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To conceptualize a composite primary endpoint for parallel-group RCTs of exercise-based cardiac rehabilitation (CR) interventions and to explore its application and statistical efficiency. We conducted a statistical exploration of sample size requirements. We combined exercise capacity and physical activity for the composite endpoint (CE), both being directly related to reduced premature mortality in patients with cardiac diseases. Based on smallest detectable and minimal clinically important changes (change in exercise capacity of 15 W and change in physical activity of 10 min/day), the CE combines 2 dichotomous endpoints (achieved/not achieved). To examine statistical efficiency, we compared sample size requirements based on the CE to single endpoints using data from 2 completed CR trials. Cardiac rehabilitation phase III. Patients in cardiac rehabilitation. Not applicable. Exercise capacity (P max assessed by incremental cycle ergometry) and physical activity (daily minutes of moderate to vigorous physical activity assessed by accelerometry). Expecting, for example, a 10% between-group difference and improvement in the clinical outcome, the CE would increase sample size by up to 21% or 61%, depending on the dataset. When expecting a 10% difference and designing an intervention with the aim of non-deterioration, the CE would allow to reduce the sample size by up to 55% or 70%. Trialists may consider the utility of the CE for future studies in exercise-based CR to reduce sample size requirements. However, perhaps surprisingly at first, the CE could also lead to an increased sample size needed, depending on the observed baseline proportions in the trial population and the aim of the intervention. [ABSTRACT FROM AUTHOR]

We introduce a unified approach for testing a variety of rather general null hypotheses that can be formulated in terms of covariance matrices. These include as special cases, for example, testing for equal variances, equal traces, or for elements of the covariance matrix taking certain values. The proposed method only requires very few assumptions and thus promises to be of broad practical use. Different test statistics are defined, and their asymptotic or approximate sampling distributions are derived. In order to particularly improve the small-sample behaviour of the resulting tests, two bootstrap-based methods are developed and theoretically justified. Several simulations shed light on the performance of the proposed tests. The analysis of a real data set illustrates the application of the procedures. • Covariance matrices contain much information, making related hypotheses important. • The approach allows using known techniques from mean-based analysis for covariances. • Bootstrap approaches ensure a good type-I error rate and power. [ABSTRACT FROM AUTHOR]

Abstract: We propose a new procedure for combining multiple tests in samples of right-censored observations. The new method is based on multiple constrained censored empirical likelihood where the constraints are formulated as linear functionals of the cumulative hazard functions. We prove a version of Wilks’ theorem for the multiple constrained censored empirical likelihood ratio, which provides a simple reference distribution for the test statistic of our proposed method. A useful application of the proposed method is, for example, examining the survival experience of different populations by combining different weighted log-rank tests. Real data examples are given using the log-rank and Gehan-Wilcoxon tests. In a simulation study of two sample survival data, we compare the proposed method of combining tests to previously developed procedures. The results demonstrate that, in addition to its computational simplicity, the combined test performs comparably to, and in some situations more reliably than previously developed procedures. Statistical software is available in the R package ‘emplik’. [Copyright &y& Elsevier]

Abstract: We propose different multivariate nonparametric tests for factorial designs and derive their asymptotic distribution for the situation where the number of replications is limited, whereas the number of treatments goes to infinity (large a, small n case). The tests are based on separate rankings for the different variables, and they are therefore invariant under separate monotone transformations of the individual variables. There are no restrictions on the covariance structure of the multivariate observations, and the methods also work for data that have ties or are measured on an ordinal scale. We compare the proposed tests to their parametric counterparts by simulating the power functions. In the presence of outliers, the new nonparametric tests show far superior power. The multivariate nonparametric tests can be used, e.g., in screening trials in agriculture or for survey data. We illustrate the application with a survey data set. [Copyright &y& Elsevier]

Abstract: In this paper, we prove a novel result about the asymptotic distribution of a class of rank statistics that can be used in a situation where the number of replications is limited, whereas the number of treatments goes to infinity (large k, small n case). The results can be applied to, e.g., data from agricultural screening trials where usually the numbers of factor levels are large, but there are only few replications per factor level. [Copyright &y& Elsevier]

Consider the factorial ANOVA model with m fixed factors, interactions, and error terms that are not necessarily normally distributed.We examine the asymptotic sensitivity against unequal variances of the ANOVA F test statistics for testing main factor effects and interactions, under the assumption that the number of levels of one factor A1 tends to infinity while the number of levels is fixed for the other factors A2,…,Am, and the number of replications per factor level remains also finite.Heteroscedasticity is allowed across the levels of factors A2,…,Am. We show that the ANOVA F test on factor A1, designed for a homoscedastic model, can still be used in the presence of this form of heteroscedasticity. That is, as long as the variance of the error term does not depend on the level of factor A1, the F test for the main effect of factor A1 is asymptotically almost unaffected by different variances in different levels of the other factors. The theoretical results derived in this paper are supported by simulation studies. [Copyright &y& Elsevier]

• The Pacific islands provide a natural experiment for studying different predictors. • Predictors of pre-European deforestation and forest replacement were analysed. • Our multivariate nonparametric analysis is based on data from 67 islands. • Regarding deforestation, rainfall, tephra and absolute latitude are most important. • Regarding forest replacement, area, dust and tephra are most important. • Environmental predictors strongly influence on deforestation and forest replacement. The many different islands of the Pacific provide a natural experiment that is ideal for studying predictors affecting plant cover and habitat-type. Previous research into pre-European deforestation and forest replacement across the Pacific islands detected multiple significant environmental and cultural variables. Here we re-analyse data for 67 islands using modern multivariate non-parametric statistical methods. For this analysis, neither parametric assumptions nor transformations are needed. According to our results there are congruities, but also differences from previous work. Although our analysis controls the familywise error rate, we found more relevant variables. Regarding deforestation, rainfall is the most important variable, but tephra and absolute latitude are also highly significant. Rainfall and tephra are negatively correlated with deforestation, whereas absolute latitude and deforestation have a positive correlation. Regarding forest replacement, area, dust and tephra are highly significant. These three variables are negatively correlated with the extent of forest replacement. In summary, we confirm the strong influence of environmental predictors. [ABSTRACT FROM AUTHOR]

Cortical reorganization can be induced by exercise below the level of the lesion after spinal cord injury (SCI). The aim of the present study was to investigate the effect of passive and active pedaling exercise on leg motor cortical area excitability of subjects with traumatic SCI. Ten subjects with chronic cervical or thoracic SCI were enrolled in the study. We found a significant effect of pedaling on short-interval intracortical inhibition (SICI), which did not interact with the experimental condition (active vs. passive). This corresponded to a significant reduction of SICI in the subjects with SCI, together with no evidence that this pattern differed for passive vs. active pedaling. We found no significant effect of pedaling on intracortical facilitation. Our results showed that also passive cycling may be beneficial in activating motor cortical regions and possibly also facilitating motor recovery after SCI. The present study confirms and extends the findings of previous studies that have observed task-specific cortical activation during passive pedaling. Therefore passive exercise therapies when applied below the level of the lesion in subjects with SCI could promote cortical neuroplastic reorganization. [ABSTRACT FROM AUTHOR]

Transcranial magnetic stimulation (TMS) is a useful non-invasive approach for studying cortical physiology. To further clarify the mechanisms of cortical reorganization after spinal cord injury (SCI), we used a non-invasive paired TMS protocol for the investigation of the corticospinal I-waves, the so-called I-wave facilitation, in eight patients with cervical SCI. We found that the pattern of I-wave facilitation significantly differs between SCI patients with normal and abnormal central motor conduction (CMCT), and healthy controls. The group with normal CMCT showed increased I-wave facilitation, while the group with abnormal CMCT showed lower I-wave facilitation compared to a control group. The facilitatory I-wave interaction occurs at the level of the motor cortex, and the mechanisms responsible for the production of I-waves are under control of GABA-related inhibition. Therefore, the findings of our small sample preliminary study provide further physiological evidence of increased motor cortical excitability in patients with preserved corticospinal projections. This is possibly due to decreased GABAergic intracortical inhibition. The excitability of networks producing short-interval intracortical facilitation could increase after SCI as a mechanism to enhance activation of residual corticospinal tract pathways and thus compensate for the impaired ability of the motor cortex to generate appropriate voluntary movements. Finally, the I-wave facilitation technique could be used in clinical neurorehabilitation as an additional method of assessing and monitoring function in SCI. [ABSTRACT FROM AUTHOR]

Due to potentially immune-escaping virus variants and waning immunity, a third SARS-CoV-2 vaccination dose is increasingly recommended. However, data in patients with cancer are limited. We measured anti-SARS-CoV-2 spike protein antibody levels after the third vaccination dose in 439 patients with cancer and 41 health care workers (HCW) at an academic centre in Austria and a rural community hospital in Italy. Adverse events were retrieved from questionnaires. Overall, 439 patients and 41 HCW were included. SARS-CoV-2 infections were observed in 62/439 (14.1%) patients before vaccination and in 5/439 (1.1%) patients after ≥1 dose. Longitudinal analysis revealed a decrease of antibody levels between 3 and 6 months after second vaccination in patients with solid tumours (p < 0.001) and haematological malignancies without anti-B cell therapies (p < 0.001). After the third dose, anti-S levels increased compared to the first/second dose. Patients receiving B cell-targeted agents had lower antibody levels than patients with haematological malignancies undergoing other treatments (p < 0.001) or patients with solid tumours (p < 0.001). Moreover, anti-S levels correlated with CD19+ (B cell) and CD56+ (NK cell) counts in peripheral blood. The most frequent adverse events after the third dose were local pain (75/160, 46.9%), fatigue (25/160, 15.6%) and fever/chills (16/160, 10.0%). Patients with cancer had lower anti-S levels than HCW (p = 0.015). This study in patients with cancer shows improved antibody levels after the third vaccination dose at an acceptable side-effect profile. Lower antibody levels than in controls underline the need for further follow-up studies and dedicated trials. • Anti-SARS-CoV-2 antibody levels diminished over time after the second vaccination. • Antibody levels increased after the third dose, supporting its administration. • Patients under B cell-targeting therapy showed considerably lower antibody levels. • Antibody levels correlated with CD19+ and CD56+ peripheral blood cell counts. • Lower antibody levels than in controls underline the need for further studies. [ABSTRACT FROM AUTHOR]

We aimed in this study to investigate whether repetitive transcranial magnetic stimulation (rTMS), given as theta burst stimulation (TBS), can interfere with non-painful phantom sensations in subjects with spinal cord injury (SCI). In double-blind, sham-controlled experiments in five subjects with cervical or thoracic traumatic SCI, we evaluated the effects of a single session of inhibitory (continuous) TBS, excitatory (intermittent) TBS, or placebo TBS, on simplex and complex non-painful phantom sensations. The interventions targeted the contralateral primary motor cortex (M1), the primary sensory cortex (S1) and the posterior parietal cortex (PPC). Measurements were carried out at baseline ( T 0), 5 min ( T 1) and 30 min later ( T 2) after the intervention. Descriptive evaluation of results shows that non-painful phantom sensations were not affected by rTMS applied over M1. Continuous (inhibitory) TBS over S1 induced a short-lasting decrease of simple non-painful phantom sensations, while continuous TBS over PPC induced a short-lasting decrease of both simple and complex phantom sensations. Intermittent (excitatory) TBS over PPC induced a slight increase of non-painful phantom sensations. Tests for significance confirm these observations, but must be interpreted with caution because of the small sample size. In conclusion, non-painful phantom sensations may be associated to a hyperexcitability of PPC and to a lesser extent of S1, which can be normalized by inhibitory rTMS. Our preliminary findings provide further evidence that neuromodulatory techniques are able to reverse phantom sensations not only after limb amputation but also in other conditions characterized by deafferentation such as SCI. [ABSTRACT FROM AUTHOR]