Safety and immunogenicity of ChAd63-KH vaccine in post-kala-azar dermal leishmaniasis patients in Sudan.

Post-kala-azar dermal leishmaniasis (PKDL) is a chronic, stigmatizing skin condition occurring frequently after apparent clinical cure from visceral leishmaniasis. Given an urgent need for new treatments, we conducted a phase IIa safety and immunogenicity trial of ChAd63-KH vaccine in Sudanese patients with persistent PKDL. LEISH2a (ClinicalTrials.gov: NCT02894008) was an open-label three-phase clinical trial involving sixteen adult and eight adolescent patients with persistent PKDL (median duration, 30 months; range, 6-180 months). Patients received a single intramuscular vaccination of 1 × 1010 viral particles (v.p.; adults only) or 7.5 × 1010 v.p. (adults and adolescents), with primary (safety) and secondary (clinical response and immunogenicity) endpoints evaluated over 42-120 days follow-up. AmBisome was provided to patients with significant remaining disease at their last visit. ChAd63-KH vaccine showed minimal adverse reactions in PKDL patients and induced potent innate and cell-mediated immune responses measured by whole-blood transcriptomics and ELISpot. 7/23 patients (30.4%) monitored to study completion showed >90% clinical improvement, and 5/23 (21.7%) showed partial improvement. A logistic regression model applied to blood transcriptomic data identified immune modules predictive of patients with >90% clinical improvement. A randomized controlled trial to determine whether these clinical responses were vaccine-related and whether ChAd63-KH vaccine has clinical utility is underway.

Performance status and trial site-level factors are associated with missing data in palliative care trials: An individual participant-level data analysis of 10 phase 3 trials.

BACKGROUND: Missing data compromise the internal and external validity of trial findings, however there is limited evidence on how best to reduce missing data in palliative care trials. AIM: To assess the association between participant and site level factors and missing data in palliative care trials. DESIGN AND SETTING: Individual participant-level data analysis of 10 phase 3 palliative care trials using multi-level cross-classified models. RESULTS: Participants with missing data at the previous time-point and poorer performance status were more likely to have missing data for the primary outcome and quality of life outcomes, at the primary follow-up point and end of follow-up. At the end of follow-up, the number of site randomisations and number of study site personnel were significantly associated with missing data. Trial duration and the number of research personnel explained most of the variance at the trial and site-level respectively, except for the primary outcome where the amount of data requested was most important at the trial-level. Variance at the trial level was more substantial than at the site level across models and considerable variance remained unexplained for all models except quality of life at the end of follow-up. CONCLUSION: Participants with a poorer performance status are at higher risk of missing data in palliative care trials and require additional support to provide complete data. Performance status is a potential auxiliary variable for missing data imputation models. Reducing trial variability should be prioritised and further factors need to be identified and explored to explain the residual variance.

Doug Altman: Driving critical appraisal and improvements in the quality of methodological and medical research.

Doug Altman was a visionary leader and one of the most influential medical statisticians of the last 40 years. Based on a presentation in the "Invited session in memory of Doug Altman" at the 40th Annual Conference of the International Society for Clinical Biostatistics (ISCB) in Leuven, Belgium and our long-standing collaborations with Doug, we discuss his contributions to regression modeling, reporting, prognosis research, as well as some more general issues while acknowledging that we cannot cover the whole spectrum of Doug's considerable methodological output. His statement "To maximize the benefit to society, you need to not just do research but do it well" should be a driver for all researchers. To improve current and future research, we aim to summarize Doug's messages for these three topics.

Airflow relieves chronic breathlessness in people with advanced disease: An exploratory systematic review and meta-analyses.

BACKGROUND: Chronic breathlessness is a neglected symptom of advanced diseases. AIM: To examine the effect of airflow for chronic breathlessness relief. DESIGN: Exploratory systematic review and meta-analysis. DATA SOURCES: Medline, CINAHL, AMED and Cochrane databases were searched (1985-2018) for observational studies or randomised controlled trials of airflow as intervention or comparator. Selection against predefined inclusion criteria, quality appraisal and data extraction was conducted by two independent reviewers with access to a third for unresolved differences. 'Before and after' breathlessness measures from airflow arms were analysed. Meta-analysis was carried out where possible. RESULTS: In all, 16 of 78 studies (n = 929) were included: 11 randomised controlled trials of oxygen versus medical air, 4 randomised controlled trials and 1 fan cohort study. Three meta-analyses were possible: (1) Fan at rest in three studies (n = 111) offered significant benefit for breathlessness intensity (0-100 mm visual analogue scale and 0-10 numerical rating scale), mean difference -11.17 (95% confidence intervals (CI) -16.60 to -5.74), p = 0.06 I2 64%. (2) Medical air via nasal cannulae at rest in two studies (n = 89) improved breathlessness intensity (visual analogue scale), mean difference -12.0 mm, 95% CI -7.4 to -16.6, p < 0.0001 I2 = 0%. (3) Medical airflow during a constant load exercise test before and after rehabilitation (n = 29) in two studies improved breathlessness intensity (modified Borg scale, 0-10), mean difference -2.9, 95% CI -3.2 to -2.7, p < 0.0001 I2 = 0%. CONCLUSION: Airflow appears to offer meaningful relief of chronic breathlessness and should be considered as an adjunct treatment in the management of breathlessness.

Effectiveness and Cost-effectiveness of Opportunistic Screening and Stepped-care Interventions for Older Alcohol Users in Primary Care.

AIMS: To compare the clinical effectiveness and cost-effectiveness of a stepped-care intervention versus a minimal intervention for the treatment of older hazardous alcohol users in primary care. METHOD: Multi-centre, pragmatic RCT, set in Primary Care in UK. Patients aged ≥ 55 years scoring ≥ 8 on the Alcohol Use Disorders Identification Test were allocated either to 5-min of brief advice or to 'Stepped Care': an initial 20-min of behavioural change counselling, with Step 2 being three sessions of Motivational Enhancement Therapy and Step 3 referral to local alcohol services (progression between each Step being determined by outcomes 1 month after each Step). Outcome measures included average drinks per day, AUDIT-C, alcohol-related problems using the Drinking Problems Index, health-related quality of life using the Short Form 12, costs measured from a NHS/Personal Social Care perspective and estimated health gains in quality adjusted life-years measured assessed EQ-5D. RESULTS: Both groups reduced alcohol consumption at 12 months but the difference between groups was small and not significant. No significant differences were observed between the groups on secondary outcomes. In economic terms stepped care was less costly and more effective than the minimal intervention. CONCLUSIONS: Stepped care does not confer an advantage over a minimal intervention in terms of reduction in alcohol use for older hazardous alcohol users in primary care. However, stepped care has a greater probability of being more cost-effective. TRIAL REGISTRATION: Current controlled trials ISRCTN52557360. SHORT SUMMARY: A stepped care approach was compared with brief intervention for older at-risk drinkers attending primary care. While consumption reduced in both groups over 12 months there was no significant difference between the groups. An economic analysis indicated the stepped care which had a greater probability of being more cost-effective than brief intervention.

Seroprevalence of HTLV-1 and HTLV-2 amongst mothers and children in Malawi within the context of a systematic review and meta-analysis of HTLV seroprevalence in Africa.

OBJECTIVES: Human T-lymphotropic virus (HTLV)-1 causes T-cell leukaemia and myelopathy. Together with HTLV-2, it is endemic in some African nations. Seroprevalence data from Malawi are scarce, with no reports on associated disease incidence. HTLV seroprevalence and type were tested in 418 healthy mothers from Malawi. In addition, we tested the sera of 534 children to investigate mother-to-child transmission. To provide context, we conducted a systematic review and meta-analysis of HTLV seroprevalence in African women and children. METHODS: Stored samples from a previous childhood cancer and BBV study were analysed. ELISA was used for HTLV screening followed by immunoblot for confirmation and typing. Standard methods were used for the systematic review. RESULTS: HTLV seroprevalence was 2.6% (11/418) in mothers and 2.2% (12/534) in children. Three mothers carried HTLV-1 alone, seven had HTLV-2 and one was dually infected. Three children carried HTLV-1 alone, seven had HTLV-2 and two were dually infected. Only two corresponding mothers of the 12 HTLV-positive children were HTLV positive. The systematic review included 66 studies of women and 13 of children conducted in 25 African countries. Seroprevalence of HTLV-1 varied from 0 to 17% and of HTLV-2 from 0 to 4%. CONCLUSIONS: In contrast to findings from other studies in Africa, the seroprevalence of HTLV-2 was higher than that of HTLV-1 in Malawi and one of the highest for the African region. The lack of mother-child concordance suggests alternative sources of infection among children. Our data and analyses contribute to HTLV prevalence mapping in Africa.

Alexander Technique Lessons or Acupuncture Sessions for Persons With Chronic Neck Pain: A Randomized Trial.

BACKGROUND: Management of chronic neck pain may benefit from additional active self-care-oriented approaches. OBJECTIVE: To evaluate clinical effectiveness of Alexander Technique lessons or acupuncture versus usual care for persons with chronic, nonspecific neck pain. DESIGN: Three-group randomized, controlled trial. (Current Controlled Trials: ISRCTN15186354). SETTING: U.K. primary care. PARTICIPANTS: Persons with neck pain lasting at least 3 months, a score of at least 28% on the Northwick Park Questionnaire (NPQ) for neck pain and associated disability, and no serious underlying pathology. INTERVENTION: 12 acupuncture sessions or 20 one-to-one Alexander lessons (both 600 minutes total) plus usual care versus usual care alone. MEASUREMENTS: NPQ score (primary outcome) at 0, 3, 6, and 12 months (primary end point) and Chronic Pain Self-Efficacy Scale score, quality of life, and adverse events (secondary outcomes). RESULTS: 517 patients were recruited, and the median duration of neck pain was 6 years. Mean attendance was 10 acupuncture sessions and 14 Alexander lessons. Between-group reductions in NPQ score at 12 months versus usual care were 3.92 percentage points for acupuncture (95% CI, 0.97 to 6.87 percentage points) (P = 0.009) and 3.79 percentage points for Alexander lessons (CI, 0.91 to 6.66 percentage points) (P = 0.010). The 12-month reductions in NPQ score from baseline were 32% for acupuncture and 31% for Alexander lessons. Participant self-efficacy improved for both interventions versus usual care at 6 months (P < 0.001) and was significantly associated (P < 0.001) with 12-month NPQ score reductions (acupuncture, 3.34 percentage points [CI, 2.31 to 4.38 percentage points]; Alexander lessons, 3.33 percentage points [CI, 2.22 to 4.44 percentage points]). No reported serious adverse events were considered probably or definitely related to either intervention. LIMITATION: Practitioners belonged to the 2 main U.K.-based professional associations, which may limit generalizability of the findings. CONCLUSION: Acupuncture sessions and Alexander Technique lessons both led to significant reductions in neck pain and associated disability compared with usual care at 12 months. Enhanced self-efficacy may partially explain why longer-term benefits were sustained. PRIMARY FUNDING SOURCE: Arthritis Research UK.

Effectiveness of Transdiagnostic Cognitive Behaviour Therapy for Anxiety and Depression in Adults: A Systematic Review and Meta-analysis.

BACKGROUND: Transdiagnostic Cognitive Behaviour Therapy (CBT) seeks to identify core cognitive-behavioural processes hypothesized to be important across a range of disorders and to develop a treatment that targets these. This contrasts with standard CBT approaches that are disorder-specific. Proponents of transdiagnostic CBT suggest that it may offer advantages over disorder-specific CBT, but little is known about the effectiveness of this approach. AIMS: The review aimed to summarize trial-based clinical and cost-effectiveness data on transdiagnostic CBT for anxiety and depression. METHOD: A systematic review of electronic databases, including peer-reviewed and grey literature sources, was conducted (n = 1167 unique citations). RESULTS: Eight trials were eligible for inclusion in the review. There was evidence of an effect for transdiagnostic CBT when compared to a control condition. There were no differences between transdiagnostic CBT and active treatments in two studies. We found no evidence of cost-effectiveness data. CONCLUSIONS: Quality assessment of the primary studies indicated a number of methodological concerns that may serve to inflate the observed effects of transdiagnostic approaches. Although there are positive signs of the value of transdiagnostic CBT, there is as yet insufficient evidence to recommend its use in place of disorder-specific CBT.

Alcohol screening and brief interventions for offenders in the probation setting (SIPS Trial): a pragmatic multicentre cluster randomized controlled trial.

AIM: To evaluate the effectiveness of different brief intervention strategies at reducing hazardous or harmful drinking in the probation setting. Offender managers were randomized to three interventions, each of which built on the previous one: feedback on screening outcome and a client information leaflet control group, 5 min of structured brief advice and 20 min of brief lifestyle counselling. METHODS: A pragmatic multicentre factorial cluster randomized controlled trial. The primary outcome was self-reported hazardous or harmful drinking status measured by Alcohol Use Disorders Identification Test (AUDIT) at 6 months (negative status was a score of <8). Secondary outcomes were AUDIT status at 12 months, experience of alcohol-related problems, health utility, service utilization, readiness to change and reduction in conviction rates. RESULTS: Follow-up rates were 68% at 6 months and 60% at 12 months. At both time points, there was no significant advantage of more intensive interventions compared with the control group in terms of AUDIT status. Those in the brief advice and brief lifestyle counselling intervention groups were statistically significantly less likely to reoffend (36 and 38%, respectively) than those in the client information leaflet group (50%) in the year following intervention. CONCLUSION: Brief advice or brief lifestyle counselling provided no additional benefit in reducing hazardous or harmful drinking compared with feedback on screening outcome and a client information leaflet. The impact of more intensive brief intervention on reoffending warrants further research.

Do nurses reason 'adaptively' in time limited situations: the findings of a descriptive regression analysis.

BACKGROUND: Time pressure is common in acute healthcare and significantly influences clinical judgement and decision making. Despite nurses' judgements being studied since the 1960s, the empirical picture of how time pressure impacts on nurses' judgement strategies and outcomes remain undeveloped. This paper aims to assess alterations in nurses' judgement strategies and outcomes under time pressure in a simulated acute care setting. METHODS: In a simulated acute care environment, ninety-seven nurses were exposed to 25 clinical scenarios under time pressured and no time pressured conditions. Scenarios were randomly sampled from a large dataset of patient cases. A reference standard (judgement correctness) was generated from the same patient case records. In 12 of the scenarios only 20 seconds per judgement was allowed, in the other 13 scenarios no time pressure existed. Percentage of correct judgments in both conditions was calculated. Logistic regression modelling (of 2,425 observations) described the relationship between information cues used and judgments made. The degree of attention paid to particular cues was captured by calculating cue relative weights. The clustering effect of nurses was countered by estimating robust standard errors. The Chow test was used to test the null hypothesis that differences in regression coefficients in time pressure and no time pressure models were zero. RESULTS: Compared to no time pressure, no significant difference was observed in the proportion of correct judgments when nurses were put under time pressure. However, time pressure significantly impacted on the judgment strategies employed. Whilst nurses predominantly used respiration rate to make judgements, they used fewer cues to reach their clinical judgements under time pressure. The relative weighting afforded to heart rate was much smaller in the time pressure regression model, indicating that nurses paid significantly less attention to it when making judgements under time pressure. CONCLUSIONS: Time pressure had a significant effect on nurses' judgement strategies but not outcomes. Nurses tended to use less information to reach judgements under time pressure, but not at the expense of judgment accuracy. Findings imply that nurses are capable of using adaptive judgement strategies to cope with moderate time pressures when making clinical judgements in acute care.

Acupuncture and counselling for depression in primary care: a randomised controlled trial.

BACKGROUND: Depression is a significant cause of morbidity. Many patients have communicated an interest in non-pharmacological therapies to their general practitioners. Systematic reviews of acupuncture and counselling for depression in primary care have identified limited evidence. The aim of this study was to evaluate acupuncture versus usual care and counselling versus usual care for patients who continue to experience depression in primary care. METHODS AND FINDINGS: In a randomised controlled trial, 755 patients with depression (Beck Depression Inventory BDI-II score ≥ 20) were recruited from 27 primary care practices in the North of England. Patients were randomised to one of three arms using a ratio of 2.2.1 to acupuncture (302), counselling (302), and usual care alone (151). The primary outcome was the difference in mean Patient Health Questionnaire (PHQ-9) scores at 3 months with secondary analyses over 12 months follow-up. Analysis was by intention-to-treat. PHQ-9 data were available for 614 patients at 3 months and 572 patients at 12 months. Patients attended a mean of ten sessions for acupuncture and nine sessions for counselling. Compared to usual care, there was a statistically significant reduction in mean PHQ-9 depression scores at 3 months for acupuncture (-2.46, 95% CI -3.72 to -1.21) and counselling (-1.73, 95% CI -3.00 to -0.45), and over 12 months for acupuncture (-1.55, 95% CI -2.41 to -0.70) and counselling (-1.50, 95% CI -2.43 to -0.58). Differences between acupuncture and counselling were not significant. In terms of limitations, the trial was not designed to separate out specific from non-specific effects. No serious treatment-related adverse events were reported. CONCLUSIONS: In this randomised controlled trial of acupuncture and counselling for patients presenting with depression, after having consulted their general practitioner in primary care, both interventions were associated with significantly reduced depression at 3 months when compared to usual care alone. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN63787732 Please see later in the article for the Editors' Summary.

Meta-analysis of randomised trials with a continuous outcome according to baseline imbalance and availability of individual participant data.

We describe methods for meta-analysis of randomised trials where a continuous outcome is of interest, such as blood pressure, recorded at both baseline (pre treatment) and follow-up (post treatment). We used four examples for illustration, covering situations with and without individual participant data (IPD) and with and without baseline imbalance between treatment groups in each trial. Given IPD, meta-analysts can choose to synthesise treatment effect estimates derived using analysis of covariance (ANCOVA), a regression of just final scores, or a regression of the change scores. When there is baseline balance in each trial, treatment effect estimates derived using ANCOVA are more precise and thus preferred. However, we show that meta-analysis results for the summary treatment effect are similar regardless of the approach taken. Thus, without IPD, if trials are balanced, reviewers can happily utilise treatment effect estimates derived from any of the approaches. However, when some trials have baseline imbalance, meta-analysts should use treatment effect estimates derived from ANCOVA, as this adjusts for imbalance and accounts for the correlation between baseline and follow-up; we show that the other approaches can give substantially different meta-analysis results. Without IPD and with unavailable ANCOVA estimates, reviewers should limit meta-analyses to those trials with baseline balance. Trowman's method to adjust for baseline imbalance without IPD performs poorly in our examples and so is not recommended. Finally, we extend the ANCOVA model to estimate the interaction between treatment effect and baseline values and compare options for estimating this interaction given only aggregate data.

The effect of improving task representativeness on capturing nurses' risk assessment judgements: a comparison of written case simulations and physical simulations.

BACKGROUND: The validity of studies describing clinicians' judgements based on their responses to paper cases is questionable, because - commonly used - paper case simulations only partly reflect real clinical environments. In this study we test whether paper case simulations evoke similar risk assessment judgements to the more realistic simulated patients used in high fidelity physical simulations. METHODS: 97 nurses (34 experienced nurses and 63 student nurses) made dichotomous assessments of risk of acute deterioration on the same 25 simulated scenarios in both paper case and physical simulation settings. Scenarios were generated from real patient cases. Measures of judgement 'ecology' were derived from the same case records. The relationship between nurses' judgements, actual patient outcomes (i.e. ecological criteria), and patient characteristics were described using the methodology of judgement analysis. Logistic regression models were constructed to calculate Lens Model Equation parameters. Parameters were then compared between the modeled paper-case and physical-simulation judgements. RESULTS: Participants had significantly less achievement (ra) judging physical simulations than when judging paper cases. They used less modelable knowledge (G) with physical simulations than with paper cases, while retaining similar cognitive control and consistency on repeated patients. Respiration rate, the most important cue for predicting patient risk in the ecological model, was weighted most heavily by participants. CONCLUSIONS: To the extent that accuracy in judgement analysis studies is a function of task representativeness, improving task representativeness via high fidelity physical simulations resulted in lower judgement performance in risk assessments amongst nurses when compared to paper case simulations. Lens Model statistics could prove useful when comparing different options for the design of simulations used in clinical judgement analysis. The approach outlined may be of value to those designing and evaluating clinical simulations as part of education and training strategies aimed at improving clinical judgement and reasoning.

Sodium channel-inhibiting drugs and cancer-specific survival: a population-based study of electronic primary care data.

OBJECTIVES: Antiepileptic and antiarrhythmic drugs inhibit voltage-gated sodium (Na+) channels (VGSCs), and preclinical studies show that these medications reduce tumour growth, invasion and metastasis. We investigated the association between VGSC inhibitor use and survival in patients with breast, bowel and prostate cancer. DESIGN: Retrospective cohort study. SETTING: Individual electronic primary healthcare records extracted from the Clinical Practice Research Datalink. PARTICIPANTS: Records for 132 996 patients with a diagnosis of breast, bowel or prostate cancer. OUTCOME MEASURES: Adjusted Cox proportional hazards regression was used to analyse cancer-specific survival associated with exposure to VGSC inhibitors. Exposure to non-VGSC-inhibiting antiepileptic medication and other non-VGSC blockers were also considered. Drug exposure was treated as a time-varying covariate to account for immortal time bias. RESULTS: During 1 002 225 person-years of follow-up, there were 42 037 cancer-specific deaths. 53 724 (40.4%) patients with cancer had at least one prescription for a VGSC inhibitor of interest. Increased risk of cancer-specific mortality was associated with exposure to this group of drugs (HR 1.59, 95% CI 1.56 to 1.63, p<0.001). This applied to VGSC-inhibiting tricyclic antidepressants (HR 1.61, 95% CI 1.50 to 1.65, p<0.001), local anaesthetics (HR 1.49, 95% CI 1.43 to 1.55, p<0.001) and anticonvulsants (HR 1.40, 95% CI 1.34 to 1.48, p<0.001) and persisted in sensitivity analyses. In contrast, exposure to VGSC-inhibiting class 1c and 1d antiarrhythmics was associated with significantly improved cancer-specific survival (HR 0.75, 95% CI 0.64 to 0.88, p<0.001 and HR 0.54, 95% CI 0.33 to 0.88, p=0.01, respectively). CONCLUSIONS: Association between VGSC inhibitor use and mortality in patients with cancer varies according to indication. Exposure to VGSC-inhibiting antiarrhythmics, but not anticonvulsants, supports findings from preclinical data, with improved survival. However, additional confounding factors may underlie these associations, highlighting the need for further study.

Statistical analysis of the primary outcome in acute stroke trials.

Common outcome scales in acute stroke trials are ordered categorical or pseudocontinuous in structure but most have been analyzed as binary measures. The use of fixed dichotomous analysis of ordered categorical outcomes after stroke (such as the modified Rankin Scale) is rarely the most statistically efficient approach and usually requires a larger sample size to demonstrate efficacy than other approaches. Preferred statistical approaches include sliding dichotomous, ordinal, or continuous analyses. Because there is no best approach that will work for all acute stroke trials, it is vital that studies are designed with a full understanding of the type of patients to be enrolled (in particular their case mix, which will be critically dependent on their age and severity), the potential mechanism by which the intervention works (ie, will it tend to move all patients somewhat, or some patients a lot, and is a common hazard present), a realistic assessment of the likely effect size, and therefore the necessary sample size, and an understanding of what the intervention will cost if implemented in clinical practice. If these approaches are followed, then the risk of missing useful treatment effects for acute stroke will diminish.

The effect of clinical experience, judgment task difficulty and time pressure on nurses' confidence calibration in a high fidelity clinical simulation.

BACKGROUND: Misplaced or poorly calibrated confidence in healthcare professionals' judgments compromises the quality of health care. Using higher fidelity clinical simulations to elicit clinicians' confidence 'calibration' (i.e. overconfidence or underconfidence) in more realistic settings is a promising but underutilized tactic. In this study we examine nurses' calibration of confidence with judgment accuracy for critical event risk assessment judgments in a high fidelity simulated clinical environment. The study also explores the effects of clinical experience, task difficulty and time pressure on the relationship between confidence and accuracy. METHODS: 63 student and 34 experienced nurses made dichotomous risk assessments on 25 scenarios simulated in a high fidelity clinical environment. Each nurse also assigned a score (0-100) reflecting the level of confidence in their judgments. Scenarios were derived from real patient cases and classified as easy or difficult judgment tasks. Nurses made half of their judgments under time pressure. Confidence calibration statistics were calculated and calibration curves generated. RESULTS: Nurse students were underconfident (mean over/underconfidence score -1.05) and experienced nurses overconfident (mean over/underconfidence score 6.56), P = 0.01. No significant differences in calibration and resolution were found between the two groups (P = 0.80 and P = 0.51, respectively). There was a significant interaction between time pressure and task difficulty on confidence (P = 0.008); time pressure increased confidence in easy cases but reduced confidence in difficult cases. Time pressure had no effect on confidence or accuracy. Judgment task difficulty impacted significantly on nurses' judgmental accuracy and confidence. A 'hard-easy' effect was observed: nurses were overconfident in difficult judgments and underconfident in easy judgments. CONCLUSION: Nurses were poorly calibrated when making risk assessment judgments in a high fidelity simulated setting. Nurses with more experience tended toward overconfidence. Whilst time pressure had little effect on calibration, nurses' over/underconfidence varied significantly with the degree of task difficulty. More research is required to identify strategies to minimize such cognitive biases.

Adapting and validating the Autism Diagnostic Interview - Revised for use with deaf children and young people.

LAY ABSTRACT: Autism assessment processes need to improve for deaf children as they are currently being diagnosed later than their hearing counterparts and misdiagnosis can occur. We took one of the most commonly used parent developmental interviews for autism spectrum disorder the Autism Diagnostic Interview-Revised and adapted it using international expert advice. Modifications were proposed and agreed by the expert panel for 45% of items; the remaining 55% of items were unchanged. We then tested the revised version, adapted for deaf children (Autism Diagnostic Interview-Revised Deaf Adaptation), in a UK sample of 78 parents/carers of deaf children with autism spectrum disorder and 126 parents/carers with deaf children without autism spectrum disorder. When compared to National Institute for Health and Care Excellence guideline standard clinical assessments, the Autism Diagnostic Interview-Revised Deaf Adaptation diagnostic algorithm threshold scores could identify those deaf children with a definite diagnosis (true autism spectrum disorder positives) well (sensitivity of 89% (79%-96%)) and those deaf children who did not have autism spectrum disorder (true autism spectrum disorder negatives) well (specificity of 81% (70%-89%)). Our findings indicate that the Autism Diagnostic Interview-Revised Deaf Adaptation is likely to prove a useful measure for the assessment of deaf children with suspected autism spectrum disorder and that further research would be helpful.

Adapting and validating the Autism Diagnostic Observation Schedule Version 2 for use with deaf children and young people.

We report a Delphi Consensus modification and first validation study of the Autism Diagnostic Observation Schedule - 2 with deaf children and young people (ADOS-2 Deaf adaptation). Validation included 122 deaf participants (aged 2-18 years), 63 with an Autism Spectrum Disorder (ASD). This was compared to a National Institute for Health and Clinical Excellence (NICE) guideline standard clinical assessment by blinded independent specialist clinicians. Results showed overall sensitivity 73% (95%CI 60%, 83%); specificity 71% (95%CI 58%, 82%), and for the more common modules 1-3 (combined as in previous studies) sensitivity 79% (95% CI 65-89%); specificity 79% (95% CI 66-89%) suggesting this instrument will be a helpful addition for use with deaf children and young people.

Efficacy of Corticosteroid Therapy for HTLV-1-Associated Myelopathy: A Randomized Controlled Trial (HAMLET-P).

Corticosteroids are most commonly used to treat HTLV-1-associated myelopathy (HAM); however, their clinical efficacy has not been tested in randomized clinical trials. This randomized controlled trial included 8 and 30 HAM patients with rapidly and slowly progressing walking disabilities, respectively. Rapid progressors were assigned (1:1) to receive or not receive a 3-day course of intravenous methylprednisolone in addition to oral prednisolone therapy. Meanwhile, slow progressors were assigned (1:1) to receive oral prednisolone or placebo. The primary outcomes were a composite of ≥1-grade improvement in the Osame Motor Disability Score or ≥30% improvement in the 10 m walking time (10 mWT) at week 2 for rapid progressors and changes from baseline in 10 mWT at week 24 for slow progressors. In the rapid progressor trial, all four patients with but only one of four without intravenous methylprednisolone achieved the primary outcome (p = 0.14). In the slow progressor trial, the median changes in 10 mWT were -13.8% (95% CI: -20.1--7.1; p < 0.001) and -6.0% (95% CI: -12.8-1.3; p = 0.10) with prednisolone and placebo, respectively (p for between-group difference = 0.12). Whereas statistical significance was not reached for the primary endpoints, the overall data indicated the benefit of corticosteroid therapy. (Registration number: UMIN000023798, UMIN000024085).

Meta-analyses of adverse effects data derived from randomised controlled trials as compared to observational studies: methodological overview.

BACKGROUND: There is considerable debate as to the relative merits of using randomised controlled trial (RCT) data as opposed to observational data in systematic reviews of adverse effects. This meta-analysis of meta-analyses aimed to assess the level of agreement or disagreement in the estimates of harm derived from meta-analysis of RCTs as compared to meta-analysis of observational studies. METHODS AND FINDINGS: Searches were carried out in ten databases in addition to reference checking, contacting experts, citation searches, and hand-searching key journals, conference proceedings, and Web sites. Studies were included where a pooled relative measure of an adverse effect (odds ratio or risk ratio) from RCTs could be directly compared, using the ratio of odds ratios, with the pooled estimate for the same adverse effect arising from observational studies. Nineteen studies, yielding 58 meta-analyses, were identified for inclusion. The pooled ratio of odds ratios of RCTs compared to observational studies was estimated to be 1.03 (95% confidence interval 0.93-1.15). There was less discrepancy with larger studies. The symmetric funnel plot suggests that there is no consistent difference between risk estimates from meta-analysis of RCT data and those from meta-analysis of observational studies. In almost all instances, the estimates of harm from meta-analyses of the different study designs had 95% confidence intervals that overlapped (54/58, 93%). In terms of statistical significance, in nearly two-thirds (37/58, 64%), the results agreed (both studies showing a significant increase or significant decrease or both showing no significant difference). In only one meta-analysis about one adverse effect was there opposing statistical significance. CONCLUSIONS: Empirical evidence from this overview indicates that there is no difference on average in the risk estimate of adverse effects of an intervention derived from meta-analyses of RCTs and meta-analyses of observational studies. This suggests that systematic reviews of adverse effects should not be restricted to specific study types. Please see later in the article for the Editors' Summary.