the low uptake of invitations and compare the case mix for invited and opportunistic health checks. DESIGN: Three-arm randomised trial and cohort study. PARTICIPANTS: All participants invited for a health check from 18 general practices. Individual participants were randomised. INTERVENTIONS: (1) Standard health check invitation only; (2) QBE questionnaire followed by a standard invitation; and (3) QBE questionnaire with offer of a financial incentive to return the questionnaire, followed by a standard invitation. MAIN OUTCOME MEASURES: The primary outcome was completion of the health check within 6 months of invitation. A p-value of 0.0167 was used for significance. In the cohort study of all health checks completed during the study period, the case mix was compared for participants responding to invitations and those receiving 'opportunistic' health checks. Participants were not aware that several types of invitation were in use. The research team were blind to trial arm allocation at outcome data extraction. RESULTS: In total, 12,459 participants were included in the trial and health check uptake was evaluated for 12,052 participants for whom outcome data were collected. Health check uptake was as follows: standard invitation, 590 out of 4095 (14.41%); QBE questionnaire, 630 out of 3988 (15.80%); QBE questionnaire and financial incentive, 629 out of 3969 (15.85%). The increase in uptake associated with the QBE questionnaire was 1.43% [95% confidence interval (CI) -0.12% to 2.97%; p = 0.070] and the increase in uptake associated with the QBE questionnaire and offer of financial incentive was 1.52% (95% CI -0.03% to 3.07%; p = 0.054). The difference in uptake associated with the offer of an incentive to return the QBE questionnaire was -0.01% (95% CI -1.59% to 1.58%; p = 0.995). During the study period, 58% of health check cardiovascular risk assessments did not follow a trial invitation. People who received an 'opportunistic' health check had greater odds of a ≥ 10% CVD risk than those who received an invited health check (adjusted odds ratio 1.70, 95% CI 1.45 to 1.99; p < 0.001). CONCLUSIONS: Uptake of a health check following an invitation letter is low and is not increased through an enhanced invitation method using the QBE. The offer of a £5 incentive did not increase the rate of return of the QBE questionnaire. A high proportion of all health checks are performed opportunistically and not in response to a standard invitation letter. Participants receiving opportunistic checks are at higher risk of CVD than those responding to standard invitations. Future research should aim to increase the accessibility of preventative medical interventions to increase uptake. Research should also explore the wider use of electronic health records in delivering efficient trials. TRIAL REGISTRATION: Current Controlled Trials ISRCTN42856343. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 84. See the NIHR Journals Library website for further project information.

Electronically delivered, multicomponent intervention to reduce unnecessary antibiotic prescribing for respiratory infections in primary care: a cluster randomised trial using electronic health records-REDUCE Trial study original protocol.

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.

Primary care randomised controlled trial of a tailored interactive website for the self-management of respiratory infections (Internet Doctor).

OBJECTIVE: To assess an internet-delivered intervention providing advice to manage respiratory tract infections (RTIs). DESIGN: Open pragmatic parallel group randomised controlled trial. SETTING: Primary care in UK. PARTICIPANTS: Adults (aged ≥18) registered with general practitioners, recruited by postal invitation. INTERVENTION: Patients were randomised with computer-generated random numbers to access the intervention website (intervention) or not (control). The intervention tailored advice about the diagnosis, natural history, symptom management (particularly paracetamol/ibuprofen use) and when to seek further help. OUTCOMES: Primary: National Health Service (NHS) contacts for those reporting RTIs from monthly online questionnaires for 20 weeks. Secondary: hospitalisations; symptom duration/severity. RESULTS: Results 3044 participants were recruited. 852 in the intervention group and 920 in the control group reported one or more RTIs, among whom there a modest increase in NHS Direct contacts in the intervention group (intervention 44/1734 (2.5%) versus control 24/1842 (1.3%); multivariate Risk Ratio (RR) 2.53 (95% CI 1.10 to 5.82, p=0.029)). Conversely reduced contact with doctors occurred (283/1734 (16.3%) vs 368/1845 (20.0%); risk ratio 0.71, 0.53 to 0.95, p=0.019). Reduction in contacts occurred despite slightly longer illness duration (11.3 days versus 10.9 days respectively; multivariateestimate 0.48 days longer (-0.16 to 1.12, p=0.141) and more days of illness rated moderately bad or worse illness (0.53 days; 0.12 to 0.94, p=0.012). The estimate of slower symptom resolution in the intervention group was attenuated when controlling for whether individuals had used webpages which advocated ibuprofen use (length of illness 0.22 days, −0.51 to 0.95, p=0.551; moderately bad or worse symptoms 0.36 days, −0.08 to 0.80, p=0.105). There was no evidence of increased hospitalisations (risk ratio 0.13; 0.02 to 1.01; p=0.051). CONCLUSIONS: An internet-delivered intervention for the self-management of RTIs modifies help-seeking behaviour, and does not result in more hospital admissions due to delayed help seeking. Advising the use of ibuprofen may not be helpful. TRIAL REGISTRATION NUMBER: ISRCTN91518452.

Do health checks improve risk factor detection in primary care? Matched cohort study using electronic health records.

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.

Transcranial Magnetic Stimulation for Schizophrenia.

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.

Transcranial magnetic stimulation (TMS) for schizophrenia.

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.

Estimating the yield of NHS Health Checks in England: a population-based cohort study.

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 (≥140/90 mmHg) 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.