A comparison of methods for treatment selection in seamless phase II/III clinical trials incorporating information on short-term endpoints

In an adaptive seamless phase II/III clinical trial interim analysis data are used for treatment selection, enabling resources to be focussed on comparison of more effective treatment(s) with a control. In this paper we compare two methods recently proposed to enable use of short-term endpoint data for decision-making at the interim analysis. The comparison focusses on the power and the probability of correctly identifying the most promising treatment. We show that the choice of method depends on how well short-term data predict the best treatment, which may be measured by the correlation between treatment effects on short-term and long-term endpoints

Hooped Structures

Panel members each made a brief presentation, after which discussion was open among the 60-some persons attending this session. Vic Madsen has a couple of hoop house units that were constructed in 1995. Fred Tilstra has seven units put up over the last four years; he uses them mainly for finishing and gestation. Tim Goode\u27s unit at Rhodes has been up two years but has been used once for finishing/gestation. Homer Schowman has put up six units in three years for finishing. Archie Kunz has four units; he can also discuss manure values and economics with us today

Blinded versus unblinded estimation of a correlation coefficient to inform interim design adaptations

Regulatory authorities require that the sample size of a confirmatory trial is calculated prior to the start of the trial. However, the sample size quite often depends on parameters which might not be known in advance of the study. Misspecification of these parameters can lead to under- or overestimation of the sample size. Both situations are unfavourable as the first one decreases the power and the latter one leads to a waste of resources. Hence, designs have been suggested that allow a re-assessment of the sample size in an ongoing trial. These methods usually focus on estimating the variance. However, for some methods the performance depends not only on the variance but also on the correlation between measurements. We develop and compare different methods for blinded estimation of the correlation coefficient which are less likely to introduce operational bias when the blinding is maintained. Their performance with respect to bias and standard error is compared to the unblinded estimator. We simulated two different settings: one assuming that all group means are the same and one assuming that different groups have different means. Simulation results show that the naïve (onesample) estimator is only slightly biased and has a standard error comparable to that of the unblinded estimator. However, if the group means differ, other estimators have better performance depending on the sample size per group and the number of groups

Dynamical evolution of North Atlantic ridges and poleward Jet Stream displacements

The development of a particular wintertime atmospheric circulation regime over the North Atlantic, comprising a northward shift of the North Atlantic eddy-driven jet stream and an associated strong and persistent ridge in the subtropics, is investigated. Several different methods of analysis are combined to describe the temporal evolution of the events and relate it to shifts in the phase of the North Atlantic Oscillation and East Atlantic pattern. First, the authors identify a close relationship between northward shifts of the eddy-driven jet, the establishment and maintenance of strong and persistent ridges in the subtropics, and the occurrence of upper-tropospheric anticyclonic Rossby wave breaking over Iberia. Clear tropospheric precursors are evident prior to the development of the regime, suggesting a preconditioning of the Atlantic jet stream and an upstream influence via a large-scale Rossby wave train from the North Pacific. Transient (2–6 days) eddy forcing plays a dual role, contributing to both the initiation and then the maintenance of the circulation anomalies. During the regime there is enhanced occurrence of anticyclonic Rossby wave breaking, which may be described as low-latitude blocking-like events over the southeastern North Atlantic. A strong ridge is already established at the time of wave-breaking onset, suggesting that the role of wave-breaking events is to amplify the circulation anomalies rather than to initiate them. Wave breaking also seems to enhance the persistence, since it is unlikely that a persistent ridge event occurs without being also accompanied by wave breaking

Combined Clinical, Epidemiological, and Genome-Based Analysis Identified a Nationwide Outbreak of Burkholderia cepacia Complex Infections Caused by Contaminated Mouthwash Solutions

Background: In September 2018, Burkholderia cepacia complex (BCC) infections in 3 patients associated with exposure to a mouthwash solution (MWS) were reported to the Robert Koch Institute (RKI). As the product was still on the market and the scale of the outbreak was unclear, a nation-wide investigation was initiated. Methods: We aimed to investigate BCC infections/colonizations associated with MWS. Hospitals, laboratories, and public health services were informed that BCC isolates should be sent to the RKI. These isolates were typed by pulsed-field gel electrophoresis (PFGE) and whole-genome sequencing (WGS) including development of an ad hoc core genome MLST (cgMLST) scheme. Results: In total, 36 patients from 6 hospitals met the case definition, the last patient in November 2018. Twenty-nine isolates from 26 of these patients were available for typing. WGS analysis revealed 2 distinct cgMLST clusters. Cluster 1 (Burkholderia arboris) contained isolates from patients and MWS obtained from 4 hospitals and isolates provided by the manufacturer. Patient and MWS isolates from another hospital were assigned to cluster 2 (B. cepacia). Conclusions: The combined clinical, epidemiological, and microbiological investigation, including whole-genome analysis, allowed for uncovering a supraregional BCC outbreak in health care settings. Strains of B. arboris and B. cepacia were identified as contaminating species of MWS bottles and subsequent colonization and putative infection of patients in several hospitals. Despite a recall of the product by the manufacturer in August 2018, the outbreak lasted until December 2018. Reporting of contaminated medical products and recalls should be optimized to protect patients.Peer Reviewe

Clinical trials impacted by the COVID-19 pandemic : adaptive designs to the rescue?

Very recently the new pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified and the coronavirus disease 2019 (COVID-19) declared a pandemic by the World Health Organization. The pandemic has a number of consequences for ongoing clinical trials in non-COVID-19 conditions. Motivated by four current clinical trials in a variety of disease areas we illustrate the challenges faced by the pandemic and sketch out possible solutions including adaptive designs. Guidance is provided on (i) where blinded adaptations can help; (ii) how to achieve type I error rate control, if required; (iii) how to deal with potential treatment effect heterogeneity; (iv) how to utilize early read-outs; and (v) how to utilize Bayesian techniques. In more detail approaches to resizing a trial affected by the pandemic are developed including considerations to stop a trial early, the use of group-sequential designs or sample size adjustment. All methods considered are implemented in a freely available R shiny app. Furthermore, regulatory and operational issues including the role of data monitoring committees are discussed

Spectral and spatial shaping of laser-driven proton beams using a pulsed high-field magnet beamline

Intense laser-driven proton pulses, inherently broadband and highly divergent, pose a challenge to established beamline concepts on the path to application-adapted irradiation field formation, particularly for 3D. Here we experimentally show the successful implementation of a highly efficient (50% transmission) and tuneable dual pulsed solenoid setup to generate a homogeneous (8.5% uniformity laterally and in depth) volumetric dose distribution (cylindrical volume of 5 mm diameter and depth) at a single pulse dose of 0.7 Gy via multi-energy slice selection from the broad input spectrum. The experiments have been conducted at the Petawatt beam of the Dresden Laser Acceleration Source Draco and were aided by a predictive simulation model verified by proton transport studies. With the characterised beamline we investigated manipulation and matching of lateral and depth dose profiles to various desired applications and targets. Using a specifically adapted dose profile, we successfully performed first proof-of-concept laser-driven proton irradiation studies of volumetric in-vivo normal tissue (zebrafish embryos) and in-vitro tumour tissue (SAS spheroids) samples.Comment: Submitted to Scientific Report

Ten-year assessment of the 100 priority questions for global biodiversity conservation

In 2008, a group of conservation scientists compiled a list of 100 priority questions for the conservation of the world's biodiversity ?Sutherland et al. (2009) Conservation Biology, 23, 557?567?. However, now almost a decade later, no one has yet published a study gauging how much progress has been made in addressing these 100 high?priority questions in the peer?reviewed literature. Here we take a first step toward re?examining the 100 questions and identify key knowledge gaps that still remain. Through a combination of a questionnaire and a literature review, we evaluated each of the 100 questions on the basis of two criteria: relevance and effort. We defined highly?relevant questions as those which ? if answered ? would have the greatest impact on global biodiversity conservation, while effort was quantified based on the number of review publications addressing a particular question, which we used as a proxy for research effort. Using this approach we identified a set of questions that, despite being perceived as highly relevant, have been the focus of relatively few review publications over the past ten years. These questions covered a broad range of topics but predominantly tackled three major themes: the conservation and management of freshwater ecosystems, the role of societal structures in shaping interactions between people and the environment, and the impacts of conservation interventions. We see these questions as important knowledge gaps that have so far received insufficient attention and may need to be prioritised in future research

Relationship of aerobic fitness and motor skills with memory and attention in preschoolers (Ballabeina): A cross-sectional and longitudinal study

BACKGROUND: The debate about a possible relationship between aerobic fitness and motor skills with cognitive development in children has recently re-emerged, because of the decrease in children's aerobic fitness and the concomitant pressure of schools to enhance cognitive performance. As the literature in young children is scarce, we examined the cross-sectional and longitudinal relationship of aerobic fitness and motor skills with spatial working memory and attention in preschool children. METHODS: Data from 245 ethnically diverse preschool children (mean age: 5.2 (0.6) years, girls: 49.4%) analyzed at baseline and 9 months later. Assessments included aerobic fitness (20 m shuttle run) and motor skills with agility (obstacle course) and dynamic balance (balance beam). Cognitive parameters included spatial working memory (IDS) and attention (KHV-VK). All analyses were adjusted for age, sex, BMI, migration status, parental education, native language and linguistic region. Longitudinal analyses were additionally adjusted for the respective baseline value. RESULTS: In the cross-sectional analysis, aerobic fitness was associated with better attention (r=0.16, p=0.03). A shorter time in the agility test was independently associated with a better performance both in working memory (r=-0.17, p=0.01) and in attention (r=-0.20, p=0.01). In the longitudinal analyses, baseline aerobic fitness was independently related to improvements in attention (r=0.16, p=0.03), while baseline dynamic balance was associated with improvements in working memory (r=0.15, p=0.04). CONCLUSIONS: In young children, higher baseline aerobic fitness and motor skills were related to a better spatial working memory and/or attention at baseline, and to some extent also to their future improvements over the following 9 months. TRIAL REGISTRATION: clinicaltrials.gov NCT0067454