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.

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.

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.

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 (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.

Point-of-care cluster randomized trial in stroke secondary prevention using electronic health records.

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.

Electronic health records for intervention research: a cluster randomized trial to reduce antibiotic prescribing in primary care (eCRT study).

PURPOSE: This study aimed to implement a point-of-care cluster randomized trial using electronic health records. We evaluated the effectiveness of electronically delivered decision support tools at reducing antibiotic prescribing for respiratory tract infections in primary care. METHODS: Family practices from England and Scotland participating in the Clinical Practice Research Datalink (CPRD) were included in the trial; 53 family practices were allocated to intervention and 51 practices were allocated to usual care. Patients aged 18 to 59 years consulting for respiratory tract infections were eligible. The intervention was through remotely installed, computer-delivered decision support tools accessed during the consultations. Control practices provided usual care. The primary outcome was the proportion of consultations for respiratory tract infections with an antibiotic prescribed based on electronic health records. Family practice-specific proportions were included in a cluster-level analysis. RESULTS: Data were analyzed for 603,409 patients: 317,717 at intervention practices and 285,692 at control practices. Use of the intervention was less than anticipated, varying among practices. There was a reduction in proportion of consultations with antibiotics prescribed of 1.85% (95% CI, 0.10%-3.59%, P=.038) and in the rate of antibiotic prescribing for respiratory tract infections (9.69%; 95% CI, 0.75%-18.63%, fewer prescriptions per 1,000 patient-years, P=.034). There were no adverse events. CONCLUSIONS: Cluster randomized trials may be implemented efficiently in large samples from routine care settings by using primary care electronic health records. Future studies should develop and test multicomponent methods for remotely delivered intervention.

Process evaluation of a point-of-care cluster randomised trial using a computer-delivered intervention to reduce antibiotic prescribing in primary care.

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).

Magnetic resonance imaging in late-life depression: vascular and glucocorticoid cascade hypotheses.

BACKGROUND: Late-life depression is a common and heterogeneous illness, associated with structural abnormalities in both grey and white matter. AIMS: To examine the relationship between age at onset and magnetic resonance imaging (MRI) measures of grey and white matter to establish whether they support particular hypotheses regarding the anatomy and aetiology of network disruption in late-life depression. METHOD: We studied 36 participants with late-life depression. Grey matter was examined using T(1)-weighted MRI and analysed using voxel-based morphometry. The hippocampus was automatically segmented and volume and shape analysis performed. White matter was examined using diffusion tensor imaging and analysed using tract-based spatial statistics. RESULTS: Later age at onset was significantly associated with reduced fractional anisotropy of widespread tracts, in particular the anterior thalamic radiation and superior longitudinal fasciculus. Earlier age at onset was associated with reduced hippocampal volume normalised to whole brain size bilaterally. However, no significant correlations were detected using hippocampal shape analysis or voxel-based morphometry. CONCLUSIONS: Overall, the results were compatible with the vascular hypothesis, and provided some support for the glucocorticoid cascade hypothesis.

Does the Framingham Stroke Risk Profile predict white-matter changes in late-life depression?

BACKGROUND: Cardiovascular risk factors and diseases are important etiological factors in depression, particularly late-life depression. Brain changes associated with vascular disease and depression can be detected using magnetic resonance imaging. Using diffusion tensor imaging (DTI), we investigated whether the Framingham Stroke Risk Profile (FSRP), a well-validated risk prediction algorithm, is associated with changes in white-matter connectivity. We hypothesized that depressed participants would show reduced white-matter integrity with higher FSRP, and non-depressed controls (matched for mean vascular risk) would show minimal co-variance with white-matter changes. METHODS: Thirty-six participants with major depression (age 71.8 ± 7.7 years, mean FSRP 10.3 ± 7.6) and 25 controls (age 71.8 ± 7.3 years, mean FSRP 10.1 ± 7.7) were clinically interviewed and examined, followed by 60-direction DTI on a 3.0 Tesla scanner. Image analysis was performed using FSL tools (www.fmrib.ox.ac.uk/fsl) to assess the correlation between FSRP and fractional anisotropy (FA). Voxelwise statistical analysis of the FA data was carried out using Tract Based Spatial Statistics. The significance threshold for correlations was set at p < 0.05 using threshold-free cluster-enhancement. Partial correlation analysis investigated significant correlations in each group. RESULTS: Participants in the depressed group showed highly significant correlations between FSRP and FA within the body of corpus callosum (r = -0.520, p = 0.002), genu of corpus callosum (r = -0.468, p = 0.005), splenium of corpus callosum (r = -0.536, p = 0.001), and cortico-spinal tract (r = -0.473, p = 0.005). In controls, there was only one significant correlation in the body of corpus callosum (r = -0.473, p = 0.023). CONCLUSIONS: FSRP is associated with impairment in white-matter integrity in participants with depression; these results suggest support for the vascular depression hypothesis.

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.

Developing a computer delivered, theory based intervention for guideline implementation in general practice.

BACKGROUND: Non-adherence to clinical guidelines has been identified as a consistent finding in general practice. The purpose of this study was to develop theory-informed, computer-delivered interventions to promote the implementation of guidelines in general practice. Specifically, our aim was to develop computer-delivered prompts to promote guideline adherence for antibiotic prescribing in respiratory tract infections (RTIs), and adherence to recommendations for secondary stroke prevention. METHODS: A qualitative design was used involving 33 face-to-face interviews with general practitioners (GPs). The prompts used in the interventions were initially developed using aspects of social cognitive theory, drawing on nationally recommended standards for clinical content. The prompts were then presented to GPs during interviews, and iteratively modified and refined based on interview feedback. Inductive thematic analysis was employed to identify responses to the prompts and factors involved in the decision to use them. RESULTS: GPs reported being more likely to use the prompts if they were perceived as offering support and choice, but less likely to use them if they were perceived as being a method of enforcement. Attitudes towards using the prompts were also related to anticipated patient outcomes, individual prescriber differences, accessibility and presentation of prompts and acceptability of guidelines. Comments on the prompts were largely positive after modifying them based on participant feedback. CONCLUSIONS: Acceptability and satisfaction with computer-delivered prompts to follow guidelines may be increased by working with practitioners to ensure that the prompts will be perceived as valuable tools that can support GPs' practice.

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.

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.

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.

Psychosocial consequences of developmental prosopagnosia: a problem of recognition.

OBJECTIVE: To provide the first systematic in-depth description of the consequences of developmental prosopagnosia (DP; 'face blindness') for psychosocial functioning and occupational disability, in order to determine what kind of professional intervention may be needed. METHODS: Semi-structured telephone interviews were carried out with 25 people whose self-reports of face recognition problems were confirmed by impaired scores on the Cambridge Face Recognition Test. Thematic analysis was used to inductively identify and understand common psychosocial consequences of DP. RESULTS: All participants described recurrent and sometimes traumatic social interaction difficulties caused by recognition problems, such as failing to recognize close friends, work colleagues, and family members. These problems often led to chronic anxiety about offending others and feelings of embarrassment, guilt, and failure. Most participants described some degree of fear and avoidance of social situations in which face recognition was important, including family and social gatherings, and meetings at work. Long-term consequences could include dependence on others, a restricted social circle, more limited employment opportunities, and loss of self-confidence. CONCLUSION: The potential for negative psychosocial consequences and occupational disability posed by DP is as great as that posed by conditions which are currently afforded professional recognition and support, such as stuttering and dyslexia. Wider recognition of the problems prosopagnosia can cause could reduce anxiety about social interaction difficulties by making it easier to explain and justify recognition problems to other people, including employers. Greater professional awareness could facilitate detection and referral of those requiring support with coping with social interactions.