Publishing interim results of randomised clinical trials in peer-reviewed journals

Background: Interim analyses of randomised controlled trials are sometimes published before the final results are available. In several cases, the treatment effects were noticeably different after patient recruitment and follow-up completed. We therefore conducted a literature review of peer-reviewed journals to compare the reported treatment effects between interim and final publications and to examine the magnitude of the difference. Methods: We performed an electronic search of MEDLINE from 1990 to 2014 (keywords: ‘clinical trial’ OR ‘clinical study’ AND ‘random*’ AND ‘interim’ OR ‘preliminary’), and we manually identified the corresponding final publication. Where the electronic search produced a final report in which the abstract cited interim results, we found the interim publication. We also manually searched every randomised controlled trial in eight journals, covering a range of impact factors and general medical and specialist publications (1996–2014). All paired articles were checked to ensure that the same comparison between interventions was available in both. Results: In all, 63 studies are included in our review, and the same quantitative comparison was available in 58 of these. The final treatment effects were smaller than the interim ones in 39 (67%) trials and the same size or larger in 19 (33%). There was a marked reduction, defined as a ≥20% decrease in the size of the treatment effect from interim to final analysis, in 11 (19%) trials compared to a marked increase in 3 (5%), p = 0.057. The magnitude of percentage change was larger in trials where commercial support was reported, and increased as the proportion of final events at the interim report decreased in trials where commercial support was reported (interaction p = 0.023). There was no evidence of a difference between trials that stopped recruitment at the interim analysis where this was reported as being pre-specified versus those that were not pre-specified (interaction p = 0.87). Conclusion: Published interim trial results were more likely to be associated with larger treatment effects than those based on the final report. Publishing interim results should be discouraged, in order to have reliable estimates of treatment effects for clinical decision-making, regulatory authority reviews and health economic analyses. Our work should be expanded to include conference publications and manual searches of additional journal publications

A framework for the simulation of structural software evolution

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2008 ACM.As functionality is added to an aging piece of software, its original design and structure will tend to erode. This can lead to high coupling, low cohesion and other undesirable effects associated with spaghetti architectures. The underlying forces that cause such degradation have been the subject of much research. However, progress in this field is slow, as its complexity makes it difficult to isolate the causal flows leading to these effects. This is further complicated by the difficulty of generating enough empirical data, in sufficient quantity, and attributing such data to specific points in the causal chain. This article describes a framework for simulating the structural evolution of software. A complete simulation model is built by incrementally adding modules to the framework, each of which contributes an individual evolutionary effect. These effects are then combined to form a multifaceted simulation that evolves a fictitious code base in a manner approximating real-world behavior. We describe the underlying principles and structures of our framework from a theoretical and user perspective; a validation of a simple set of evolutionary parameters is then provided and three empirical software studies generated from open-source software (OSS) are used to support claims and generated results. The research illustrates how simulation can be used to investigate a complex and under-researched area of the development cycle. It also shows the value of incorporating certain human traits into a simulation—factors that, in real-world system development, can significantly influence evolutionary structures

Powering lights with piezoelectric energy harvesting floors

The present work introduces a new technology for converting energy from steps into electricity. It starts with a study of the mechanical energy available from steps in a busy corridor. The subsequent development efforts and devices are presented, with an iterative approach to prototyping. Methods for enhancing the piezoelectric conversion efficiency have been determined as a part of the process and are introduced in the present article. Capitalizing on these findings, we have fabricated energy-harvesting devices for stairs that power embedded emergency lighting. The typical working unit comprises an energy-harvesting stair nosing, a power management circuit, and an embedded light-emitting diode that lights the tread in front of the user with an illuminance corresponding to emergency standards. The stair nosing generates up to 17.7 mJ of useful electrical energy per activation to provide up to 10.6 seconds of light. The corresponding energy density is 0.49 J per meter square and per step, with an 8.5 mm thick active layer

Maximum tumor diameter is associated with event-free survival in PET-negative patients with stage I/IIA Hodgkin lymphoma.

Introduction: the high cure rates achieved in early-stage (ES) Hodgkin lymphoma (HL) are one of the great successes of hemato-oncology, but late treatment-related toxicity undermines long-term survival. Improving overall survival and quality of life further will require maintaining disease control while potentially de-escalating chemotherapy and/or omitting radiotherapy to reduce late toxicity. Accurate stratification of patients is required to facilitate individualized treatment approaches. Response assessment using 18F-fluorodeoxyglucose positron emission tomography (PET) is a powerful predictor of outcome in HL,1,2 and has been used in multiple studies, including the United Kingdom National Cancer Research Institute Randomised Phase III Trial to Determine the Role of FDG–PET Imaging in Clinical Stages IA/IIA Hodgkin’s Disease (UK NCRI RAPID) trial, to investigate whether patients achieving complete metabolic remission (CMR) can be treated with chemotherapy alone.3-5 These PET-adapted trials have demonstrated that omitting radiotherapy results in higher relapse rates, but without compromising overall survival.3-5 For the 75% of patients who achieved CMR in RAPID, neither baseline clinical risk stratification (favorable/unfavorable) nor PET (Deauville score 1/2) predicted disease relapse; additional biomarkers are needed.1 Tumor bulk has long been recognized as prognostic in HL,1,6 but there remains uncertainty about the significance and definition of bulk in the era of PET-adapted treatment.7 We performed a subsidiary analysis of RAPID to assess the prognostic value of baseline maximum tumor dimension (MTD) in patients achieving CMR. Methods: ee have previously reported the RAPID trial design, primary results, and outcomes according to pretreatment risk stratification and PET score.1,3 Patients were aged 16 to 75 years with untreated ES-HL and without B-symptoms or mediastinal bulk (mass > 1/3 internal mediastinal diameter at T5/6).6 Metabolic response after 3 cycles of ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine) was centrally assessed using PET (N = 562). Patients with CMR (ie, Deauville score 1-2) were randomly assigned to receive involved field radiotherapy (IFRT; n = 208) or no further therapy (NFT; n = 211). PET-positive patients (score, 3-5; n = 143) received a fourth cycle of ABVD and IFRT. Baseline disease assessment was performed by computed tomography, and bidimensional target lesion measurements were reported by local radiologists in millimeters. The association of baseline MTD with HL-related event-free survival (EFS: progression or HL-related death) and progression-free survival (PFS) (progression or any-cause death) was assessed using Kaplan-Meier and Cox regression analyses. Non-HL deaths were either related to primary treatment toxicity or occurred in HL remission.1 United Kingdom ethical approval for the RAPID trial was via the UK Multicentre Research ethics committee. Results and discussion: baseline patient characteristics have been previously described.1 Median age was 34 years (range, 16-75 years); 184 (37.4%) of 492 patients had unfavorable risk by European Organisation for Research and Treatment of Cancer criteria, and 155 (32.3%) of 480 by German Hodgkin Study Groupcriteria. Median MTD for patients achieving CMR was 3.0 cm (interquartile range, 2.0-4.0 cm) and 3.0 cm (interquartile range, 1.8-4.5 cm) in the NFT and IFRT groups, respectively, whereas PET-positive patients had a median MTD of 3.9 cm (interquartile range, 2.8-5.1 cm). After a median follow-up of 61.6 m, 44 HL progression events occurred: 21 NFT, 9 IFRT and 14 PET-positive. No patient received salvage treatment without documented progression. Only 5 HL-related deaths occurred (1 IFRT, 4 PET-positive), and 12 non-HL deaths (4 NFT, 6 IFRT, 2 PET-positive).1 For patients with CMR (N = 419), there was a strong association between MTD and EFS (hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.02-1.39; P = .02), adjusting for treatment group, with an approximate 19% increase in HL risk per centimeter increase in MTD. The association was similar in both treatment groups (NFT HR, 1.20 [95% CI, 0.99-1.44; P = .06]; IFRT HR, 1.19 [95% CI, 0.92-1.55; P = .19]). The observed effect sizes did not markedly change after adjusting for baseline clinical risk factors, and similar results were observed for PFS (supplemental Table 1). In contrast, for PET-positive patients, there was no association between MTD and EFS (HR, 0.88; 95% CI, 0.70-1.11; P = .29) or PFS (HR, 0.87; 95% CI, 0.70-1.08; P = .21). In an exploratory analysis within the NFT group, MTD was dichotomized using increasing 1-cm intervals to investigate the relationship between MTD thresholds and EFS. The largest effect size was observed with an MTD threshold of ≥5 cm (Table 1). Similar results were observed for PFS; this threshold also performed best in time-dependent receiver operating characteristic curve analyses. It was not possible to assess MTD thresholds in the IFRT group with only 9 events. Among all randomized patients, 79 (18.9%) had MTD of ≥5 cm, the majority with mediastinal (n = 43), supraclavicular (n = 17), or cervical (n = 16) locations. Five-year EFS for patients with MTD of ≥5 cm randomly assigned to NFT and IFRT was 79.3% (n = 39; 95% CI, 66.6%-92.0%) and 94.9% (n = 40; 95% CI, 88.0%-100%), respectively (P = .03; Figure 1)

An exploration of the challenges facing developers of affordable dwellings following low carbon and ecological principles, in rural locations in Wales

This paper discusses the challenges in developing ecological, low carbon and affordable dwellings in rural areas of Wales; since much of the funding in the UK is often focused on urban development. The Welsh Assembly Government (WAG) is committed to the aim that the construction of new homes moves towards zero carbon as soon as possible. There is a need to ensure that this strategy recognises that one size does not fit all; and understanding and addressing these issues will be fundamental if WAG objectives are too achieved in rural areas. This paper discusses a three year research project, which commenced in autumn 2010 in collaboration with the University of Wales Institute Cardiff (UWIC) and Pembrokeshire Housing Association (PHA), a registered social landlord and developer of affordable dwellings; to create a development model for affordable, low carbon, ecological rural dwellings to achieve WAG targets. This paper will be of use to rural developers, designers and architects

Two approaches to developing low carbon dwellings in west Wales

In October 2010 Pembrokeshire Housing Association (PHA) completed a development of six residential units, in Pembroke Dock, in west Wales, as part of a Welsh Government pilot project to promote the development of low carbon housing in Wales based on the Code for Sustainable Homes (CfSH). In the same year, in the same town, a small scale developer undertook the design and construction of two houses based on ecological principles using strawbale construction. The houses built by this developer were designed and built outside of the requirements of the CfSH and utilised passive design approaches along with local and natural materials to reduce operational and embodied energy. Researchers from the Ecological Built Environment Research and Enterprise group, at Cardiff Metropolitan University, are working in collaboration with PHA to develop a best practice model for low carbon housing in rural areas of Wales and these two projects provide an opportunity for the researchers to investigate and compare two distinct approaches to low carbon design each with the aim to deliver sustainable, affordable dwellings. To evaluate these two schemes structured interviews were held with the design team of the pilot project and the designer/builder of the eco-house to understand their respective approaches; the influences and obstacles that affected the development of the schemes; and how they considered user behaviour. The paper concludes by considering the lessons that registered social landlords might learn from small scale ecological developers for the design and construction of low and zero energy housing in rural areas

The effect of multiple developers on structural attributes: a study based on Java software

Context: Long-term software projects employ different software developers who collaborate on shared artifacts. The accumulation of changes pushed by different developers leave traces on the underlying code, that have an effect on its future maintainability, and even reuse. Objective: This study focuses on the how the changes by different developers might have an impact on the code: we investigate whether the work of multiple developers, and their experience, have a visible effect on the structural metrics of the underlying code. Method: We consider nine object-oriented (OO) attributes and we measure them in a GitHub sample containing the top 200 ‘forked’ projects. For each of their classes, we evaluated the number of distinct developers contributing to its source code, and their experience in the project. Results: We show that the presence of multiple developers working on the same class has a visible effect on the chosen OO metrics, and often in the opposite direction to what the guidelines for each attribute suggest. We also show how the relative experience of developers in a project plays an important role in the distribution of those metrics, and the future maintenance of the Java classes. Conclusions: Our results show how distributed development has an effect on the structural attributes of a software system and how the experience of developers plays a fundamental role in that effect. We also discover workarounds and best practices in 4 applied case studies

Text-message Reminders in Colorectal Cancer Screening (TRICCS): a randomised controlled trial

BACKGROUND: We investigated the effectiveness of a text-message reminder to improve uptake of the English Bowel Cancer Screening programme in London. METHODS: We performed a randomised controlled trial across 141 general practices in London. Eight thousand two hundred sixty-nine screening-eligible adults (aged 60-74 years) were randomised in a 1 : 1 ratio to receive either a text-message reminder (n=4134) or no text-message reminder (n=4135) if they had not returned their faecal occult blood test kit within 8 weeks of initial invitation. The primary outcome was the proportion of adults returning a test kit at the end of an 18-week screening episode (intention-to-treat analysis). A subgroup analysis was conducted for individuals receiving an invitation for the first time. RESULTS: Uptake was 39.9% in the control group and 40.5% in the intervention group. Uptake did not differ significantly between groups for the whole study population of older adults (adjusted odds ratio (OR) 1.03, 95% confidence interval (CI) 0.94-1.12; P=0.56) but did vary between the groups for first-time invitees (uptake was 34.9% in the control and 40.5% in the intervention; adjusted OR 1.29, 95% CI 1.04-1.58; P=0.02). CONCLUSIONS: Although text-message reminders did not significantly increase uptake of the overall population, the improvement among first-time invitees is encouraging.British Journal of Cancer advance online publication, 25 April 2017; doi:10.1038/bjc.2017.117 www.bjcancer.com

The effect of vehicle on the tissue distribution profiles of radioiodinated cholesterol esters in the rat

Several groups have examined the possible use of radioiodinated cholesterol esters to achieve selective uptake of radioactivity in the adrenal cortex and have obtained variable results. This study indicates that the tissue distribution profile varies not only with the type of ester, but also with the vehicle employed for administration. Radioiodinated 19-iodocholesteryl (125-IC), iodocholesteryl palmitate (125-ICP)and iodocholesteryl oleate (125-ICO) were dissolved in either tween vehicle (saline containing 1.6% tween 80 and 10% ethanol) or myristate vehicle (isopropyl myristate-ethanol, 1:5 v/v) and administered i.v. to rats. Irrespective of the agent, considerably more radioactivity appeared in the target organs when the tween vehicle was employed. When the myristate vehicle was used, higher levels of radioactivity appeared in the lung. This finding suggests precipitation of the agents from the myristate vehicle occurred upon administration. In the tween vehicle, 125-ICO showed almost three times greater predilection for adrenal cortex than 125-ICP with levels of activity approaching those seen for 125-IC. Adrenal activity and adrenal to non-target ratios were sufficient for visualization of the adrenals at 5 days after injection of 125-ICO in the tween vehicle. Lipid extraction and TLC analysis of tissue radioactivity revealed that radioactivity in the adrenal and ovary was predominantly in an esterified form. Further analysis of the esters present after injection of 125-ICP showed these to be a mixture of mono and polyunsaturated esters. The site of hydrolysis and subsequent reesterification is an interesting biochemical aspect that remains to be elucidated.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24488/1/0000764.pd