The Use of a Cap-mounted Tri-axial Accelerometer for Measurement of Distance, Lap Times and Stroke Rates in Swim Training

This paper will report some of the findings from a trial which recorded accelerometer data from six elite level swimmers (three female and three male, varying primary event stroke and distance) over the course of a regular 15 week training block. Measurements from a head-mounted accelerometer are used to determine when the athlete is swimming, marking of turning points (and therefore distance and lap-time measurements), and is processed by frequency analysis to determine stroke-rate. Comparison with video where available, and with training plans and literature where not, have proven this method to be accurate and reliable for determining these performance metrics. The primary objective of this project was to develop a low-cost, simple and highly usable system for use in swim coaching, feedback from elite coaches has indicated that development of this could be an extremely useful addition to their training regime

A multi-arm multi-stage clinical trial design for binary outcomes with application to tuberculosis

Randomised controlled trials are becoming increasingly costly and time-consuming. In 2011, Royston and colleagues proposed a particular class of multi-arm multi-stage (MAMS) designs intended to speed up the evaluation of new treatments in phase II and III clinical trials. Their design, which controls the type I error rate and power for each pairwise comparison, discontinues randomisation to poorly performing arms at interim analyses if they fail to show a pre-specified level of benefit over the control arm. Arms in which randomisation is continued to the final stage of the trial are compared against the control on a definitive time-to-event outcome measure. To increase efficiency, interim comparisons can be made on an intermediate time-to-event outcome which is on the causal pathway to the definitive outcome

Type I error rates of multi-arm multi-stage clinical trials: strong control and impact of intermediate outcomes

BACKGROUND: The multi-arm multi-stage (MAMS) design described by Royston et al. [Stat Med. 2003;22(14):2239-56 and Trials. 2011;12:81] can accelerate treatment evaluation by comparing multiple treatments with a control in a single trial and stopping recruitment to arms not showing sufficient promise during the course of the study. To increase efficiency further, interim assessments can be based on an intermediate outcome (I) that is observed earlier than the definitive outcome (D) of the study. Two measures of type I error rate are often of interest in a MAMS trial. Pairwise type I error rate (PWER) is the probability of recommending an ineffective treatment at the end of the study regardless of other experimental arms in the trial. Familywise type I error rate (FWER) is the probability of recommending at least one ineffective treatment and is often of greater interest in a study with more than one experimental arm. METHODS: We demonstrate how to calculate the PWER and FWER when the I and D outcomes in a MAMS design differ. We explore how each measure varies with respect to the underlying treatment effect on I and show how to control the type I error rate under any scenario. We conclude by applying the methods to estimate the maximum type I error rate of an ongoing MAMS study and show how the design might have looked had it controlled the FWER under any scenario. RESULTS: The PWER and FWER converge to their maximum values as the effectiveness of the experimental arms on I increases. We show that both measures can be controlled under any scenario by setting the pairwise significance level in the final stage of the study to the target level. In an example, controlling the FWER is shown to increase considerably the size of the trial although it remains substantially more efficient than evaluating each new treatment in separate trials. CONCLUSIONS: The proposed methods allow the PWER and FWER to be controlled in various MAMS designs, potentially increasing the uptake of the MAMS design in practice. The methods are also applicable in cases where the I and D outcomes are identical

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)

May I have your consent? Informed consent in clinical trials- feasibility in emergency situations

Clinical researchers in acute emergency settings are commonly faced with the difficulty of satisfying the conventional ethical requirement of obtaining informed consent, whilst ensuring a representative group of patients is recruited into studies. We discuss our own experience in addressing institutional ethical requirements to obtain informed consent in a multi-centre trial, recruiting highly agitated patients in the emergency setting in Melbourne, Australia. We suggest that, through the application of existing ethical and legal frameworks and pre-emptive communication with the key stakeholders in ethics committees, hospital insurers and legal representatives, a balance can be struck between ethical and legal requirements on the one hand, and the integrity of the research question, on the other.published_or_final_versio

The Extremes of Thermonuclear Supernovae

The majority of thermonuclear explosions in the Universe seem to proceed in a rather standardised way, as explosions of carbon-oxygen (CO) white dwarfs in binary systems, leading to 'normal' Type Ia supernovae (SNe Ia). However, over the years a number of objects have been found which deviate from normal SNe Ia in their observational properties, and which require different and not seldom more extreme progenitor systems. While the 'traditional' classes of peculiar SNe Ia - luminous '91T-like' and faint '91bg-like' objects - have been known since the early 1990s, other classes of even more unusual transients have only been established 20 years later, fostered by the advent of new wide-field SN surveys such as the Palomar Transient Factory. These include the faint but slowly declining '02es-like' SNe, 'Ca-rich' transients residing in the luminosity gap between classical novae and supernovae, extremely short-lived, fast-declining transients, and the very luminous so-called 'super-Chandrasekhar' SNe Ia. Not all of them are necessarily thermonuclear explosions, but there are good arguments in favour of a thermonuclear origin for most of them. The aim of this chapter is to provide an overview of the zoo of potentially thermonuclear transients, reviewing their observational characteristics and discussing possible explosion scenarios.Comment: Author version of a chapter for the 'Handbook of Supernovae', edited by A. Alsabti and P. Murdin, Springer. 50 pages, 7 figure

Magnetic structure and spin-wave excitations in the multiferroic magnetic metal-organic framework (CD3)(2)ND2[Mn(DCO2)(3)]

The authors thank STFC for the award of beam time at ISIS Neutron and Muon Source. A.E.P. is grateful to EPSRC for funding (EP/L024977/1

Behavioural responses of reptile predators to invasive cane toads in tropical Australia

The ecological impact of an invasive species can depend on the behavioural responses of native fauna to the invader. For example, the greatest risk posed by invasive cane toads (Rhinella marinaBufonidae) in tropical Australia is lethal poisoning of predators that attempt to eat a toad; and thus, a predator's response to a toad determines its vulnerability. We conducted standardized laboratory trials on recently captured (toad-naïve) predatory snakes and lizards, in advance of the toad invasion front as it progressed through tropical Australia. Responses to a live edible-sized toad differed strongly among squamate species. We recorded attacks (and hence, predator mortality) in scincid, agamid and varanid lizards, and in elapid, colubrid and pythonid snakes. Larger-bodied predators were at greater risk, and some groups (elapid snakes and varanid lizards) were especially vulnerable. However, feeding responses differed among species within families and within genera. Some taxa (notably, many scincid and agamid lizards) do not attack toads; and many colubrid snakes either do not consume toads, or are physiologically resistant to the toad's toxins. Intraspecific variation in responses means that even in taxa that apparently are unaffected by toad invasion at the population level, some individual predators nonetheless may be fatally poisoned by invasive cane toads. © 2013 Ecological Society of Australia