The Yo-Yo Intermittent Tests: A Systematic Review and Structured Compendium of Test Results

Background: Although Yo-Yo intermittent tests are frequently used in a variety of sports and research studies to determine physical fitness, no structured reference exists for comparison and rating of test results. This systematic review of the most common Yo-Yo tests aimed to provide reference values for test results by statistical aggregation of published data.Methods: A systematic literature search for articles published until August 2017 was performed in MEDLINE, Web of Science, SPORTDiscus and Google Scholar. Original reports on healthy females and males ≥16 years were eligible for the analysis. Sub-maximal test versions and the Yo-Yo Intermittent Recovery Level 1 Children's test (YYIR1C) were not included.Results: 248 studies with 9,440 participants were included in the structured analysis. The Yo-Yo test types most frequently used were the Yo-Yo Intermittent Recovery Level 1 (YYIR1, 57.7%), the Yo-Yo Intermittent Recovery Level 2 (YYIR2, 28.0%), the Yo-Yo Intermittent Endurance Level 2 (YYIE2, 11.4%), and the Yo-Yo Intermittent Endurance Level 1 (YYIE1, 2.9%) test. For each separate test, reference values (global means and percentiles) for sports at different levels and both genders were calculated.Conclusions: Our analysis provides evidence that Yo-Yo intermittent tests reference values differ with respect to the type and level of sport performed.The presented results may be used by practitioners, trainers and athletes to rate Yo-Yo intermittent test performance levels and monitor training effects

Outcome of 11 children with ependymoblastoma treated within the prospective HIT-trials between 1991 and 2006

Ependymoblastoma is a rare malignant brain tumor of early childhood. Data on clinical behavior and optimal treatment strategies are scarce. We report on 11 consecutively treated children with centrally confirmed diagnosis of CNS ependymoblastoma, registered between February 1994 and October 2006 to the prospective GPOH-HIT multicenter brain tumor trials, and treated by multimodal regimens. Median age at diagnosis was 3.5years (range, 1.8-5.6years), and the median follow-up of survivors was 5.9years (range, 2.2-12.7years). Initial stage was M0 in 9, and M0/1 (no cerebrospinal fluid examination done) in 2 patients. Gross-total tumor resection was achieved in 7 patients, incomplete resection in 4 patients. Further primary therapy included chemotherapy in all patients, craniospinal radiotherapy in 5 patients and high-dose chemotherapy in 2 patients. Tumor response to chemotherapy was observed in 1 of 4 evaluable patients. Tumor progression occurred in 7 patients after a median time of 5.0months (range, 2.5-19.2months). Five-year progression-free survival was 36.4% (±14.5%), 5-year overall survival 30.3% (±15.9%). Of 4 survivors, 3 had gross-total tumor resection, and all were treated by either craniospinal radiotherapy and/or high-dose chemotherapy with autologous blood stem cell rescue. Prognosis of children with ependymoblastoma is poor, but sustained remissions have been achieved after multimodal treatment. Considerable diagnostic discrepancies between local and central pathologists underscore the importance of central review. Further studies are needed to improve survival of children with this rare malignant central nervous system tumo

Local and systemic therapy of recurrent medulloblastomas in children and adolescents: results of the P-HIT-REZ 2005 study

SIMPLE SUMMARY: A medulloblastoma recurrence is usually associated with an unfavorable prognosis. The German P-HIT-REZ 2005 Study gathered data from patients with relapsed medulloblastomas treated in different, non-randomized therapy arms dependent on preconditions of the patients (previous treatment, comorbidities, relapse pattern), the decision of treating physicians, and the patients’/parents’ choice. A total of 93 evaluable patients with refractory or relapsed medulloblastoma were enrolled. The main aim of this study was to analyze the impact of patient and disease characteristics as well as local and systemic therapies on post-relapse progression-free (PFS) and overall survival (OS). In multivariate analysis, a short time until the first recurrence (<18 months) was the strongest predictor for a worse PFS and OS, which was mainly associated with molecular subgroup 3. Metastatic disease, at relapse, only had a significant impact on OS. Re-biopsy, at relapse, is highly recommended to investigate the histopathological and molecular genetic tumor characteristics and to exclude a secondary malignancy. ABSTRACT: Recurrent medulloblastomas are associated with survival rates <10%. Adequate multimodal therapy is being discussed as having a major impact on survival. In this study, 93 patients with recurrent medulloblastoma treated in the German P-HIT-REZ 2005 Study were analyzed for survival (PFS, OS) dependent on patient, disease, and treatment characteristics. The median age at the first recurrence was 10.1 years (IQR: 6.9–16.1). Median PFS and OS, at first recurrence, were 7.9 months (CI: 5.7–10.0) and 18.5 months (CI: 13.6–23.5), respectively. Early relapses/progressions (<18 months, n = 30/93) found mainly in molecular subgroup 3 were associated with markedly worse median PFS (HR: 2.34) and OS (HR: 3.26) in regression analyses. A significant survival advantage was found for the use of volume-reducing surgery as well as radiotherapy. Intravenous chemotherapy with carboplatin and etoposide (ivCHT, n = 28/93) showed improved PFS and OS data and the best objective response rate (ORR) was 66.7% compared to oral temozolomide (oCHT, n = 47/93) which was 34.8%. Intraventricular (n = 43) as well as high-dose chemotherapy (n = 17) at first relapse was not related to a significant survival benefit. Although the results are limited due to a non-randomized study design, they may serve as a basis for future treatment decisions in order to improve the patients’ survival

Studies on the Utilization of Sugar Beet Leaves as the Rock-Horn Cockerels Green Feed

Purpose: To compare event-free survival (EFS), overall survival (OS), pattern of relapse, and hearing loss in children with standard-risk medulloblastoma treated by postoperative hyperfractionated or conventionally fractionated radiotherapy followed by maintenance chemotherapy. Patients and Methods: In all, 340 children age 4 to 21 years from 122 European centers were postoperatively staged and randomly assigned to treatment with hyperfractionated radiotherapy (HFRT) or standard (conventional) fractionated radiotherapy (STRT) followed by a common chemotherapy regimen consisting of eight cycles of cisplatin, lomustine, and vincristine. Results: After a median follow-up of 4.8 years (range, 0.1 to 8.3 years), survival rates were not significantly different between the two treatment arms: 5-year EFS was 77% ± 4% in the STRT group and 78% ± 4% in the HFRT group; corresponding 5-year OS was 87% ± 3% and 85% ± 3%, respectively. A postoperative residual tumor of more than 1.5 cm2 was the strongest negative prognostic factor. EFS of children with all reference assessments and no large residual tumor was 82% ± 2% at 5 years. Patients with a delay of more than 7 weeks to the start of RT had a worse prognosis. Severe hearing loss was not significantly different for the two treatment arms at follow-up. Conclusion: In this large randomized European study, which enrolled patients with standard-risk medulloblastoma from more than 100 centers, excellent survival rates were achieved in patients without a large postoperative residual tumor and without RT treatment delays. EFS and OS for HFRT was not superior to STRT, which therefore remains standard of care in this disease

Implementing online interventions in ICare: A biostatistical perspective

The implementation of research studies is a highly complex process. All decisions with respect to the study design impact the statistical analyses and interpretation of the results. Within the ICare research project (EU H2020 Grant agreement 634757) seven research trials are conducted to generate evidence on efficacy, effectiveness and the dissemination potential of online interventions targeting eating disorders, common mental health problems and resilience. Within the project a central biometrical unit was established to manage and coordinate data collection, processing and statistical data analysis. This allows for harmonized trial planning, conduct, data management processes and analysis strategies. The purpose of this article is to describe the common concepts underlying all seven ICare trials. This includes development of (adaptive sequential) study designs, handling of missing values, general data management and processing as well as data protection aspects. Keywords: Biostatistics, Study designs, Statistical analysis, Data management and protection, Randomized controlled trial

Degradation of phosphatidylethanol counteracts the apparent phospholipase D-mediated formation in heart and other organs

Phosphatidylalcohols, such as phosphatidylethanol (PEth), are formed from phosphatidylcholine in the presence of a primary alcohol (e.g., ethanol). This 'transphosphatidylation' reaction is used as specific phospholipase D (PLD) assay. Accumulation of PEth in tissues is recognized as a reliable measure of PLD activity, as PEth is allegedly metabolically stable. The general validity of this assumption was reinvestigated in isolated rat heart, small intestine and brain slices. The half-times of 3H-PEth degradation (labelled with 3H-myristic acid and preformed by ethanol exposure for 30 min) were about 1 h in heart and small intestine, but 17 h in brain. As the formation of PEth is superimposed by simultaneous degradation, a mathematical model was established to calculate the differences between 'true' and 'apparent' PEth formation. As expected, this difference was relevant in heart and intestine, but not in brain tissue. For example, ischemia in the perfused heart for 30 min reversibly blocked PEth degradation and seemingly enhanced PEth formation; the block was reversed by ischemic preconditioning (IPC) and by pretreatment with diazoxide, an opener of mitochondrial K(ATP) channels. In conclusion, PEth degradation in heart was energy-dependent and rapid, which, when ignored, may lead to misinterpretation of PEth values with respect to PLD activity

Confirmatory adaptive group sequential designs for single-arm phase II studies with multiple time-to-event endpoints

Existing methods concerning the assessment of long-term survival outcomes in one-armed trials are commonly restricted to one primary endpoint. Corresponding adaptive designs suffer from limitations regarding the use of information from other endpoints in interim design changes. Here we provide adaptive group sequential one-sample tests for testing hypotheses on the multivariate survival distribution derived from multi-state models, while making provision for data-dependent design modifications based on all involved time-to-event endpoints. We explicitly elaborate application of the methodology to one-sample tests for the joint distribution of (i) progression-free survival (PFS) and overall survival (OS) in the context of an illness-death model, and (ii) time to toxicity and time to progression while accounting for death as a competing event. Large sample distributions are derived using a counting process approach. Small sample properties are studied by simulation. An already established multi-state model for non-small cell lung cancer is used to illustrate the adaptive procedure

Reference curve sampling variability in one–sample log–rank tests

The one–sample log–rank test is the method of choice for single–arm Phase II trials with time–to–event endpoint. It allows to compare the survival of patients to a reference survival curve that typically represents the expected survival under standard of care. The one–sample log–rank test, however, assumes that the reference survival curve is known. This ignores that the reference curve is commonly estimated from historic data and thus prone to sampling error. Ignoring sampling variability of the reference curve results in type I error rate inflation. We study this inflation in type I error rate analytically and by simulation. Moreover we derive the actual distribution of the one–sample log–rank test statistic, when the sampling variability of the reference curve is taken into account. In particular, we provide a consistent estimate of the factor by which the true variance of the one-sample log–rank statistic is underestimated when reference curve sampling variability is ignored. Our results are further substantiated by a case study using a real world data example in which we demonstrate how to estimate the error rate inflation in the planning stage of a trial

Confirmatory adaptive group sequential designs for clinical trials with multiple time-to-event outcomes in Markov models

The analysis of multiple time-to-event outcomes in a randomised controlled clinical trial can be accomplished with exisiting methods. However, depending on the characteristics of the disease under investigation and the circumstances in which the study is planned, it may be of interest to conduct interim analyses and adapt the study design if necessary. Due to the expected dependency of the endpoints, the full available information on the involved endpoints may not be used for this purpose. We suggest a solution to this problem by embedding the endpoints in a multi-state model. If this model is Markovian, it is possible to take the disease history of the patients into account and allow for data-dependent design adaptiations. To this end, we introduce a flexible test procedure for a variety of applications, but are particularly concerned with the simultaneous consideration of progression-free survival (PFS) and overall survival (OS). This setting is of key interest in oncological trials. We conduct simulation studies to determine the properties for small sample sizes and demonstrate an application based on data from the NB2004-HR study.Comment: 32 pages, including 16 pages of Appendix; 3 figures; 4 table