A nonparametric relative treatment effect for direct comparisons of censored paired survival outcomes.

A frequently addressed issue in clinical trials is the comparison of censored paired survival outcomes, for example, when individuals were matched based on their characteristics prior to the analysis. In this regard, a proper incorporation of the dependence structure of the paired censored outcomes is required and, up to now, appropriate methods are only rarely available in the literature. Moreover, existing methods are not motivated by the strive for insights by means of an easy-to-interpret parameter. Hence, we seek to develop a new estimand-driven method to compare the effectiveness of two treatments in the context of right-censored survival data with matched pairs. With the help of competing risks techniques, the so-called relative treatment effect is estimated. This estimand describes the probability that individuals under Treatment 1 have a longer lifetime than comparable individuals under Treatment 2. We derive hypothesis tests and confidence intervals based on a studentized version of the estimator, where resampling-based inference is established by means of a randomization method. In a simulation study, we demonstrate for numerous sample sizes and different amounts of censoring that the developed test exhibits a good power. Finally, we apply the methodology to a well-known benchmark data set from a trial with patients suffering from diabetic retinopathy.

Wearable based monitoring and self-supervised contrastive learning detect clinical complications during treatment of Hematologic malignancies.

Serious clinical complications (SCC; CTCAE grade ≥ 3) occur frequently in patients treated for hematological malignancies. Early diagnosis and treatment of SCC are essential to improve outcomes. Here we report a deep learning model-derived SCC-Score to detect and predict SCC from time-series data recorded continuously by a medical wearable. In this single-arm, single-center, observational cohort study, vital signs and physical activity were recorded with a wearable for 31,234 h in 79 patients (54 Inpatient Cohort (IC)/25 Outpatient Cohort (OC)). Hours with normal physical functioning without evidence of SCC (regular hours) were presented to a deep neural network that was trained by a self-supervised contrastive learning objective to extract features from the time series that are typical in regular periods. The model was used to calculate a SCC-Score that measures the dissimilarity to regular features. Detection and prediction performance of the SCC-Score was compared to clinical documentation of SCC (AUROC ± SD). In total 124 clinically documented SCC occurred in the IC, 16 in the OC. Detection of SCC was achieved in the IC with a sensitivity of 79.7% and specificity of 87.9%, with AUROC of 0.91 ± 0.01 (OC sensitivity 77.4%, specificity 81.8%, AUROC 0.87 ± 0.02). Prediction of infectious SCC was possible up to 2 days before clinical diagnosis (AUROC 0.90 at -24 h and 0.88 at -48 h). We provide proof of principle for the detection and prediction of SCC in patients treated for hematological malignancies using wearable data and a deep learning model. As a consequence, remote patient monitoring may enable pre-emptive complication management.

Sodium evolution in hyponatraemia: a mixed effects model analysis of the Hyponatraemia Registry.

OBJECTIVE: Achieving recommended targets of sodium correction is challenging to physicians treating hyponatraemia. Plasma sodium has to be increased effectively, yet overcorrection must be prevented. This is often hampered by a high variability of responses to treatment. Here, we sought to delineate factors influencing sodium evolution. DESIGN: We retrospectively analysed 3460 patients from the multinational Hyponatraemia Registry comprising a wide range of hyponatraemia aetiologies and treatment strategies. METHODS: Multivariable linear mixed effects models were applied to identify predictors of plasma sodium evolution within the first 24 h of treatment. RESULTS: Evolution of sodium levels over time showed a curvilinear pattern with steeper rise at earlier time points. Baseline sodium showed the most pronounced impact with an additional increment of 3.12 mEq/L for every 10 mEq/L initial sodium reduction. With sodium increments of 1.9 mEq/L and 1.4 mEq/L per 24 h, respectively, the entities hypovolaemic and thiazide-associated hyponatraemia were independent factors for sodium evolution. Therapeutic regimens using hypertonic saline (4.6 mEq/L/24 h), tolvaptan (3.4 mEq/L/24 h), or combination therapy (2.6 mEq/L/24 h) were also associated with a significantly larger sodium rise when compared with no active treatment. CONCLUSIONS: Choice and dosing of active hyponatraemia therapy should be adjusted not only according to aetiology but most importantly to pretreatment sodium. Although counterintuitive, less aggressive therapy in more profound hyponatraemia might be safer but yet effective at least in less severe cases.

Selective internal radiotherapy in Germany: a review of indications and hospital mortality from 2012 to 2019.

Background and Aim: Selective internal radiotherapy (SIRT) is a minimal invasive tumor therapy for hepatocellular carcinoma (HCC), biliary tract cancer (BTC), and liver metastasis of extrahepatic tumors. Comprehensive data on past and current trends of SIRT as well as outcome parameters such as in-hospital mortality and adverse events in Germany are missing. Methods: We evaluated current clinical developments and outcomes of SIRT in Germany based on standardized hospital discharge data, provided by the German Federal Statistical Office from 2012 to 2019. Results: A total of 11,014 SIRT procedures were included in the analysis. The most common indication was hepatic metastases (54.3%; HCC: 39.7%; BTC: 6%) with a trend in favor of HCC and BTC over time. Most SIRTs were performed with yttrium-90 (99.6%) but the proportion of holmium-166 SIRTs increased in recent years. There were significant differences in the mean length of hospital stay between 90Y (3.67 ± 2 days) and 166Ho (2.9 ± 1.3 days) based SIRTs. Overall in-hospital mortality was 0.14%. The mean number of SIRTs/hospital was 22.9 (SD ± 30.4). The 20 highest case volume centers performed 25.6% of all SIRTs. Conclusion: Our study gives a detailed insight into indications, patient-related factors, and the incidence of adverse events as well as the overall in-hospital mortality in a large SIRT collective in Germany. SIRT is a safe procedure with low overall in-hospital mortality and a well-definable spectrum of adverse events. We report differences in the regional distribution of performed SIRTs and changes in the indications and used radioisotopes over the years. Relevance for Patients: SIRT is a safe procedure with very low overall mortality and a well-definable spectrum of adverse events, particularly gastrointestinal. Complications are usually treatable or self-limiting. Acute liver failure is a potentially fatal but exceptionally rare complication. 166Ho has promising beneficial bio-physical characteristics and 166Ho-based SIRT should be further evaluated against 90Y-based SIRT as the current standard of care.

Investigating non-inferiority or equivalence in time-to-event data under non-proportional hazards.

The classical approach to analyze time-to-event data, e.g. in clinical trials, is to fit Kaplan-Meier curves yielding the treatment effect as the hazard ratio between treatment groups. Afterwards, a log-rank test is commonly performed to investigate whether there is a difference in survival or, depending on additional covariates, a Cox proportional hazard model is used. However, in numerous trials these approaches fail due to the presence of non-proportional hazards, resulting in difficulties of interpreting the hazard ratio and a loss of power. When considering equivalence or non-inferiority trials, the commonly performed log-rank based tests are similarly affected by a violation of this assumption. Here we propose a parametric framework to assess equivalence or non-inferiority for survival data. We derive pointwise confidence bands for both, the hazard ratio and the difference of the survival curves. Further we propose a test procedure addressing non-inferiority and equivalence by directly comparing the survival functions at certain time points or over an entire range of time. Once the model's suitability is proven the method provides a noticeable power benefit, irrespectively of the shape of the hazard ratio. On the other hand, model selection should be carried out carefully as misspecification may cause type I error inflation in some situations. We investigate the robustness and demonstrate the advantages and disadvantages of the proposed methods by means of a simulation study. Finally, we demonstrate the validity of the methods by a clinical trial example.

Identifying alert concentrations using a model-based bootstrap approach.

The determination of alert concentrations, where a pre-specified threshold of the response variable is exceeded, is an important goal of concentration-response studies. The traditional approach is based on investigating the measured concentrations and attaining statistical significance of the alert concentration by using a multiple t-test procedure. In this paper, we propose a new model-based method to identify alert concentrations, based on fitting a concentration-response curve and constructing a simultaneous confidence band for the difference of the response of a concentration compared to the control. In order to obtain these confidence bands, we use a bootstrap approach which can be applied to any functional form of the concentration-response curve. This particularly offers the possibility to investigate also those situations where the concentration-response relationship is not monotone and, moreover, to detect alerts at concentrations which were not measured during the study, providing a highly flexible framework for the problem at hand.

Performance Assessment for a Guided Wave-Based SHM System Applied to a Stiffened Composite Structure.

To assess the ability of structural health monitoring (SHM) systems, a variety of prerequisites and contributing factors have to be taken into account. Within this publication, this variety is analyzed for actively introduced guided wave-based SHM systems. For these systems, it is not possible to analyze their performance without taking into account their structure and their applied system parameters. Therefore, interdependencies of performance assessment are displayed in an SHM pyramid based on the structure and its monitoring requirements. Factors influencing the quality, capability and reliability of the monitoring system are given and put into relation with state-of-the-art performance analysis in a non-destructive evaluation. While some aspects are similar and can be treated in similar ways, others, such as location, environmental condition and structural dependency, demand novel solutions. Using an open-access data set from the Open Guided Waves platform, a detailed method description and analysis of path-based performance assessment is presented.The adopted approach clearly begs the question about the decision framework, as the threshold affects the reliability of the system. In addition, the findings show the effect of the propagation path according to the damage position. Indeed, the distance of damage directly affects the system performance. Otherwise, the propagation direction does not alter the potentiality of the detection approach despite the anisotropy of composites. Nonetheless, the finite waveguide makes it necessary to look at the whole paths, as singular phenomena associated with the reflections may appear. Numerical investigation helps to clarify the centrality of wave mechanics and the necessity to take sensor position into account as an influencing factor. Starting from the findings achieved, all the issues are discussed, and potential future steps are outlined.

Awareness of Human Papillomavirus (HPV) and HPV Vaccination amongst the General Population in Germany: Lack of Awareness and Need for Action.

INTRODUCTION: The oncogenic human papillomaviruses (HPV) types 16 and 18 contribute to more than 73% cases of all HPV-related cancers and commonly affect the anogenital and head and neck region, with rapidly rising incidence rates of HPV-related oropharyngeal squamous cell carcinomas (OPSCC). HPV vaccination has the potential to decrease the burden of HPV-related disease, but vaccination rates remain low in many countries. We investigated the level of awareness of HPV, and HPV-OPSCC in particular, in a representative sample of the German population. MATERIALS AND METHODS: As part of an online, population-based survey, an electronic questionnaire was administered to a representative sample of 1,095 adult individuals with a specific emphasis on awareness of HPV, transmission, and indicator symptoms of oropharyngeal cancer. Statistical analysis of levels of awareness and relation of these to age, gender, and socioeconomic background were conducted using the IBM SPSS Statistics Version 25.0. RESULTS: 699/1,095 (63.8%) subjects had never heard of HPV. Of the subjects with awareness for HPV, 210 knew that HPV could be transmitted during sex (58.3%) and 138 recognized HPV as a risk factor for OPSCC (14.2%), unrelated to gender (p = 0.357), educational status (p = 0.581), or family status (p = 0.719). 416 subjects knew that a preventive vaccine against HPV existed (44.9%). Women were significantly more aware of HPV (34.2% vs. 22.8%, p < 0.001) and the vaccination (56.4% vs. 32.7%, p < 0.001) as were men. Younger individuals (age group 25-34) were significantly more aware of HPV (p < 0.001), likely as they were offered and/or had received the HPV vaccination. There was no regional variation of HPV awareness within the German state (p = 0.051). CONCLUSION: Here we demonstrate a significant lack of awareness of HPV and HPV vaccination in a representative sample of the German population. Levels of awareness of the link of HPV and oropharyngeal cancer are particularly low, bearing in mind that this cancer is commonly affecting men and incidence rates are rapidly rising in many European countries and the USA. Awareness programs and further education are required to tackle the low awareness rates and increase the uptake of the vaccination program not only in Germany, but also worldwide.

Prevalence of Cancer Predisposition Germline Variants in Male Breast Cancer Patients: Results of the German Consortium for Hereditary Breast and Ovarian Cancer.

Male breast cancer (mBC) is associated with a high prevalence of pathogenic variants (PVs) in the BRCA2 gene; however, data regarding other BC predisposition genes are limited. In this retrospective multicenter study, we investigated the prevalence of PVs in BRCA1/2 and 23 non-BRCA1/2 genes using a sample of 614 patients with mBC, recruited through the centers of the German Consortium for Hereditary Breast and Ovarian Cancer. A high proportion of patients with mBC carried PVs in BRCA2 (23.0%, 142/614) and BRCA1 (4.6%, 28/614). The prevalence of BRCA1/2 PVs was 11.0% in patients with mBC without a family history of breast and/or ovarian cancer. Patients with BRCA1/2 PVs did not show an earlier disease onset than those without. The predominant clinical presentation of tumor phenotypes was estrogen receptor (ER)-positive, progesterone receptor (PR)-positive, and HER2-negative (77.7%); further, 10.2% of the tumors were triple-positive, and 1.2% were triple-negative. No association was found between ER/PR/HER2 status and BRCA1/2 PV occurrence. Comparing the prevalence of protein-truncating variants (PTVs) between patients with mBC and control data (ExAC, n = 27,173) revealed significant associations of PTVs in both BRCA1 and BRCA2 with mBC (BRCA1: OR = 17.04, 95% CI = 10.54−26.82, p < 10−5; BRCA2: OR = 77.71, 95% CI = 58.71−102.33, p < 10−5). A case-control investigation of 23 non-BRCA1/2 genes in 340 BRCA1/2-negative patients and ExAC controls revealed significant associations of PTVs in CHEK2, PALB2, and ATM with mBC (CHEK2: OR = 3.78, 95% CI = 1.59−7.71, p = 0.002; PALB2: OR = 14.77, 95% CI = 5.02−36.02, p < 10−5; ATM: OR = 3.36, 95% CI = 0.89−8.96, p = 0.04). Overall, our findings support the benefit of multi-gene panel testing in patients with mBC irrespective of their family history, age at disease onset, and tumor phenotype.

Similarity of competing risks models with constant intensities in an application to clinical healthcare pathways involving prostate cancer surgery.

The recent availability of routine medical data, especially in a university-clinical context, may enable the discovery of typical healthcare pathways, that is, typical temporal sequences of clinical interventions or hospital readmissions. However, such pathways are heterogeneous in a large provider such as a university hospital, and it is important to identify similar care pathways that can still be considered typical pathways. We understand the pathway as a temporal process with possible transitions from a single initial treatment state to hospital readmission of different types, which constitutes a competing risks setting. In this article, we propose a multi-state model-based approach to uncover pathway similarity between two groups of individuals. We describe a new bootstrap procedure for testing the similarity of constant transition intensities from two competing risk models. In a large simulation study, we investigate the performance of our similarity approach with respect to different sample sizes and different similarity thresholds. The studies are motivated by an application from urological clinical routine and we show how the results can be transferred to the application example.

Catalytically Active Inclusion Bodies─Benchmarking and Application in Flow Chemistry.

In industries, enzymes are often immobilized to obtain stable preparations that can be utilized in batch and flow processes. In contrast to traditional immobilization methods that rely on carrier binding, various immobilization strategies have been recently presented that enable the simultaneous production and in vivo immobilization of enzymes. Catalytically active inclusion bodies (CatIBs) are a promising example for such in vivo enzyme immobilizates. CatIB formation is commonly induced by fusion of aggregation-inducing tags, and numerous tags, ranging from small synthetic peptides to protein domains or whole proteins, have been successfully used. However, since these systems have been characterized by different groups employing different methods, a direct comparison remains difficult, which prompted us to benchmark different CatIB-formation-inducing tags and fusion strategies. Our study highlights that important CatIB properties like yield, activity, and stability are strongly influenced by tag selection and fusion strategy. Optimization enabled us to obtain alcohol dehydrogenase CatIBs with superior activity and stability, which were subsequently applied for the first time in a flow synthesis approach. Our study highlights the potential of CatIB-based immobilizates, while at the same time demonstrating the robust use of CatIBs in flow chemistry.

Clonal Hematopoiesis-Associated Gene Mutations in a Clinical Cohort of 448 Patients With Ovarian Cancer.

BACKGROUND: Cancer patients are at risk of secondary therapy-related myeloid neoplasms (t-MNs). Acquired blood-specific mutations in clonal hematopoiesis (CH)-associated genes are t-MN risk factors, and their occurrence associated with cancer therapy and age. Patients with ovarian cancer (OC) showed a particularly high prevalence of CH-associated gene mutations, which may additionally be explained by the high proportion of a hereditary disease cause in this cancer entity. METHODS: We performed a retrospective analysis of 448 OC patients enrolled in the AGO-TR1 study; 249 were enrolled at primary diagnosis and 199 at platinum-sensitive recurrence. Analyses included the most frequently altered CH-associated genes (ASXL1, DNMT3A, GNAS, JAK2, PPM1D, SF3B1, SH2B3, SRSF2, TET2, TP53). Results were analyzed according to the BRCA1/2 germline (gBRCA1/2) mutation status. All statistical tests were 2-sided. RESULTS: Advanced age at blood draw and a high number of prior platinum-based chemotherapy lines were risk factors to acquire CH-associated gene mutations, with gene-specific effects observed. Binomial logistic regression suggested increased probabilities for gBRCA1/2 mutation carriers to acquire CH-associated PPM1D and TP53 gene mutations (PPM1D: odds ratio = 4.30, 95% confidence interval = 1.48 to 12.46, P = .007; TP53: odds ratio = 6.20, 95% confidence interval = 0.98 to 53.9, P = .06). This observation was due to a statistically significantly increased number of platinum-based chemotherapy lines in gBRCA1/2 mutation carriers vs noncarriers (PPM1D: mean [SD] = 2.04 [1.27] vs 1.04 [0.99], P < .001; TP53: mean [SD] = 2.83 [1.33] vs 1.07 [1.01], P < .001). No interaction between platinum-based chemotherapy and gBRCA1/2 mutation status with the occurrence of CH-associated gene mutations was observed. CONCLUSIONS: A positive gBRCA1/2 mutation status is not a risk factor to acquire CH-associated gene mutations. OC patients may benefit from monitoring CH-associated gene mutations, especially following carboplatin exposure. Future clinical studies are required to assess whether treatment regimen should be adapted according to individual t-MN risks.

Efficient model-based bioequivalence testing.

The classical approach to analyze pharmacokinetic (PK) data in bioequivalence studies aiming to compare two different formulations is to perform noncompartmental analysis (NCA) followed by two one-sided tests (TOST). In this regard, the PK parameters area under the curve (AUC) and $C_{\max}$ are obtained for both treatment groups and their geometric mean ratios are considered. According to current guidelines by the U.S. Food and Drug Administration and the European Medicines Agency, the formulations are declared to be sufficiently similar if the $90\%$ confidence interval for these ratios falls between $0.8$ and $1.25 $. As NCA is not a reliable approach in case of sparse designs, a model-based alternative has already been proposed for the estimation of $\rm AUC$ and $C_{\max}$ using nonlinear mixed effects models. Here we propose another, more powerful test than the TOST and demonstrate its superiority through a simulation study both for NCA and model-based approaches. For products with high variability on PK parameters, this method appears to have closer type I errors to the conventionally accepted significance level of $0.05$, suggesting its potential use in situations where conventional bioequivalence analysis is not applicable.

Testing for similarity of binary efficacy-toxicity responses.

Clinical trials often aim to compare two groups of patients for efficacy and/or toxicity depending on covariates such as dose. Examples include the comparison of populations from different geographic regions or age classes or, alternatively, of different treatment groups. Similarity of these groups can be claimed if the difference in average outcome is below a certain margin over the entire covariate range. In this article, we consider the problem of testing for similarity in the case that efficacy and toxicity are measured as binary outcome variables. We develop a new test for the assessment of similarity of two groups for a single binary endpoint. Our approach is based on estimating the maximal deviation between the curves describing the responses of the two groups, followed by a parametric bootstrap test. Further, using a two-dimensional Gumbel-type model we develop methodology to establish similarity for (correlated) binary efficacy-toxicity outcomes. We investigate the operating characteristics of the proposed methodology by means of a simulation study and present a case study as an illustration.

Upfront Surgery vs. Primary Chemoradiation in an Unselected, Bicentric Patient Cohort with Oropharyngeal Squamous Cell Carcinoma-A Matched-Pair Analysis.

The two pillars of therapy for oropharyngeal squamous cell carcinoma (OPSCC) are upfront surgery and primary chemoradiotherapy. Substantial regional preferences exist with regard to the selection of treatment. Despite new therapeutic approaches, patient survival remains poor, with an approximate overall survival (OS) rate of 50% at five years. This study was conducted to investigate a potential survival benefit depending on the treatment modality in OPSCC patients. We retrospectively collected data of 853 patients with histologically confirmed OPSCC from the Giessen and Maastricht cancer databases. To identify risk factors affecting survival, a Cox-proportional hazard model was applied to 442 patients with complete data sets. Based on this cohort a matched-pair analysis with 158 patients was performed to compare OS rates of patients treated either with upfront surgery or primary chemoradiation. For the collective cohort, patients treated with upfront surgery had significantly improved OS rates compared to patients treated with primary chemoradiation. In the matched-pair analysis adjusted for patients' T-, N- and HPV-status as well as risk profile, we observed that both treatment approaches offered equivalent OS rates. Our study emphasizes that treatment recommendations should be made whenever possible on the basis of side-effect profiles caused by the therapeutic approach used. To draw further conclusions, results of the ongoing "best of" (NCT2984410) study are eagerly awaited, investigating the functional outcome after treatment of OPSCC patients.

New Model-Based Bioequivalence Statistical Approaches for Pharmacokinetic Studies with Sparse Sampling.

In traditional pharmacokinetic (PK) bioequivalence analysis, two one-sided tests (TOST) are conducted on the area under the concentration-time curve and the maximal concentration derived using a non-compartmental approach. When rich sampling is unfeasible, a model-based (MB) approach, using nonlinear mixed effect models (NLMEM) is possible. However, MB-TOST using asymptotic standard errors (SE) presents increased type I error when asymptotic conditions do not hold. In this work, we propose three alternative calculations of the SE based on (i) an adaptation to NLMEM of the correction proposed by Gallant, (ii) the a posteriori distribution of the treatment coefficient using the Hamiltonian Monte Carlo algorithm, and (iii) parametric random effects and residual errors bootstrap. We evaluate these approaches by simulations, for two-arms parallel and two-period, two-sequence cross-over design with rich (n = 10) and sparse (n = 3) sampling under the null and the alternative hypotheses, with MB-TOST. All new approaches correct for the inflation of MB-TOST type I error in PK studies with sparse designs. The approach based on the a posteriori distribution appears to be the best compromise between controlled type I errors and computing times. MB-TOST using non-asymptotic SE controls type I error rate better than when using asymptotic SE estimates for bioequivalence on PK studies with sparse sampling.

[Effort-Reward Imbalance among otolaryngology residents in Germany]. / Psychosoziale Arbeitsbelastung von Ärzten in der HNO-Facharztweiterbildung.

INTRODUCTION: An increased psychosocial workload can have an negative impact on health. An effective way to record this is the effort reward imbalance model postulated by Siegrist. Values on this topic from ENT residents are missing, which is why the concept and corresponding questions were included in the survey on the current situation in further education. MATERIAL AND METHODS: An online survey on the current situation of the ENT residency including the recording of psychosocial workload was developed by ENT physicians on the basis of a well-known questionnaire of colleagues of the Alliance of Young Physicians. The short version of the validated questionnaire on the effort reward imbalance model according to Siegrist with 16 items was used. An online survey was carried out addressing all ENT residents in Germany known to the German society of Oto-Rhino-Laryngology, Head and Neck surgery. The survey was sent by e-mail and was available from April 1st to July 31st in 2019. RESULTS: 92,3 % of the participants had an effort-reward imbalance. The mean value of effort reward imbalance was 1.57 ± 0.43, adjusted 2.16 ±â€Š1.36. The effort scale was 10.71 ±â€Š1.40 (3-12), adjusted 85.72 ±â€Š15.52, reward scale 16.58 ±â€Š2.86 (7-28), adjusted 45.61 ±â€Š13.63, over commitment 17 ±â€Š3.37, adjusted 61.14 ±â€Š18.73. A high effort reward imbalance had positive significant correlations with regard to the duration of residency, the number of working hours per week and the number of duty hours per month. CONCLUSION: The effort and reward imbalance is comparable to other specialty physicians in residency. It is related to working hours, services and the progress of training. It can be improved through personal initiative and could be supplemented with the support of the hospital's internal stakeholders.

[Survey on current situation in otolaryngology residency]. / Umfrage der "Jungen HNO" zur aktuellen Situation der Weiterbildung von HNO-Ärzten.

BACKGROUND: Residents of ENT were asked about their situation in residency. A good and well structured training is the key for an attractive residency. METHODS: Between April 25-August 1, 2019, 691 residents registered with the German Society of Otorhinolaryngology, Head- and Neck Surgery ENT society were invited to anonymously participate in an online survey using SurveyMonkey® on the situation of the education in ENT and their working conditions. 25 of 80 questions were asked on the topics of structure and quality of the education in residency. RESULTS: The response rate was 36 % (n = 249). The participants attested their further training an average result. Mainly they see deficits in the further education and training structure and culture with a desire for improved feedback and improved surgical training. Participants were more dissatisfied with advanced further training time, regardless of ownership of the institution and level of care. CONCLUSIONS: The survey proposes concrete advice for improvement of ENT medical training in Germany. Suggestions for improvement are further development of the associated training and continuing education programs in cooperation with professional associations, structured feedback and supervision as well as transparent rotation plans and reliable working conditions.

Equivalence of regression curves sharing common parameters.

In clinical trials, the comparison of two different populations is a common problem. Nonlinear (parametric) regression models are commonly used to describe the relationship between covariates, such as concentration or dose, and a response variable in the two groups. In some situations, it is reasonable to assume some model parameters to be the same, for instance, the placebo effect or the maximum treatment effect. In this paper, we develop a (parametric) bootstrap test to establish the similarity of two regression curves sharing some common parameters. We show by theoretical arguments and by means of a simulation study that the new test controls its significance level and achieves a reasonable power. Moreover, it is demonstrated that under the assumption of common parameters, a considerably more powerful test can be constructed compared with the test that does not use this assumption. Finally, we illustrate the potential applications of the new methodology by a clinical trial example.

Assessing the similarity of dose response and target doses in two non-overlapping subgroups.

We consider 2 problems of increasing importance in clinical dose finding studies. First, we assess the similarity of 2 non-linear regression models for 2 non-overlapping subgroups of patients over a restricted covariate space. To this end, we derive a confidence interval for the maximum difference between the 2 given models. If this confidence interval excludes the pre-specified equivalence margin, similarity of dose response can be claimed. Second, we address the problem of demonstrating the similarity of 2 target doses for 2 non-overlapping subgroups, using again an approach based on a confidence interval. We illustrate the proposed methods with a real case study and investigate their operating characteristics (coverage probabilities, Type I error rates, power) via simulation.