Sally R. Wilkes

Risk and Cause of Death in Patients Diagnosed With Myeloproliferative Neoplasms in Sweden Between 1973 and 2005: A Population-Based Study

PURPOSE Myeloproliferative neoplasms (MPNs) are associated with a shortened life expectancy. We assessed causes of death in patients with MPN and matched controls using both relative risks and absolute probabilities in the presence of competing risks. PATIENTS AND METHODS From Swedish registries, we identified 9,285 patients with MPN and 35,769 matched controls. A flexible parametric model was used to estimate cause-specific hazard ratios (HRs) of death and cumulative incidence functions, each with 95% CIs. RESULTS In patients with MPN, the HRs of death from hematologic malignancies and infections were 92.8 (95% CI, 70.0 to 123.1) and 2.7 (95% CI, 2.4 to 3.1), respectively. In patients age 70 to 79 years at diagnosis (the largest patient group), the HRs of death from cardiovascular and cerebrovascular disease were 1.5 (95% CI, 1.4 to 1.7) and 1.5 (95% CI, 1.3 to 1.8), respectively; all were statistically significantly elevated compared with those of controls. In the same age group, no difference was observed in the 10-year probability of death resulting from cardiovascular disease in patients with MPN versus controls (16.8% v 15.2%) or cerebrovascular disease (5.6% v 5.2%). In patients age 50 to 59 years at diagnosis, the 10-year probability of death resulting from cardiovascular and cerebrovascular disease was elevated, 4.2% versus 2.1% and 1.9% versus 0.4%, respectively. Survival in patients with MPN increased over time, mainly because of decreased probabilities of dying as a result of hematologic malignancies, infections, and, in young patients, cardiovascular disease. CONCLUSION Patients with MPN had an overall higher mortality rate than that of matched controls, primarily because of hematologic malignancy, infections, and vascular events in younger patients. Evidently, there is still a need for effective disease-modifying agents to improve patient outcomes.

National trends in acute kidney injury requiring dialysis in England between 1998 and 2013

Acute kidney injury (AKI) severe enough to require dialysis is increasing and associated with high mortality, yet robust information about temporal epidemiology of AKI requiring dialysis in England is lacking. In this retrospective observational study of the Hospital Episode Statistics (HES) data set covering the entire English National Health Service, we identified all patients with a diagnosis of AKI requiring dialysis between 1998 and 2013. This incidence increased from 774 cases (15.9 per million people) in 1998-1999 to 11,164 cases (208.7 per million people) in 2012-2013. The unadjusted in-hospital case-fatality was 30.3% in 1998-2003 and 30.2% in 2003-2008, but significantly increased to 41.1% in 2008-2013. Compared with 2003-2008, the multivariable adjusted odds ratio for death was higher in 1998-2003 at 1.20 (95% CI: 1.10-1.30) and in 2008-2013 at 1.13 (1.07-1.18). Charlson comorbidity scores of more than five (odds ratio 2.35; 95% CI: 2.20-2.51) and emergency admissions (2.46 (2.32-2.61) had higher odds for death. The odds for death decreased in patients over 85 years from 4.83 (3.04-7.67) in 1998-2003 to 2.19 (1.99-2.41) in 2008-2013. AKI in secondary diagnosis and in other diagnoses codes had higher odds for death compared with AKI in primary diagnosis code in all three periods. Thus, the incidence of AKI requiring dialysis has increased progressively over 15 years in England. Improvement in case-fatality in 2003-2008 has not been sustained in the last 5 years.

The epidemiology of hospitalised acute kidney injury not requiring dialysis in England from 1998 to 2013: retrospective analysis of hospital episode statistics

Epidemiology studies of acute kidney injury (AKI) have focused on cases requiring dialysis but those not requiring dialysis represent the majority. To address this gap, we interrogated hospital episode statistics (HES) to investigate population trends in temporal epidemiology of AKI not requiring dialysis between 1998 and 2013.

Report from the kick-off meeting of the Cochrane Skin Group Core Outcome Set Initiative (CSG-COUSIN).

A major obstacle of evidence‐based clinical decision making is the use of nonstandardized, partly untested outcome measurement instruments. Core Outcome Sets (COSs) are currently developed in different medical fields to standardize and improve the selection of outcomes and outcome measurement instruments in clinical trials, in order to pool results of trials or to allow indirect comparison between interventions. A COS is an agreed minimum set of outcomes that should be measured and reported in all clinical trials of a specific disease or trial population. The international, multidisciplinary Cochrane Skin Group Core Outcome Set Initiative (CSG‐COUSIN) aims to develop and implement COSs in dermatology, thus making trial evidence comparable and, herewith, more useful for clinical decision making. The inaugural meeting of CSG‐COUSIN was held on 17–18 March 2015 in Dresden, Germany, as the exclusive theme of the Annual Cochrane Skin Group Meeting. In total, 29 individuals representing a broad mix of different stakeholder groups, professions, skills and perspectives attended. This report provides a description of existing COS initiatives in dermatology, highlights current methodological challenges in COS development, and presents the concept, aims and structure of CSG‐COUSIN.

Physiotherapy treatment for atraumatic recurrent shoulder instability: early results of a specific exercise protocol using pathology-specific outcome measures

Background Recurrent shoulder instability is usually caused by a traumatic event resulting in structural pathology, although a small subgroup of patients experience symptomatic recurrent shoulder instability without trauma. These patients are usually treated non-operatively but limited evidence exists regarding effective conservative management. In particular, there is a lack of reproducible exercise regimes and none that have been tested with condition-specific outcome measures. Methods A service evaluation was conducted over a 15-month period to assess our current treatment protocol used in the management of patients with atraumatic recurrent shoulder instability. The regime is reproducible with target-led progression milestones. Oxford Instability Shoulder Scores (OISS) and Western Ontario Shoulder Index (WOSI) scores were compared between baseline and final follow-up. Results Eighteen consecutive patients were included with mean follow-up of 4.5 months (range 1.35 months to 11.77 months). A statistically significant improvement was seen in both outcome measures. Mean OISS improved by 16.67 points (confidence interval: 12.34 to 20.99; p < 0.001). Mean WOSI improved by 36.76% (confidence interval: 28.46 to 45.06; p < 0.001). Conclusions For this small group of patients with recurrent atraumatic shoulder instability, the Derby Shoulder Instability Programme produced significant improvements over the short term, with a high level of patient compliance. This is the first study to include pathology-specific patient-reported outcome measures to assess outcomes from a specific and reproducible exercise regime in this group of patients. The findings support further research to evaluate the exercise protocol in a larger group of patients over the longer term.

How Clinically Relevant Are Treatment Comparisons of Topical Calcineurin Inhibitor Trials for Atopic Eczema

We sought to explore the architecture of trials of calcineurin inhibitors for atopic eczema to document the extent to which comparisons with active treatments such as topical corticosteroids might have been included or avoided. We identified all eligible randomized controlled trials using the Global Resource for EczemA Trials (GREAT) database. Network plots were produced where the nodes represented a treatment type and the lines between the nodes represented the number of trials or participants involved in the various treatment comparisons. A total of 174 randomized controlled trials for atopic eczema treatments were identified in which pimecrolimus, tacrolimus, or topical corticosteroids were compared with another intervention or a vehicle/emollient. Of 39 trials involving pimecrolimus and 41 trials involving tacrolimus, 8 (20.5%) and 13 (31.7%), respectively, made comparisons with topical corticosteroids, and 25 (64.1%) and 15 (36.6%), respectively, were vehicle-controlled studies. The high rate of comparisons with vehicle controls in randomized controlled trials that assessed the efficacy of pimecrolimus or tacrolimus long after efficacy had been established is a matter of concern. Active comparators (mild topical corticosteroids for pimecrolimus and moderate to potent topical corticosteroids for tacrolimus) are best placed to determine how topical calcineurin inhibitors compare with established clinical practice.

Flexible parametric modelling of the cause-specific cumulative incidence function: P. C. LAMBERT, S. R. WILKES AND M. J. CROWTHER

Competing risks arise with time-to-event data when individuals are at risk of more than one type of event and the occurrence of one event precludes the occurrence of all other events. A useful measure with competing risks is the cause-specific cumulative incidence function (CIF), which gives the probability of experiencing a particular event as a function of follow-up time, accounting for the fact that some individuals may have a competing event. When modelling the cause-specific CIF, the most common model is a semi-parametric proportional subhazards model. In this paper, we propose the use of flexible parametric survival models to directly model the cause-specific CIF where the effect of follow-up time is modelled using restricted cubic splines. The models provide smooth estimates of the cause-specific CIF with the important advantage that the approach is easily extended to model time-dependent effects. The models can be fitted using standard survival analysis tools by a combination of data expansion and introducing time-dependent weights. Various link functions are available that allow modelling on different scales and have proportional subhazards, proportional odds and relative absolute risks as particular cases. We conduct a simulation study to evaluate how well the spline functions approximate subhazard functions with complex shapes. The methods are illustrated using data from the European Blood and Marrow Transplantation Registry showing excellent agreement between parametric estimates of the cause-specific CIF and those obtained from a semi-parametric model. We also fit models relaxing the proportional subhazards assumption using alternative link functions and/or including time-dependent effects. Copyright

Identifying priority areas for research into the diagnosis, treatment and prevention of cellulitis (erysipelas):results of a James Lind Alliance Priority Setting Partnership

Priority setting partnerships give patients and heath care professionals an equal voice in driving priorities for future research. This ensures that research answers the most important questions that are needed to inform clinical practice1. Cellulitis (also known as erysipelas) is an acute infection of the skin and underlying tissue that often recurs.

Risk of bias does not differ between full papers and letters reporting dermatological randomized controlled trials.

DEAR EDITOR, Results of randomized controlled trials (RCTs) are often reported in letters rather than published within full papers. Trial results that are published as letters are often missed from bibliographic searches, especially if the term ‘randomized controlled trial’ is not included in the title of the letter. Such RCT letters generally require ‘hand searching’ in order to identify them. Based on our experience of critically appraising hundreds of RCTs when conducting systematic reviews, we hypothesized that the reporting quality of trial results in letters would be poorer than that of trials reported fully as original articles. We came to this view based on a perception that trials published as letters occupied a middle ground between not being good enough to be published as a full report, but not bad enough to be rejected completely by journals. It is also clear that less printed journal space is available for trials submitted as letters, which would probably influence the degree to which essential items are included in trial reports. Such deficiencies mean that systematic reviewers would usually need to contact authors to obtain further details. As authors may not respond effectively to the systematic reviewers, this would increase the number of ‘unclear’ risk-of-bias assessments. We aimed to examine the risk of bias of RCTs reported as letters in published Cochrane Skin Group systematic reviews, and to compare the results with full papers published in the same year and journal. To perform this assessment, we searched the Cochrane Skin Group’s Cochrane Register of Studies database using the freetext term ‘letter’. We limited any results generated from these searches to records linked to a Cochrane review. We crosschecked the results of the Cochrane Register of Studies search against Medline to confirm that they were indexed by the National Library of Medicine in America with the publication type as ‘letter’. We excluded letters that were not the primary reference to a study in the Cochrane review, not RCTs, or not included in the published Cochrane review. For each trial published as a letter, we identified two trials published in full, matched on Cochrane review paper and on year of publication to the identified letter ( 4 years). The rationale for the 1 : 2 letters to full report ratio was based on a preliminary samplesize calculation whereby we hypothesized that low risk of bias would be recorded in 10% of letters and 30% of full papers. Assuming 80% power and a 5% significance level we would require 56 letters and 111 full papers. Using the risk-of-bias tables included in the individual Cochrane reviews, two authors independently obtained the Cochrane risk-of-bias assessment (low, high or unclear) for the following three areas: (i) random sequence generation and allocation concealment, (ii) blinding of participants/personnel and outcome assessments and (iii) incomplete outcome data. For studies where risk-of-bias information was missing from the Cochrane review, the risk of bias was determined independently by two authors, with discrepancies resolved by a third party. We retrieved each letter and full paper in order to assess whether the trial reported a statistically significant result. Analysis was performed to compare the proportion of letters with low, high or unclear risk of bias with that of full papers. In total we identified 31 letters reporting RCTs across 20 different Cochrane Skin Group systematic reviews between the years 1980 and 2010. We matched these 31 letters to 62 full papers. The full papers were published between 1978 and 2011. Only eleven (35%) of the letters compared with 42 (68%) of the full papers reported statistically significant results, confirming our suspicion that ‘positive’ results were more likely to be published as full papers. We assessed the risk of bias for allocation concealment, blinding and incomplete data for all publications (Table 1; Fig. 1). A greater proportion of letters were assessed as having an unclear risk of bias for allocation concealment compared with full

How Often Do Comparative Randomised Controlled Trials in the Field of Eczema Fail to Directly Compare the Treatments Being Tested

The objective of the study was to identify all parallel design randomised controlled trials (RCTs) comparing treatments for eczema in recent dermatology literature that have failed to report a between-group analysis. The GREAT database (www.greatdatabase.org.uk) was searched to identify parallel group RCTs comparing two or more interventions published in the English language in the last decade, 2004 to 2013. The primary outcome was the number of studies that had not reported a between-group analysis for any of the outcomes. Where possible we re-analysed the data to determine whether a between-group analysis would have given a different conclusion to that reported. Out of a total of 304 RCTs in the study period, 173 (56.9%) met the inclusion criteria. Of the 173 eligible studies, 12 (6.9%) had not conducted a between-group analysis for any of the reported outcomes. There was no clear improvement over time. Five of the eight studies that were re-analysed yielded non-significant between-group differences yet reported significant within-group comparisons. All but one of the 12 studies implied that the experimental intervention was successful despite not undertaking any between-group comparisons. Although the proportion of all RCTs that fail to report an appropriate between-group analysis is small, the fact that any scientist who purports to compare one treatment against another then chooses to omit the key comparison statistic is worrying.