Digital pathology for reporting histopathology samples, including cancer screening samples - definitive evidence from a multisite study.

AIMS: To conduct a definitive multicentre comparison of digital pathology (DP) with light microscopy (LM) for reporting histopathology slides including breast and bowel cancer screening samples. METHODS: A total of 2024 cases (608 breast, 607 GI, 609 skin, 200 renal) were studied, including 207 breast and 250 bowel cancer screening samples. Cases were examined by four pathologists (16 study pathologists across the four speciality groups), using both LM and DP, with the order randomly assigned and 6 weeks between viewings. Reports were compared for clinical management concordance (CMC), meaning identical diagnoses plus differences which do not affect patient management. Percentage CMCs were computed using logistic regression models with crossed random-effects terms for case and pathologist. The obtained percentage CMCs were referenced to 98.3% calculated from previous studies. RESULTS: For all cases LM versus DP comparisons showed the CMC rates were 99.95% [95% confidence interval (CI) = 99.90-99.97] and 98.96 (95% CI = 98.42-99.32) for cancer screening samples. In speciality groups CMC for LM versus DP showed: breast 99.40% (99.06-99.62) overall and 96.27% (94.63-97.43) for cancer screening samples; [gastrointestinal (GI) = 99.96% (99.89-99.99)] overall and 99.93% (99.68-99.98) for bowel cancer screening samples; skin 99.99% (99.92-100.0); renal 99.99% (99.57-100.0). Analysis of clinically significant differences revealed discrepancies in areas where interobserver variability is known to be high, in reads performed with both modalities and without apparent trends to either. CONCLUSIONS: Comparing LM and DP CMC, overall rates exceed the reference 98.3%, providing compelling evidence that pathologists provide equivalent results for both routine and cancer screening samples irrespective of the modality used.

Adjusting for treatment selection in phase II/III clinical trials with time to event data.

Phase II/III clinical trials are efficient two-stage designs that test multiple experimental treatments. In stage 1, patients are allocated to the control and all experimental treatments, with the data collected from them used to select experimental treatments to continue to stage 2. Patients recruited in stage 2 are allocated to the selected treatments and the control. Combined data of stage 1 and stage 2 are used for a confirmatory phase III analysis. Appropriate analysis needs to adjust for selection bias of the stage 1 data. Point estimators exist for normally distributed outcome data. Extending these estimators to time to event data is not straightforward because treatment selection is based on correlated treatment effects and stage 1 patients who do not get events in stage 1 are followed-up in stage 2. We have derived an approximately uniformly minimum variance conditional unbiased estimator (UMVCUE) and compared its biases and mean squared errors to existing bias adjusted estimators. In simulations, one existing bias adjusted estimator has similar properties as the practically unbiased UMVCUE while the others can have noticeable biases but they are less variable than the UMVCUE. For confirmatory phase II/III clinical trials where unbiased estimators are desired, we recommend the UMVCUE or the existing estimator with which it has similar properties.

CORRECTED ARTICLE: Effect of Dietary Potassium Restriction on Serum Potassium, Disease Progression, and Mortality in Chronic Kidney Disease: A Systematic Review and Meta-Analysis.

OBJECTIVE: Low-potassium diets are recommended to reduce serum potassium (Sk) and prevent complications of chronic kidney disease (CKD), but evidence underpinning this recommendation has not been systematically reviewed and synthesized. We conducted a systematic review comparing change in Sk, CKD progression, and mortality between those on a low-potassium versus unrestricted potassium diet. METHODS: We searched Medline, AMED, PsycINFO, CINAHL, Cochrane Central Register of Controlled Trials, and Clinicaltrials.org from inception to 3 April 2018. We included randomized and observational studies that compared these outcomes in adults with CKD who ate a restricted versus unrestricted amount of dietary potassium. We pooled mean change in Sk and adjusted hazard ratios of disease progression and mortality using random-effects meta-analyses. RESULTS: We identified 5,563 articles, of which seven studies (3,489 participants) met our inclusion criteria. We found very low-quality evidence that restricted (1,295 mg/d) versus unrestricted (1,570 mg/d) dietary potassium lowered Sk by -0.22 mEq/L (95% confidence interval [CI]: -0.33, -0.10; I2 = 0%). Higher (4,558 mg/d) versus lower (1,725 mg/d) dietary potassium was not significantly associated with disease progression (hazard ratio [HR]: 1.14, 95% CI: [0.77, 1.70] I² = 57%). Higher (4,414 mg/d) compared with lower (1,670 mg/d) dietary potassium intake was not significantly associated with reduced mortality risk (HR: 0.80, 95% CI: [0.46, 1.41] I² = 78%). CONCLUSIONS: Very-low-quality evidence supports consensus that dietary potassium restriction reduces Sk in normokalemia but whether this is associated with risk of death in those with CKD is uncertain. High-quality randomized controlled trials are needed.

Utilisation of pharmacy-based sexual and reproductive health services: a quantitative retrospective study.

OBJECTIVES: To explore the utilisation of pharmacy-based sexual and reproductive health services (SRHS) in order to optimise delivery and identify barriers to access. METHODS: The health provider Umbrella offers six SRHS from over 120 pharmacies in Birmingham (England). In this retrospective study, data collected between August 2015 and August 2018 were used to analyse uptake, user characteristics and attendance patterns according to day of the week. RESULTS: A total of 60 498 requests for a pharmacy service were included in the analysis. Emergency contraception (50.4%), condoms (33.1%) and STI self-sampling kits (9.6%) accounted for more than 90% of all requests. A lower uptake of services was observed for the contraceptive injection (0.6%), oral contraception (5.4%) and chlamydia treatment (1.0%). Services were most likely to be requested by those self-identifying as female (85.6%), and those aged 16-24 years (53.8%). Based on available ethnicity data (n=54 668), most requests for a service were made by White/White British individuals (43.4%) and Asian/Asian British people (23.1%). The largest number of services were delivered on Mondays (20.9%) and the lowest on Sundays (5.0%). A high proportion of requests for services on Saturdays (57.0%), Sundays (67.6%) and Mondays (54.4%) were made by females presenting for emergency contraception. CONCLUSION: The evaluation of healthcare utilisation is important to help refine and optimise the delivery of services. However, information relating to pharmacy-based SRHS is scarce and often limited to a single type of service provision. Overall, a wide range of pharmacy-based services were accessed by a diverse range of people, suggesting that pharmacies are a suitable provider of many SRHS. However, the routinely collected data analysed in the study had several limitations restricting the analysis. Sexual health providers should ensure they collect data which are as comprehensive as is possible in order to help understand the utilisation of services.

Point and interval estimation in two-stage adaptive designs with time to event data and biomarker-driven subpopulation selection.

In personalized medicine, it is often desired to determine if all patients or only a subset of them benefit from a treatment. We consider estimation in two-stage adaptive designs that in stage 1 recruit patients from the full population. In stage 2, patient recruitment is restricted to the part of the population, which, based on stage 1 data, benefits from the experimental treatment. Existing estimators, which adjust for using stage 1 data for selecting the part of the population from which stage 2 patients are recruited, as well as for the confirmatory analysis after stage 2, do not consider time to event patient outcomes. In this work, for time to event data, we have derived a new asymptotically unbiased estimator for the log hazard ratio and a new interval estimator with good coverage probabilities and probabilities that the upper bounds are below the true values. The estimators are appropriate for several selection rules that are based on a single or multiple biomarkers, which can be categorical or continuous.

Effect of Dietary Potassium Restriction on Serum Potassium, Disease Progression, and Mortality in Chronic Kidney Disease: A Systematic Review and Meta-Analysis.

OBJECTIVE: Low-potassium diets are recommended to reduce serum potassium (Sk) and prevent complications of chronic kidney disease (CKD), but evidence underpinning this recommendation has not been systematically reviewed and synthesized. We conducted a systematic review comparing change in Sk, CKD progression, and mortality between those on a low-potassium versus unrestricted potassium diet. METHODS: We searched Medline, AMED, PsycINFO, CINAHL, Cochrane Central Register of Controlled Trials, and Clinicaltrials.org from inception to 3 April 2018. We included randomized and observational studies that compared these outcomes in adults with CKD who ate a restricted versus unrestricted amount of dietary potassium. We pooled mean change in Sk and adjusted hazard ratios of disease progression and mortality using random-effects meta-analyses. RESULTS: We identified 5,563 articles, of which seven studies (3,489 participants) met our inclusion criteria. We found very low-quality evidence that restricted (1,295 mg/d) versus unrestricted (1,570 mg/d) dietary potassium lowered Sk by -0.22 mEq/L (95% confidence interval [CI]: -0.33, -0.10; I2 = 0%). Lower (1,725 mg/d) versus higher (4,558 mg/d) dietary potassium was not significantly associated with disease progression (hazard ratio [HR]: 1.14; 95% CI: 0.77, 1.70; I2 = 57%). Lower (1,670 mg/d), compared with higher (4,414 mg/d) dietary potassium intake was associated with a 40% reduction in mortality hazard (HR: 0.60; 95% CI: 0.40, 0.89; I2 = 56%). CONCLUSIONS: Very-low-quality evidence supports consensus that dietary potassium restriction reduces Sk in normokalemia and is associated with a reduced risk of death in those with CKD. High-quality randomized controlled trials are needed.

Point estimation following two-stage adaptive threshold enrichment clinical trials.

Recently, several study designs incorporating treatment effect assessment in biomarker-based subpopulations have been proposed. Most statistical methodologies for such designs focus on the control of type I error rate and power. In this paper, we have developed point estimators for clinical trials that use the two-stage adaptive enrichment threshold design. The design consists of two stages, where in stage 1, patients are recruited in the full population. Stage 1 outcome data are then used to perform interim analysis to decide whether the trial continues to stage 2 with the full population or a subpopulation. The subpopulation is defined based on one of the candidate threshold values of a numerical predictive biomarker. To estimate treatment effect in the selected subpopulation, we have derived unbiased estimators, shrinkage estimators, and estimators that estimate bias and subtract it from the naive estimate. We have recommended one of the unbiased estimators. However, since none of the estimators dominated in all simulation scenarios based on both bias and mean squared error, an alternative strategy would be to use a hybrid estimator where the estimator used depends on the subpopulation selected. This would require a simulation study of plausible scenarios before the trial.

Is there sufficient evidence for a causal association between antiretroviral therapy and diabetes in HIV-infected patients? A meta-analysis.

The association of antiretroviral therapy (ART) with diabetes is inconsistent and varies widely across primary epidemiological studies. A comprehensive and more precise estimate of this association is fundamental to establishing a plausible causal link between ART and diabetes. We identified epidemiological studies that compared mean fasting plasma glucose (FPG) concentrations and proportions of diabetes and metabolic syndrome between HIV-infected patients naïve and exposed to ART. Mean difference in FPG concentrations and odds ratios of diabetes and metabolic syndrome were pooled using random-effects meta-analyses. Data on 20 178 participants from 41 observational studies were included in the meta-analyses. Mean FPG concentrations (Pooled mean difference: 4.66 mg/dL; 95% confidence interval [CI], 2.52 to 6.80; 24 studies) and the odds of diabetes (Pooled odds ratios: 3.85; 95% CI, 2.93 to 5.07; 10 studies) and metabolic syndrome (Pooled odds ratios: 1.45; 95% CI, 1.03 to 2.03; 18 studies) were significantly higher among ART-exposed patients, compared to their naïve counterparts. ART was also associated with significant increases in FPG levels in studies with mean ART duration ≥18 months (Pooled mean difference: 4.97 mg/dL; 95% CI, 3.10 to 6.84; 14 studies), but not in studies with mean ART duration <18 months (Pooled mean difference: 4.40 mg/dL, 95% CI, -0.59 to 9.38; 7 studies). ART may potentially be the single most consistent determinant of diabetes in people living with HIV worldwide. However, given the preponderance of cross-sectional studies in the meta-analysis, the association between ART and diabetes cannot be interpreted as cause and effect.

Timely Digital Patient-Clinician Communication in Specialist Clinical Services for Young People: A Mixed-Methods Study (The LYNC Study).

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.

Front of neck access: A survey among anesthetists and surgeons.

BACKGROUND AND AIMS: Emergency front of neck access (FONA) is the final step in a Can't Intubate-Can't Oxygenate (CICO) scenario. In view of maintaining simplicity and promoting standardized training, the 2015 Difficult Airway Society guidelines recommend surgical cricothyroidotomy using scalpel, bougie, and tube (SBT) as the preferred technique. MATERIAL AND METHODS: We undertook a survey over a 2-week period to evaluate the knowledge and training, preferred rescue technique, and confidence in performing the SBT technique. Data were collected from both anesthetists and surgeons. RESULTS: One hundred and eighty-nine responses were collected across four hospitals in the United Kingdom. The majority of participants were anesthetists (55%). One hundred and eleven (59%) respondents were aware of the national guidelines (96.2% among anesthetists and 12.9% among surgeons). Only 71 (37.6%) respondents indicated that they had formal FONA training within the last one year. Seventy-five anesthetists (72.8%) knew that SBT equipment was readily available in their department, while most surgeons (81.2%) did not know what equipment available. One hundred and five (55.5%) respondents were confident in performing surgical cricothyroidotomy in a situation where the membrane was palpable and only in 33 (17.5%) where the cricothyroid membrane was not palpable. CONCLUSION: This survey has demonstrated that despite evidence of good training for anesthetists in FONA, there are still shortfalls in the training and knowledge of our surgical colleagues. In an emergency, surgeons may be required to assist or secure an airway in a CICO situation. Regular multidisciplinary training of all clinicians working with anesthetized patients should be encouraged and supported.

Validation of digital pathology imaging for primary histopathological diagnosis.

AIMS: 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. METHODS AND RESULTS: Seventeen pathologists re-reported 3017 cases by DP. Of these, 1009 were re-reported by the same pathologist, and 2008 by a different pathologist. Re-examination of 10 138 scanned slides (2.22 terabytes) produced 72 variances between GS and DP reports, including 21 clinically significant variances. Ground truth lay with GS in 12 cases and with DP in nine cases. These results are within the 95% confidence interval for existing intraobserver and interobserver variability, proving that DP is non-inferior to GS. In three cases, the digital platform was deemed to be responsible for the variance, including a gastric biopsy, where Helicobacter pylori only became visible on slides scanned at the ×60 setting, and a bronchial biopsy and penile biopsy, where dysplasia was reported on DP but was not present on GS. CONCLUSIONS: This is one of the largest studies proving that DP is equivalent to GS for the diagnosis of histopathology specimens. Error rates are similar in both platforms, although some problems e.g. detection of bacteria, are predictable.

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

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.

During the development of new therapies, it is not uncommon to test whether a new treatment works better than the existing treatment for all patients who suffer from a condition (full population) or for a subset of the full population (subpopulation). One approach that may be used for this objective is to have two separate trials, where in the first trial, data are collected to determine if the new treatment benefits the full population or the subpopulation. The second trial is a confirmatory trial to test the new treatment in the population selected in the first trial. In this paper, we consider the more efficient two-stage adaptive seamless designs (ASDs), where in stage 1, data are collected to select the population to test in stage 2. In stage 2, additional data are collected to perform confirmatory analysis for the selected population. Unlike the approach that uses two separate trials, for ASDs, stage 1 data are also used in the confirmatory analysis. Although ASDs are efficient, using stage 1 data both for selection and confirmatory analysis introduces selection bias and consequently statistical challenges in making inference. We will focus on point estimation for such trials. In this paper, we describe the extent of bias for estimators that ignore multiple hypotheses and selecting the population that is most likely to give positive trial results based on observed stage 1 data. We then derive conditionally unbiased estimators and examine their mean squared errors for different scenarios.

A comparison of methods for constructing confidence intervals after phase II/III clinical trials.

Recently, in order to accelerate drug development, trials that use adaptive seamless designs such as phase II/III clinical trials have been proposed. Phase II/III clinical trials combine traditional phases II and III into a single trial that is conducted in two stages. Using stage 1 data, an interim analysis is performed to answer phase II objectives and after collection of stage 2 data, a final confirmatory analysis is performed to answer phase III objectives. In this paper we consider phase II/III clinical trials in which, at stage 1, several experimental treatments are compared to a control and the apparently most effective experimental treatment is selected to continue to stage 2. Although these trials are attractive because the confirmatory analysis includes phase II data from stage 1, the inference methods used for trials that compare a single experimental treatment to a control and do not have an interim analysis are no longer appropriate. Several methods for analysing phase II/III clinical trials have been developed. These methods are recent and so there is little literature on extensive comparisons of their characteristics. In this paper we review and compare the various methods available for constructing confidence intervals after phase II/III clinical trials.

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

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.

Validation of the Mothers Object Relations scales in 2-4 year old children and comparison with the Child-Parent Relationship Scale.

BACKGROUND: The quality of the parent-child relationship has an important effect on a wide range of child outcomes. The evaluation of interventions to promote healthy parenting and family relationships is dependent on outcome measures which can quantify the quality of parent-child relationships. Between the Mothers' Object Relations - Short Form (MORS-SF) scale for babies and the Child-parent Relationship Scale (C-PRS) there is an age gap where no validated scales are available. We report the development and testing of an adaptation of the MORS-SF; the MORS (Child) scale and its use in children from the age of 2 years to 4 years. This scale aims to capture the nature of the parent-child relationship in a form which is short enough to be used in population surveys and intervention evaluations. METHODS: Construct and criterion validity, item salience and internal consistency were assessed in a sample of 166 parents of children aged 2-4 years old and compared with that of the C-PRS. The performance of the MORS (Child) as part of a composite measure with the HOME inventory was compared with that of the C-PRS using data collected in a randomised controlled trial and the national evaluation of Sure Start. RESULTS: MORS (Child) performed well in children aged 2-4 with high construct and criterion validity, item salience and internal consistency. One item in the C-PRS failed to load on either subscale and parents found this scale slightly more difficult to complete than the MORS (Child). The two measures performed very similarly in a factor analysis with the HOME inventory producing almost identical loadings. CONCLUSIONS: Adapting the MORS-SF for children aged 2-4 years old produces a scale to assess parent-child relationships that is easy to use and outperforms the more commonly used C-PRS in several respects.

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 $438 per participant for electronic ALS training and $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).

Rising arterial stiffness with accumulating comorbidities associates with heart failure with preserved ejection fraction.

AIMS: Comorbidities play a significant role towards the pathophysiology of heart failure with preserved ejection fraction (HFpEF), characterized by abnormal macrovascular function and altered ventricular-vascular coupling. However, our understanding of the role of comorbidities and arterial stiffness in HFpEF remains incomplete. We hypothesized that HFpEF is preceded by a cumulative rise in arterial stiffness as cardiovascular comorbidities accumulate, beyond that associated with ageing. METHODS AND RESULTS: Arterial stiffness was assessed using pulse wave velocity (PWV) in five groups: Group A, healthy volunteers (n = 21); Group B, patients with hypertension (n = 21); Group C, hypertension and diabetes mellitus (n = 20); Group D, HFpEF (n = 21); and Group E, HF with reduced ejection fraction (HFrEF) (n = 11). All patients were aged 70 and above. Mean PWV increased from Groups A to D (PWV 10.2, 12.2, 13.0, and 13.7 m/s, respectively) as vascular comorbidities accumulated independent of age, renal function, haemoglobin, obesity (body mass index), smoking status, and hypercholesterolaemia. HFpEF exhibited the highest PWV and HFrEF displayed near-normal levels (13.7 vs. 10 m/s, P = 0.003). PWV was inversely related to peak oxygen consumption (r = -0.304, P = 0.03) and positively correlated with left ventricular filling pressures (E/e') on echocardiography (r = -0.307, P = 0.014). CONCLUSIONS: This study adds further support to the concept of HFpEF as a disease of the vasculature, underlined by an increasing arterial stiffness that is driven by vascular ageing and accumulating vascular comorbidities, for example, hypertension and diabetes. Reflecting a pulsatile arterial afterload associated with diastolic dysfunction and exercise capacity, PWV may provide a clinically relevant tool to identify at-risk intermediate phenotypes (e.g. pre-HFpEF) before overt HFpEF occurs.

Practical guidelines for adaptive seamless phase II/III clinical trials that use Bayesian methods.

Hommel (Biometrical Journal; 45:581-589) proposed a flexible testing procedure for seamless phase II/III clinical trials. Schmidli et al. (Statistics in Medicine; 26:4925-4938), Kimani et al. (Statistics in Medicine; 28:917-936) and Brannath et al. (Statistics in Medicine; 28:1445-1463) exploited the flexible testing of Hommel to propose adaptation in seamless phase II/III clinical trials that incorporate prior knowledge by using Bayesian methods. In this paper, we show that adaptation incorporating prior knowledge may lead to higher power. Other important issues to consider in such adaptive designs are the gain in power (or saving in patients) over traditional testing and how utility values used to make the adaptation may be used to stop a trial early. In contrast to the aforementioned authors, we discuss these issues in detail and propose a unified approach to address them so that implementing the aforementioned designs and proposing similar designs is clearer.