Peter K. Kimani

Validation of digital pathology imaging for primary histopathological diagnosis

Digital pathology (DP) offers advantages over glass slide microscopy (GS), but data demonstrating a statistically valid equivalent (i.e. non‐inferior) performance of DP against GS are required to permit its use in diagnosis. The aim of this study is to provide evidence of non‐inferiority.

Improving the Efficiency of Advanced Life Support Training: A Randomized, Controlled Trial

BACKGROUND Each year, more than 1.5 million health care professionals receive advanced life support (ALS) training. OBJECTIVE To determine whether a blended approach to ALS training that includes electronic learning (e-learning) produces outcomes similar to those of conventional, instructor-led ALS training. DESIGN Open-label, noninferiority, randomized trial. Randomization, stratified by site, was generated by Sealed Envelope (Sealed Envelope, London, United Kingdom). (International Standardized Randomized Controlled Trial Number Register: ISCRTN86380392) SETTING 31 ALS centers in the United Kingdom and Australia. PARTICIPANTS 3732 health care professionals recruited between December 2008 and October 2010. INTERVENTION A 1-day course supplemented with e-learning versus a conventional 2-day course. MEASUREMENTS The primary outcome was performance in a cardiac arrest simulation test at the end of the course. Secondary outcomes comprised knowledge- and skill-based assessments, repeated assessment after remediation training, and resource use. RESULTS 440 of the 1843 participants randomly assigned to the blended course and 444 of the 1889 participants randomly assigned to conventional training did not attend the courses. Performance in the cardiac arrest simulation test after course attendance was lower in the electronic advanced life support (e-ALS) group compared with the conventional advanced life support (c-ALS) group; 1033 persons (74.5%) in the e-ALS group and 1146 persons (80.2%) in the c-ALS group passed (mean difference, -5.7% [95% CI, -8.8% to -2.7%]). Knowledge- and skill-based assessments were similar between groups, as was the final pass rate after remedial teaching, which was 94.2% in the e-ALS group and 96.7% in the c-ALS group (mean difference, -2.6% [CI, -4.1% to 1.2%]). Faculty, catering, and facility costs were

Evidence of increased blood pressure and hypertension risk among people living with HIV on antiretroviral therapy: a systematic review with meta-analysis

438 per participant for electronic ALS training and

Effectiveness and cost-effectiveness of a universal parenting skills programme in deprived communities: multicentre randomised controlled trial

935 for conventional ALS training. LIMITATIONS Many professionals (24%) did not attend the courses. The effect on patient outcomes was not evaluated. CONCLUSION Compared with conventional ALS training, an approach that included e-learning led to a slightly lower pass rate for cardiac arrest simulation tests, similar scores on a knowledge test, and reduced costs. PRIMARY FUNDING SOURCE National Institute of Health Research and Resuscitation Council (UK).

Dose selection in seamless phase II/III clinical trials based on efficacy and safety

Owing to antiretroviral drug-induced endothelial dysfunction, HIV-infected patients on antiretroviral therapy (ART) may have elevated blood pressure. We conducted a systematic review and meta-analysis to estimate the effects of ART on blood pressure levels and hypertension risk among HIV-infected populations worldwide. We sought articles that compared the mean blood pressure measurements and hypertension prevalence between HIV-infected adults naive and exposed to ART. Thirty-nine studies comprising 44 903 participants met the inclusion criteria. Overall, systolic (mean difference (MD) 4.52 mm Hg, 95% confidence interval (CI) 2.65–6.39, I2=68.1%, 19 studies) and diastolic blood pressure levels (MD 3.17 mm Hg, 95% CI 1.71–4.64, I2=72.5%, 16 studies) were significantly higher among ART-exposed patients compared with treatment-naive patients. Similarly, the risk of hypertension was significantly higher among ART-exposed patients, such that among 28 908 ART-exposed patients, 4195 (14.5%) had hypertension compared with 950 of 9086 (10.5%) in those who were treatment-naive (odds ratio 1.68, 95% CI 1.35–2.10, I2=81.5%, 32 studies). In summary, exposure to ART is significantly associated with increased systolic and diastolic blood pressure levels, and increased risk of hypertension, regardless of study-level sociodemographic differences. This meta-analysis supports the need for population-based strategies to reduce the risk of high blood pressure among people living with HIV on ART.

Conditionally unbiased estimation in phase II/III clinical trials with early stopping for futility

Objective To evaluate the effectiveness and cost utility of a universally provided early years parenting programme. Design Multicentre randomised controlled trial with cost-effectiveness analysis. Setting Early years centres in four deprived areas of South Wales. Participants Families with children aged between 2 and 4 years. 286 families were recruited and randomly allocated to the intervention or waiting list control. Intervention The Family Links Nurturing Programme (FLNP), a 10-week course with weekly 2 h facilitated group sessions. Main outcome measures Negative and supportive parenting, child and parental well-being and costs assessed before the intervention, following the course (3 months) and at 9 months using standardised measures. Results There were no significant differences in primary or secondary outcomes between trial arms at 3 or 9 months. With ‘+’ indicating improvement, difference in change in negative parenting score at 9 months was +0.90 (95%CI −1.90 to 3.69); in supportive parenting, +0.17 (95%CI −0.61 to 0.94); and 12 of the 17 secondary outcomes showed a non-significant positive effect in the FLNP arm. Based on changes in parental well-being (SF-12), the cost per quality-adjusted life year (QALY) gained was estimated to be £34 913 (range 21 485–46 578) over 5 years and £18 954 (range 11 664–25 287) over 10 years. Probability of cost per QALY gained below £30 000 was 47% at 5 years and 57% at 10 years. Attendance was low: 34% of intervention families attended no sessions (n=48); only 47% completed the course (n=68). Also, 19% of control families attended a parenting programme before 9-month follow-up. Conclusions Our trial has not found evidence of clinical or cost utility for the FLNP in a universal setting. However, low levels of exposure and contamination mean that uncertainty remains. Trial registration The trial is registered with Current Controlled Trials ISRCTN13919732.

The System-Wide Effect of Real-Time Audiovisual Feedback and Postevent Debriefing for In-Hospital Cardiac Arrest: The Cardiopulmonary Resuscitation Quality Improvement Initiative*

Seamless phase II/III clinical trials are attractive in development of new drugs because they accelerate the drug development process. Seamless phase II/III trials are carried out in two stages. After stage 1 (phase II stage), an interim analysis is performed and a decision is made on whether to proceed to stage 2 (phase III stage). If the decision is to continue with further testing, some dose-selection procedure is used to determine the set of doses to be tested in stage 2. In this paper, we propose a dose-selection procedure for binary outcomes in adaptive seamless phase II/III clinical trials that incorporates the dose-response relationship when the experimental treatments are different dose levels of the same drug, and explicitly incorporates both efficacy and safety. The choice of the doses to continue to stage 2 is made by comparing the predictive power of the potential sets of doses, which might continue.

Timely digital patient-clinician communication in specialist clinical services for young people: A mixed-methods study (the LYNC study)

Seamless phase II/III clinical trials combine traditional phases II and III into a single trial that is conducted in two stages, with stage 1 used to answer phase II objectives such as treatment selection and stage 2 used for the confirmatory analysis, which is a phase III objective. Although seamless phase II/III clinical trials are efficient because the confirmatory analysis includes phase II data from stage 1, inference can pose statistical challenges. In this paper, we consider point estimation following seamless phase II/III clinical trials in which stage 1 is used to select the most effective experimental treatment and to decide if, compared with a control, the trial should stop at stage 1 for futility. If the trial is not stopped, then the phase III confirmatory part of the trial involves evaluation of the selected most effective experimental treatment and the control. We have developed two new estimators for the treatment difference between these two treatments with the aim of reducing bias conditional on the treatment selection made and on the fact that the trial continues to stage 2. We have demonstrated the properties of these estimators using simulations. Copyright

A plausible causal link between antiretroviral therapy and increased blood pressure in a sub-Saharan African setting: A propensity score-matched analysis.

Objective: To evaluate the effect of implementing real-time audiovisual feedback with and without postevent debriefing on survival and quality of cardiopulmonary resuscitation quality at in-hospital cardiac arrest. Design: A two-phase, multicentre prospective cohort study. Setting: Three UK hospitals, all part of one National Health Service Acute Trust. Patients: One thousand three hundred and ninety-five adult patients who sustained an in-hospital cardiac arrest at the study hospitals and were treated by hospital emergency teams between November 2009 and May 2013. Interventions: During phase 1, quality of cardiopulmonary resuscitation and patient outcomes were measured with no intervention implemented. During phase 2, staff at hospital 1 received real-time audiovisual feedback, whereas staff at hospital 2 received real-time audiovisual feedback supplemented by postevent debriefing. No intervention was implemented at hospital 3 during phase 2. Measurements and Main Results: The primary outcome was return of spontaneous circulation. Secondary endpoints included other patient-focused outcomes, such as survival to hospital discharge, and process-focused outcomes, such as chest compression depth. Random-effect logistic and linear regression models, adjusted for baseline patient characteristics, were used to analyze the effect of the interventions on study outcomes. In comparison with no intervention, neither real-time audiovisual feedback (adjusted odds ratio, 0.62; 95% CI, 0.31–1.22; p = 0.17) nor real-time audiovisual feedback supplemented by postevent debriefing (adjusted odds ratio, 0.65; 95% CI, 0.35–1.21; p = 0.17) was associated with a statistically significant improvement in return of spontaneous circulation or any process-focused outcome. Despite this, there was evidence of a system-wide improvement in phase 2, leading to improvements in return of spontaneous circulation (adjusted odds ratio, 1.87; 95% CI, 1.06–3.30; p = 0.03) and process-focused outcomes. Conclusions: Implementation of real-time audiovisual feedback with or without postevent debriefing did not lead to a measured improvement in patient or process-focused outcomes at individual hospital sites. However, there was an unexplained system-wide improvement in return of spontaneous circulation and process-focused outcomes during the second phase of the study.

Estimation after subpopulation selection in adaptive seamless trials

Background Young people (aged 16-24 years) with long-term health conditions can disengage from health services, resulting in poor health outcomes, but clinicians in the UK National Health Service (NHS) are using digital communication to try to improve engagement. Evidence of effectiveness of this digital communication is equivocal. There are gaps in evidence as to how it might work, its cost, and ethical and safety issues. Objective Our objective was to understand how the use of digital communication between young people with long-term conditions and their NHS specialist clinicians changes engagement of the young people with their health care; and to identify costs and necessary safeguards. Methods We conducted mixed-methods case studies of 20 NHS specialist clinical teams from across England and Wales and their practice providing care for 13 different long-term physical or mental health conditions. We observed 79 clinical team members and interviewed 165 young people aged 16-24 years with a long-term health condition recruited via case study clinical teams, 173 clinical team members, and 16 information governance specialists from study NHS Trusts. We conducted a thematic analysis of how digital communication works, and analyzed ethics, safety and governance, and annual direct costs. Results Young people and their clinical teams variously used mobile phone calls, text messages, email, and voice over Internet protocol. Length of clinician use of digital communication varied from 1 to 13 years in 17 case studies, and was being considered in 3. Digital communication enables timely access for young people to the right clinician at the time when it can make a difference to how they manage their health condition. This is valued as an addition to traditional clinic appointments and can engage those otherwise disengaged, particularly at times of change for young people. It can enhance patient autonomy, empowerment and activation. It challenges the nature and boundaries of therapeutic relationships but can improve trust. The clinical teams studied had not themselves formally evaluated the impact of their intervention. Staff time is the main cost driver, but offsetting savings are likely elsewhere in the health service. Risks include increased dependence on clinicians, inadvertent disclosure of confidential information, and communication failures, which are mostly mitigated by young people and clinicians using common-sense approaches. Conclusions As NHS policy prompts more widespread use of digital communication to improve the health care experience, our findings suggest that benefit is most likely, and harms are mitigated, when digital communication is used with patients who already have a relationship of trust with the clinical team, and where there is identifiable need for patients to have flexible access, such as when transitioning between services, treatments, or lived context. Clinical teams need a proactive approach to ethics, governance, and patient safety.