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Background: The SAVVY project aims to improve the analyses of adverse events (AEs) in clinical trials through the use of survival techniques appropriately dealing with varying follow-up times and competing events (CEs). This paper summarizes key features and conclusions from the various SAVVY papers. Methods: Summarizing several papers reporting theoretical investigations using simulations and an empirical study including randomized clinical trials from several sponsor organizations, biases from ignoring varying follow-up times or CEs are investigated. The bias of commonly used estimators of the absolute (incidence proportion and one minus Kaplan-Meier) and relative (risk and hazard ratio) AE risk is quantified. Furthermore, we provide a cursory assessment of how pertinent guidelines for the analysis of safety data deal with the features of varying follow-up time and CEs. Results: SAVVY finds that for both, avoiding bias and categorization of evidence with respect to treatment effect on AE risk into categories, the choice of the estimator is key and more important than features of the underlying data such as percentage of censoring, CEs, amount of follow-up, or value of the gold-standard. Conclusions: The choice of the estimator of the cumulative AE probability and the definition of CEs are crucial. Whenever varying follow-up times and/or CEs are present in the assessment of AEs, SAVVY recommends using the Aalen-Johansen estimator (AJE) with an appropriate definition of CEs to quantify AE risk. There is an urgent need to improve pertinent clinical trial reporting guidelines for reporting AEs so that incidence proportions or one minus Kaplan-Meier estimators are finally replaced by the AJE with appropriate definition of CEs. [ABSTRACT FROM AUTHOR]

AbstractInnovation, defined as the successful implementation at scale of a new invention, is key for continued success of the drug development enterprise. In this article we focus on statistical innovation in the pharmaceutical industry. We discuss both components, invention and implementation at scale, typically called commercialization, of innovation for statistical methods. These concepts are illustrated using three examples that we successfully implemented in our company. We summarize factors that foster or hinder invention and commercialization. A discussion of the mindset we consider supportive of innovation and how organizational leaders and professional organizations can generate an environment that fosters innovation concludes the article. [ABSTRACT FROM AUTHOR]

Analyses of adverse events (AEs) are an important aspect of the evaluation of experimental therapies. The SAVVY (Survival analysis for AdVerse events with Varying follow-up times) project aims to improve the analyses of AE data in clinical trials through the use of survival techniques appropriately dealing with varying follow-up times, censoring, and competing events (CE). An empirical study including 17 randomized clinical trials investigates the impact on comparisons of two treatment arms with respect to AE risks. The comparisons of relative risks (RR) of standard probability-based estimators to the gold-standard Aalen-Johansen estimator or hazard-based estimators to an estimated hazard ratio (HR) from Cox regression are done descriptively, with graphical displays, and using a random effects meta-analysis on AE level. The influence of different factors on the size of the bias is investigated in a meta-regression. We find that for both, avoiding bias and categorization of evidence with respect to treatment effect on AE risk into categories, the choice of the estimator is key and more important than features of the underlying data such as percentage of censoring, CEs, amount of follow-up, or value of the gold-standard RR. There is an urgent need to improve the guidelines of reporting AEs. [ABSTRACT FROM AUTHOR]

For the analysis of a time‐to‐event endpoint in a single‐arm or randomized clinical trial it is generally perceived that interpretation of a given estimate of the survival function, or the comparison between two groups, hinges on some quantification of the amount of follow‐up. Typically, a median of some loosely defined quantity is reported. However, whatever median is reported, is typically not answering the question(s) trialists actually have in terms of follow‐up quantification. In this paper, inspired by the estimand framework, we formulate a comprehensive list of relevant scientific questions that trialists have when reporting time‐to‐event data. We illustrate how these questions should be answered, and that reference to an unclearly defined follow‐up quantity is not needed at all. In drug development, key decisions are made based on randomized controlled trials, and we therefore also discuss relevant scientific questions not only when looking at a time‐to‐event endpoint in one group, but also for comparisons. We find that different thinking about some of the relevant scientific questions around follow‐up is required depending on whether a proportional hazards assumption can be made or other patterns of survival functions are anticipated, for example, delayed separation, crossing survival functions, or the potential for cure. We conclude the paper with practical recommendations. [ABSTRACT FROM AUTHOR]

A randomized trial allows estimation of the causal effect of an intervention compared to a control in the overall population and in subpopulations defined by baseline characteristics. Often, however, clinical questions also arise regarding the treatment effect in subpopulations of patients, which would experience clinical or disease related events post‐randomization. Events that occur after treatment initiation and potentially affect the interpretation or the existence of the measurements are called intercurrent events in the ICH E9(R1) guideline. If the intercurrent event is a consequence of treatment, randomization alone is no longer sufficient to meaningfully estimate the treatment effect. Analyses comparing the subgroups of patients without the intercurrent events for intervention and control will not estimate a causal effect. This is well known, but post‐hoc analyses of this kind are commonly performed in drug development. An alternative approach is the principal stratum strategy, which classifies subjects according to their potential occurrence of an intercurrent event on both study arms. We illustrate with examples that questions formulated through principal strata occur naturally in drug development and argue that approaching these questions with the ICH E9(R1) estimand framework has the potential to lead to more transparent assumptions as well as more adequate analyses and conclusions. In addition, we provide an overview of assumptions required for estimation of effects in principal strata. Most of these assumptions are unverifiable and should hence be based on solid scientific understanding. Sensitivity analyses are needed to assess robustness of conclusions. [ABSTRACT FROM AUTHOR]

Abstract–Coronavirus disease 2019 (COVID-19) outbreak has rapidly evolved into a global pandemic. The impact of COVID-19 on patient journeys in oncology represents a new risk to interpretation of trial results and its broad applicability for future clinical practice. We identify key intercurrent events (ICEs) that may occur due to COVID-19 in oncology clinical trials with a focus on time-to-event endpoints and discuss considerations pertaining to the other estimand attributes introduced in the ICH E9 addendum. We propose strategies to handle COVID-19 related ICEs, depending on their relationship with malignancy and treatment and the interpretability of data after them. We argue that the clinical trial objective from a world without COVID-19 pandemic remains valid. The estimand framework provides a common language to discuss the impact of COVID-19 in a structured and transparent manner. This demonstrates that the applicability of the framework may even go beyond what it was initially intended for. [ABSTRACT FROM AUTHOR]

For a trial with primary endpoint overall survival for a molecule with curative potential, statistical methods that rely on the proportional hazards assumption may underestimate the power and the time to final analysis. We show how a cure proportion model can be used to get the necessary number of events and appropriate timing via simulation. If phase 1 results for the new drug are exceptional and/or the medical need in the target population is high, a phase 3 trial might be initiated after phase 1. Building in a futility interim analysis into such a pivotal trial may mitigate the uncertainty of moving directly to phase 3. However, if cure is possible, overall survival might not be mature enough at the interim to support a futility decision. We propose to base this decision on an intermediate endpoint that is sufficiently associated with survival. Planning for such an interim can be interpreted as making a randomized phase 2 trial a part of the pivotal trial: If stopped at the interim, the trial data would be analyzed, and a decision on a subsequent phase 3 trial would be made. If the trial continues at the interim, then the phase 3 trial is already underway. To select a futility boundary, a mechanistic simulation model that connects the intermediate endpoint and survival is proposed. We illustrate how this approach was used to design a pivotal randomized trial in acute myeloid leukemia and discuss historical data that informed the simulation model and operational challenges when implementing it. [ABSTRACT FROM AUTHOR]

A draft addendum to ICH E9 has been released for public consultation in August 2017. The addendum focuses on two topics particularly relevant for randomized confirmatory clinical trials: estimands and sensitivity analyses. The need to amend ICH E9 grew out of the realization of a lack of alignment between the objectives of a clinical trial stated in the protocol and the accompanying quantification of the "treatment effect" reported in a regulatory submission. We embed time‐to‐event endpoints in the estimand framework and discuss how the four estimand attributes described in the addendum apply to time‐to‐event endpoints. We point out that if the proportional hazards assumption is not met, the estimand targeted by the most prevalent methods used to analyze time‐to‐event endpoints, logrank test, and Cox regression depends on the censoring distribution. We discuss for a large randomized clinical trial how the analyses for the primary and secondary endpoints as well as the sensitivity analyses actually performed in the trial can be seen in the context of the addendum. To the best of our knowledge, this is the first attempt to do so for a trial with a time‐to‐event endpoint. Questions that remain open with the addendum for time‐to‐event endpoints and beyond are formulated, and recommendations for planning of future trials are given. We hope that this will provide a contribution to developing a common framework based on the final version of the addendum that can be applied to design, protocols, statistical analysis plans, and clinical study reports in the future. [ABSTRACT FROM AUTHOR]

Bayesian predictive power, the expectation of the power function with respect to a prior distribution for the true underlying effect size, is routinely used in drug development to quantify the probability of success of a clinical trial. Choosing the prior is crucial for the properties and interpretability of Bayesian predictive power. We review recommendations on the choice of prior for Bayesian predictive power and explore its features as a function of the prior. The density of power values induced by a given prior is derived analytically and its shape characterized. We find that for a typical clinical trial scenario, this density has a u-shape very similar, but not equal, to a β-distribution. Alternative priors are discussed, and practical recommendations to assess the sensitivity of Bayesian predictive power to its input parameters are provided. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

When performing a pivotal clinical trial, it may be of interest to assess the probability of success (PoS) of that trial. Initially evaluated when the trial is designed, PoS can be updated as the trial progresses and new information about the drug effect becomes available. Such information can be external to the trial, such as results from trials conducted in parallel, or internal, such as continuing after an interim analysis. We develop a framework to update PoS based on such internal and external information for a time-to-event endpoint and illustrate it using a realistic development program for a new molecule. [ABSTRACT FROM PUBLISHER]

Given ever increasing costs to develop a new drug and intense competition, adaptive enrichment designs are an attractive option for a development program that allows selecting a potential subgroup defined by a binary biomarker. Such designs explicitly factor in the possibility that the new drug might differentially benefit distinct biomarker subgroups. We have compared three clinical development plans for a time-to-event endpoint, such as overall survival, that all lead to a decision in a pivotal trial either in all comers only, in allcomers and biomarker positive, in the biomarker positive only, or to declare the drug futile. The decision about which hypothesis to test at the final analysis is made based on a fast time-to-event endpoint, such as progression-free survival, at an interim analysis. We quantify the time gain when using an adaptive enrichment Phase II/III design versus alternative development approaches and we outline what type of biomarker needs to be available prior to Phase II in each scenario. We conclude with a discussion of further features of each of the considered development plans. [ABSTRACT FROM AUTHOR]

Background: The early hemodynamic normalization of polytrauma patients may lead to better survival outcomes. The aim of this study was to assess the diagnostic quality of trauma and physiological scores from widely used scoring systems in polytrauma patients. Methods: In total, 770 patients with ISS > 16 who were admitted to a trauma center within the first 24 hours after injury were included in this retrospective study. The patients were subdivided into three groups: those who died on the day of admission, those who died within the first three days, and those who survived for longer than three days. ISS, NISS, APACHE II score, and prothrombin time were recorded at admission. Results: The descriptive statistics for early death in polytrauma patients who died on the day of admission, 1-3 days after admission, and > 3 days after admission were: ISS of 41.0, 34.0, and 29.0, respectively; NISS of 50.0, 50.0, and 41.0, respectively; APACHE II score of 30.0, 25.0, and 15.0, respectively; and prothrombin time of 37.0%, 56.0%, and 84%, respectively. These data indicate that prothrombin time (AUC: 0.89) and APACHE II (AUC: 0.88) have the greatest prognostic utility for early death. Conclusion: The estimated densities of the scores may suggest a direction for resuscitative procedures in polytrauma patients [ABSTRACT FROM AUTHOR]

Abstract: Dissociative disorders are frequent comorbid conditions of other mental disorders. Yet, there is controversy about their clinical relevance, and little systematic research has been done on how they influence global functioning. Outpatients and day care patients (N=160) of several psychiatric units in Switzerland were assessed with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV Axis I Disorders, Structured Clinical Interview for DSM-IV Dissociative Disorders, Global Assessment of Functioning Scale, and World Health Organization Disability Assessment Schedule-II. The association between subjects with a dissociative disorder (N=30) and functional impairment after accounting for non-dissociative axis I disorders was evaluated by linear regression models. We found a proportion of 18.8% dissociative disorders (dissociative amnesia=0%, dissociative fugue=0.6%, depersonalization disorder=4.4%, dissociative identity disorder=7.5%, dissociative disorder-not-otherwise-specified=6.3%) across treatment settings. Adjusted for other axis I disorders, subjects with a comorbid dissociative identity disorder or dissociative disorder-not-otherwise-specified had a median global assessment of functioning score that was 0.86 and 0.88 times, respectively, the score of subjects without a comorbid dissociative disorder. These findings support the hypothesis that complex dissociative disorders, i.e., dissociative identity disorder and dissociative disorder-not-otherwise-specified, contribute to functional impairment above and beyond the impact of co-existing non-dissociative axis I disorders, and that they qualify as “serious mental illness”. [Copyright &y& Elsevier]

Background--Although newer immunosuppressive agents, such as mTOR (mammalian target of rapamycin) inhibitors, have lowered the occurrence of malignancies after transplantation, cancer is still a leading cause of death late after heart transplantation. Statins may have an impact on clinical outcomes beyond their lipid-lowering effects. The aim of the present study was to delineate whether statin therapy has an impact on cancer risk and total mortality after heart transplantation Methods and Results--A total of 255 patients who underwent heart transplantation at the University Hospital Zurich between 1985 and 2007 and survived the first year were included in the present study. The primary outcome measure was the occurrence of any malignancy; the secondary end point was overall survival. During follow-up, a malignancy was diagnosed in 108 patients (42%). The cumulative incidence of tumors 8 years after transplantation was reduced in patients receiving a statin (34% versus 13%; 95% confidence interval, 0.25-0.43 versus 0.07-0.18; P<0.003). Statin use was associated with improved cancer-free and overall survival (both P<0.0001). A Cox regression model that analyzed the time to tumor formation with or without statin therapy, adjusted for age, male sex, type of cardiomyopathy, and immunosuppressive therapy (including switch to mTOR inhibitors or tacrolimus), demonstrated a superior survival in the statin group. Statins reduced the hazard of occurrence of any malignancy by 67% (hazard ratio, 0.33; 95% confidence interval, 0.21-0.51; P<0.0001). Conclusions--Although it is not possible to adjust for all potential confounders because of the very long follow-up period, this registry suggests that statin use is associated with improved cancer-free and overall survival after cardiac transplantation. These data will need to be confirmed in a prospective trial. [ABSTRACT FROM AUTHOR]

In this paper, we consider the problem of finding the least-squares estimators of two isotonic regression curves [image omitted] and [image omitted] under the additional constraint that they are ordered, for example, [image omitted] . Given two sets of n data points y1, ..., yn and z1, ..., zn observed at (the same) design points, the estimates of the true curves are obtained by minimising the weighted least-squares criterion [image omitted] over the class of pairs of vectors (a, b)∈n×n such that a1≤a2≤···≤an, b1≤b2≤···≤bn, and ai≤bi, i=1, ..., n. The characterisation of the estimators is established. To compute these estimators, we use an iterative projected subgradient algorithm, where the projection is performed with a 'generalised' pool-adjacent-violaters algorithm, a byproduct of this work. Then, we apply the estimation method to real data from mechanical engineering. [ABSTRACT FROM AUTHOR]

The use of multiscale statistics, that is, the simultaneous inference about various stretches of data via multiple localized statistics, is a natural and popular method for inference about, for example, local qualitative characteristics of a regression function, a density, or its hazard rate. We focus on the problem of providing simultaneous confidence statements for the existence of local increases and decreases of a density and address several statistical and computational issues concerning such multiscale statistics. We first review the benefits of employing scale-dependent critical values for multiscale statistics and then derive an approximation scheme that results in a fast algorithm while preserving statistical optimality properties. The main contribution is a methodology for calibrating multiscale statistics that does not require a case-by-case derivation of its specific form. We show that in the above density context the methodology possesses statistical optimality properties and allows for a fast algorithm. We illustrate the methodology with two further examples: a multiscale statistic introduced by Gijbels and Heckman for inference about a hazard rate and local rank tests introduced by Dumbgen for inference in nonparametric regression. Code for the density application is available as the R package modehunt on CRAN. Additional code to compute critical values, reproduce the hazard rate and local rank example and the plots in the paper as well as datasets containing simulation results and an appendix with all the proofs of the theorems are available online as supplemental material. [ABSTRACT FROM AUTHOR]

The two parametric distribution functions appearing in the extreme-value theory - the generalized extreme-value distribution and the generalized Pareto distribution - have log-concave densities if the extreme-value index γ∈[-1, 0]. Replacing the order statistics in tail-index estimators by their corresponding quantiles from the distribution function that is based on the estimated log-concave density ˆ fn leads to novel smooth quantile and tail-index estimators. These new estimators aim at estimating the tail index especially in small samples. Acting as a smoother of the empirical distribution function, the log-concave distribution function estimator reduces estimation variability to a much greater extent than it introduces bias. As a consequence, Monte Carlo simulations demonstrate that the smoothed version of the estimators are well superior to their non-smoothed counterparts, in terms of mean-squared error. [ABSTRACT FROM AUTHOR]

We consider the problem of estimating a density function that is assumed to be log-concave. This semi-parametric model includes many well-known parametric classes; such as Normal, Gamma, Laplace, Logistic, Beta or Extreme value distributions, for specific parameter ranges. It is known that the maximum likelihood estimator for the log-density is always a piecewise linear function with at most as many knots as observations, but typically much less. We show that this property can be exploited to design a linearly constrained optimization problem whose iteratively calculated solution yields the estimator. We compare several standard and one recently proposed algorithm regarding their performance on this problem. [ABSTRACT FROM AUTHOR]

Purpose: The objective was to assess the influence of treatment-related and patient-related factors on the risk of developing a second primary tumor (SPT) of the upper aerodigestive tract (UADT) in patients with locoregionally advanced nonmetastatic carcinomas of the head-and-neck region. Methods and Materials: The data of 521 patients with a minimum follow-up of 1 year were pooled: 224 patients from the Swiss Group for Clinical Cancer Research (SAKK) 10/94 trial, treated with 1.2 Gy b.i.d. to 74.4 Gy, and randomized to receive or not to receive simultaneous chemotherapy with cisplatin (excluding nasopharyngeal and maxillary sinus carcinomas); and 297 patients from Geneva, all treated with accelerated radiotherapy with concomitant boost to 69.9 Gy and predominantly cisplatin-based concomitant chemotherapy in 33% of patients (including 21 patients with nasopharyngeal carcinomas). An exploratory analysis using competing risk methodology was performed. Results: A total of 65 SPT of the UADT were observed after a median observation time of 4.7 years. The overall risk of experiencing an SPT of the UADT at 10 years in the presence of all other possible events was estimated to be 33%. There were no SPTs after treatment for nasopharyngeal carcinoma. In a multivariate logistic regression analysis, there was no difference in occurrence of SPT at 3 years with respect to the administration of chemotherapy (p = 0.31), age (p = 0.62), performance status (p = 0.61), gender (p = 0.27), presence of nodal disease (p = 0.51), or T stage (p = 0.72). However, patients treated with concomitant boost had fewer SPTs (p = 0.0093). Conclusions: Our data do not suggest that addition of chemotherapy to radiotherapy influences the incidence of second cancers in patients with head-and-neck cancer. The difference in the incidence of SPT between the two radiotherapy schedule groups merits further exploration. [Copyright &y& Elsevier]

In this paper, we derive the joint distribution of progression-free and overall survival as a function of transition probabilities in a multistate model. No assumptions on copulae or latent event times are needed and the model is allowed to be non-Markov. From the joint distribution, statistics of interest can then be computed. As an example, we provide closed formulas and statistical inference for Pearson's correlation coefficient between progression-free and overall survival in a parametric framework. The example is inspired by recent approaches to quantify the dependence between progression-free survival, a common primary outcome in Phase 3 trials in oncology and overall survival. We complement these approaches by providing methods of statistical inference while at the same time working within a much more parsimonious modeling framework. Our approach is completely general and can be applied to other measures of dependence. We also discuss extensions to nonparametric inference. Our analytical results are illustrated using a large randomized clinical trial in breast cancer. [ABSTRACT FROM AUTHOR]

The ICH E9 (R1) Addendum on "Estimands and Sensitivity Analysis in Clinical Trials (Step 4)" was finalized in November 2019 and subsequently implemented by many regulatory agencies, including FDA (May 2021). This article is based on a session organized to cover experience implementing the estimand framework, including its use, impact on drug/biologic development, common challenges and ways to address them, as well as keys to productive interdisciplinary collaboration. [ABSTRACT FROM AUTHOR]

We congratulate the authors of this landscape assessment on a comprehensive and stimulating article which carefully reviews many important biostatistical issues related to the use of real-world data (RWD) to support medicine development. In the article, the authors highlight the value of the estimand framework for studies using RWD. We fully support this statement and in what follows we consider the target trial framework as a tool that could be used to both embed the estimand thinking process in studies leveraging RWD and help investigators to critically reflect on whether the RWD are sufficient to address the causal question of interest. We also reflect on several practical issues relevant to studies using RWD that would merit consideration in future work and highlight the need for more published case-studies to guide practitioners working in this setting. [ABSTRACT FROM AUTHOR]

Objective A recent consensus statement has suggested ≥3 corner inflammatory lesions (CILs) or several corner fatty lesions (CFLs) as candidate criteria indicative of axial spondyloarthritis (SpA) on magnetic resonance imaging (MRI) of the spine. The aim of this study was to evaluate the diagnostic utility of these cutoffs in nonradiographic axial SpA and ankylosing spondylitis (AS). Methods One hundred thirty consecutive patients with back pain who were ≤50 years of age and newly referred to 2 university clinics (cohorts A and B) were classified according to rheumatologist expert opinion based on results of clinical examination and pelvic radiography as having nonradiographic axial SpA (n = 50), AS (n = 33), or nonspecific back pain (n = 47). Cohort A also included 20 age-matched healthy controls. Four blinded readers assessed MRIs of the spine using the standardized Canada-Denmark module. Readers recorded CILs and CFLs in 23 discovertebral units. We tested the diagnostic utility (mean sensitivity and specificity over 4 readers) of the cutoff for the number of lesions on spinal MRI as proposed in the literature (≥2 or ≥3 CILs and ≥6 CFLs), and we tested for possible thresholds (from ≥1 CIL or CFL to ≥10 CILs or CFLs) for nonradiographic axial SpA and AS patients in both cohorts. Results None of the spinal thresholds (≥2 or ≥3 CILs and ≥6 CFLs) showed clinically relevant diagnostic utility (positive likelihood ratio [LR] range 1.38-2.36) when comparing patients with nonradiographic axial SpA to patients with nonspecific back pain. A threshold of ≥6 CILs had moderate to substantial diagnostic utility (positive LR 13.26 and 6.74 in cohorts A and B, respectively) in nonradiographic axial SpA, while ≥4 CILs showed small diagnostic utility (positive LR 3.83 and 2.72 in cohorts A and B, respectively) but specificities of >0.90. Conclusion None of the previously proposed candidate criteria for a positive spinal MRI finding of axial SpA showed clinically relevant diagnostic utility in nonradiographic axial SpA. These results question the value of proposed definitions for a positive finding of SpA based on MRI of the spine alone. [ABSTRACT FROM AUTHOR]

The past decades have seen a remarkable shift in the demographics of childbearing in Western countries. The risk for offspring with chromosomal aneuploidies with advancing maternal age is well known, but most studies failed to demonstrate a paternal age effect. Retrospectively, we analyzed two case data sets containing parental ages from pre- and postnatal cases with trisomies 21, 13 and 18. The reference data set contains the parental ages of the general Swiss population. We dichotomized all couples into two distinct groups. In the first group, the mothers' integral age was as least as the father's age or older. We compared the frequency of cases in nine 5-year intervals of maternal age. In addition, we computed logistic regression models for the binary endpoint aneuploidy yes/no where paternal ages were incorporated as linear or quadratic, as well as smooth functions within a generalized additive model framework. We demonstrated that the proportion of younger fathers is uniformly different between cases and controls of live-born trisomy 21 as well, although not reaching significance, for fetuses over all mother's ages. Logistic regression models with different strategies to incorporate paternal ages confirmed our findings. The negative paternal age effect was also found in pre- and postnatal cases taken together with trisomies 13 and 18. The couples with younger fathers face almost twofold odds for a child with Down syndrome (DS). We estimated odds curves for parental ages. If confirmation of these findings can be achieved, the management of couples at risk needs a major correction of the risk stratification. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the validity of the Paediatric Palliative Screening (PaPaS) Scale in determining the need for paediatric palliative care (PPC) in children aged one to 18 years. The study is investigated using proportional-odds logistic regression analysis, statistical analysis, and online questionnaires. Results show that life expectancy and child/family preferences are considered the most urgent necessity indicators for PPC.

Ankle–brachial index (ABI) assessment by Doppler is operator dependent and limited in calcified arteries. For the detection of peripheral arterial disease (PAD), we evaluated ABI and toe–finger (ToFi) pressures by infrared (IR) sensors at the digits and compared with standard Doppler (Doppler-ABI) in 100 patients with PAD and in 15 controls. Pressure indices were obtained in 86% for Doppler-ABI, 82% for IR-ABI, and 94% for IR-ToFi (P < .01). According to Bland–Altmann analysis, IR-ABI and Doppler-ABI are exchangeable (limits of agreement [loa] −0.30; 0.30, bias −0.003, 95% confidence interval [CI] −0.02; 0.02), whereas IR-ToFi was not (loa −0.23; 0.61, bias of 0.2, 95% CI 0.16; 0.23). The IR-ToFi revealed the best inter- and intrarater agreement (0.92/0.98) followed by IR-ABI (0.74/0.98) and Doppler-ABI (0.66/0.89). Ankle–brachial arterial pressure index can be assessed by IR photosensors. Although toe–finger index is not exchangeable with standard Doppler, it will need further exploration to define its value for the diagnosis of PAD due to its excellent inter- and intrarater agreement. [ABSTRACT FROM PUBLISHER]

Background: Only few countries have cohorts enabling specific and up-to-date cardiovascular disease (CVD) risk estimation. Individual risk assessment based on study samples that differ too much from the target population could jeopardize the benefit of risk charts in general practice. Our aim was to provide up-to-date and valid CVD risk estimation for a Swiss population using a novel record linkage approach. Methods: Anonymous record linkage was used to follow-up (for mortality, until 2008) 9,853 men and women aged 25–74 years who participated in the Swiss MONICA (MONItoring of trends and determinants in CVD) study of 1983–92. The linkage success was 97.8%, loss to follow-up 1990–2000 was 4.7%. Based on the ESC SCORE methodology (Weibull regression), we used age, sex, blood pressure, smoking, and cholesterol to generate three models. We compared the 1) original SCORE model with a 2) recalibrated and a 3) new model using the Brier score (BS) and cross-validation. Results: Based on the cross-validated BS, the new model (BS = 14107×10−6) was somewhat more appropriate for risk estimation than the original (BS = 14190×10−6) and the recalibrated (BS = 14172×10−6) model. Particularly at younger age, derived absolute risks were consistently lower than those from the original and the recalibrated model which was mainly due to a smaller impact of total cholesterol. Conclusion: Using record linkage of observational and routine data is an efficient procedure to obtain valid and up-to-date CVD risk estimates for a specific population. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Electronic prescribing reduces drug prescription errors and therefore improves patient safety. • Whether electronic prescribing compared with prescribing on paper facilitates the implementation of clinical pharmacologists' recommendations in the care of patients hospitalized with medical problems is not known. WHAT THIS STUDY ADDS • The use of electronic prescriptions when compared with handwritten prescriptions increased the uptake of clinical pharmacologists' recommendations for improving drug safety in hospitalized patients. AIMS To determine whether electronic prescribing facilitates the uptake of clinical pharmacologists' recommendations for improving drug safety in medical inpatients. METHODS Electronic case records and prescription charts (either electronic or paper) of 502 patients hospitalized on medical wards in a large Swiss teaching hospital between January 2009 and January 2010 were studied by four junior and four senior clinical pharmacologists. Drug-related problems were identified and interventions proposed. The implementation and time delays of these proposed interventions were compared between the patients for whom paper drug charts were used and the patients for whom electronic drug charts were used. RESULTS One hundred and fifty-eight drug-related problems in 109 hospital admissions were identified and 145 recommendations were made, of which 51% were implemented. Admissions with an electronic prescription chart ( n= 90) were found to have 2.74 times higher odds for implementation of the change than those with a paper prescription chart ( n= 53) (95% confidence interval 1.2, 6.3, P= 0.018, adjusted for any dependency introduced by patient, ward or clinical team; follow-up for two cases missing). The time delay between recommendations being made and their implementation (if any) was minimal (median 1 day) and did not differ between the two groups. CONCLUSIONS Electronic prescribing in this hospital setting was associated with increased implementation of clinical pharmacologists' recommendations for improving drug safety when compared with handwritten prescribing on paper. [ABSTRACT FROM AUTHOR]

Abstract: Background: Numerous randomised trials have confirmed the efficacy of medical expulsive therapy with tamsulosin in patients with distal ureteral stones; however, to date, no randomised, double-blind, placebo-controlled trials have been performed. Objective: The objective of this trial was to evaluate the efficacy of medical expulsive therapy with tamsulosin in a randomised, double-blind, placebo-controlled setting. Design, setting, and participants: Patients presenting with single distal ureteral stones ≤7mm were included in this trial. Intervention: Patients were randomised in a double-blind fashion to receive either tamsulosin or placebo for 21 d. The medication was discontinued after either stone expulsion or intervention. Abdominal computed tomography was performed to assess the initial and final stone status. Measurements and limitations: The primary end point was the stone expulsion rate. Secondary end points were time to stone passage, the amount of analgesic required, the maximum daily pain score, safety of the therapy, and the intervention rate. Results: Ten of 100 randomised patients were excluded from the analysis. No statistically significant differences in patient characteristics and stone size (median: 4.1mm [tamsulosin arm] vs 3.8mm [placebo arm], p =0.3) were found between the two treatment arms. The stone expulsion rate was not significantly different between the tamsulosin arm (86.7%) and the placebo arm (88.9%; p =1.0). Median time to stone passage was 7 d in the tamsulosin arm and 10 d in the placebo arm (log-rank test, p =0.36). Patients in the tamsulosin arm required significantly fewer analgesics than patients in the placebo arm (median: 3 vs 7, p =0.011). A caveat is that the exact time of stone passage was missing for 29 patients. Conclusions: Tamsulosin treatment does not improve the stone expulsion rate in patients with distal ureteral stones ≤7mm. Nevertheless, patients may benefit from a supportive analgesic effect. Clinicaltrials.gov: NCT00831701. [Copyright &y& Elsevier]

Objectives: The purpose of this investigation was firstly to assess the overall frequency of subjectively experienced symptoms self-reported by patients receiving endocrine therapy and secondly to compare these symptoms with side effects assessed by clinicians in pivotal trials. Methods: Unselected patients with early and advanced breast cancer receiving endocrine therapy were approached consecutively during a routine outpatient visit. They received a questionnaire called Checklist for Patients with Endocrine Therapy (C-PET), a validated self-assessment tool to determine prespecified symptoms associated with endocrine therapy. Data on toxicity were also obtained from previously published trials. Results: 405 patients were approached and 373 agreed to participate in this study. Some symptoms were significantly more often recorded by the women in the adjuvant setting completing the C-PET than by physicians’ reports in pivotal trials: hot flushes/sweats (C-PET 70%, ATAC 40% and BIG1-98 38%), low energy (C-PET 45%, ATAC 15% and BIG1-98 9%), fluid retention (C-PET 22% and BIG1-98 7%) and vaginal dryness (C-PET 30% and BIG1-98 3%). Similar differences were observed in the metastatic and adjuvant setting. Conclusions: A simple tool like the C-PET questionnaire is able to reflect the treatment burden of endocrine therapies and may be helpful to improve communication between patients and care providers. Some symptoms were significantly more often reported by the women in the C-PET than by physicians in pivotal trials. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses a study on the antileukemic efficacy and the toxicity of low dose 2-chlorodeoxyadenosine (CDA) when given as a single subcutaneous injection to patients with hairy cell leukemia (HCL).

Adapting the final sample size of a trial to the evidence accruing during the trial is a natural way to address planning uncertainty. Since the sample size is usually determined by an argument based on the power of the trial, an interim analysis raises the question of how the final sample size should be determined conditional on the accrued information. To this end, we first review and compare common approaches to estimating conditional power, which is often used in heuristic sample size recalculation rules. We then discuss the connection of heuristic sample size recalculation and optimal two‐stage designs, demonstrating that the latter is the superior approach in a fully preplanned setting. Hence, unplanned design adaptations should only be conducted as reaction to trial‐external new evidence, operational needs to violate the originally chosen design, or post hoc changes in the optimality criterion but not as a reaction to trial‐internal data. We are able to show that commonly discussed sample size recalculation rules lead to paradoxical adaptations where an initially planned optimal design is not invariant under the adaptation rule even if the planning assumptions do not change. Finally, we propose two alternative ways of reacting to newly emerging trial‐external evidence in ways that are consistent with the originally planned design to avoid such inconsistencies. [ABSTRACT FROM AUTHOR]

An addendum of the ICH E9 guideline on Statistical Principles for Clinical Trials was released in November 2019 introducing the estimand framework. This new framework aims to align trial objectives and statistical analyses by requiring a precise definition of the inferential quantity of interest, that is, the estimand. This definition explicitly accounts for intercurrent events, such as switching to new anticancer therapies for the analysis of overall survival (OS), the gold standard in oncology. Traditionally, OS in confirmatory studies is analyzed using the intention‐to‐treat (ITT) approach comparing treatment groups as they were initially randomized regardless of whether treatment switching occurred and regardless of any subsequent therapy (treatment‐policy strategy). Regulatory authorities and other stakeholders often consider ITT results as most relevant. However, the respective estimand only yields a clinically meaningful comparison of two treatment arms if subsequent therapies are already approved and reflect clinical practice. We illustrate different scenarios where subsequent therapies are not yet approved drugs and thus do not reflect clinical practice. In such situations the hypothetical strategy could be more meaningful from patient's and prescriber's perspective. The cross‐industry Oncology Estimand Working Group (www.oncoestimand.org) was initiated to foster a common understanding and consistent implementation of the estimand framework in oncology clinical trials. This paper summarizes the group's recommendations for appropriate estimands in the presence of treatment switching, one of the key intercurrent events in oncology clinical trials. We also discuss how different choices of estimands may impact study design, data collection, trial conduct, analysis, and interpretation. [ABSTRACT FROM AUTHOR]

The estimand framework included in the addendum to the ICH E9 guideline facilitates discussions to ensure alignment between the key question of interest, the analysis, and interpretation. Therapeutic knowledge and drug mechanism play a crucial role in determining the strategy and defining the estimand for clinical trial designs. Clinical trials in patients with hematological malignancies often present unique challenges for trial design due to complexity of treatment options and existence of potential curative but highly risky procedures, for example, stem cell transplant or treatment sequence across different phases (induction, consolidation, maintenance). Here, we illustrate how to apply the estimand framework in hematological clinical trials and how the estimand framework can address potential difficulties in trial result interpretation. This paper is a result of a cross‐industry collaboration to connect the International Conference on Harmonisation (ICH) E9 addendum concepts to applications. Three randomized phase 3 trials will be used to consider common challenges including intercurrent events in hematologic oncology trials to illustrate different scientific questions and the consequences of the estimand choice for trial design, data collection, analysis, and interpretation. Template language for describing estimand in both study protocols and statistical analysis plans is suggested for statisticians' reference. [ABSTRACT FROM AUTHOR]

Background: The SAVVY project aims to improve the analyses of adverse events (AEs), whether prespecified or emerging, in clinical trials through the use of survival techniques appropriately dealing with varying follow-up times and competing events (CEs). Although statistical methodologies have advanced, in AE analyses, often the incidence proportion, the incidence density, or a non-parametric Kaplan-Meier estimator are used, which ignore either censoring or CEs. In an empirical study including randomized clinical trials from several sponsor organizations, these potential sources of bias are investigated. The main purpose is to compare the estimators that are typically used to quantify AE risk within trial arms to the non-parametric Aalen-Johansen estimator as the gold-standard for estimating cumulative AE probabilities. A follow-up paper will consider consequences when comparing safety between treatment groups.Methods: Estimators are compared with descriptive statistics, graphical displays, and a more formal assessment using a random effects meta-analysis. The influence of different factors on the size of deviations from the gold-standard is investigated in a meta-regression. Comparisons are conducted at the maximum follow-up time and at earlier evaluation times. CEs definition does not only include death before AE but also end of follow-up for AEs due to events related to the disease course or safety of the treatment.Results: Ten sponsor organizations provided 17 clinical trials including 186 types of investigated AEs. The one minus Kaplan-Meier estimator was on average about 1.2-fold larger than the Aalen-Johansen estimator and the probability transform of the incidence density ignoring CEs was even 2-fold larger. The average bias using the incidence proportion was less than 5%. Assuming constant hazards using incidence densities was hardly an issue provided that CEs were accounted for. The meta-regression showed that the bias depended mainly on the amount of censoring and on the amount of CEs.Conclusions: The choice of the estimator of the cumulative AE probability and the definition of CEs are crucial. We recommend using the Aalen-Johansen estimator with an appropriate definition of CEs whenever the risk for AEs is to be quantified and to change the guidelines accordingly. [ABSTRACT FROM AUTHOR]

Objective Assessment of combined semi-axial and semi-coronal SI joint MRI in two cohorts of young athletes to explore frequency and topography of non-specific bone marrow oedema (BMO), its association with four constitutional SI joint features, and potential restriction of false-positive assignments of Assessment of SpondyloArthritis International Society-defined sacroiliitis on standard semi-coronal scans alone. Methods Combined semi-axial and semi-coronal SI joint MRI scans of 20 recreational runners before/after running and 22 elite ice-hockey players were evaluated by three blinded readers for BMO and its association with four constitutional SI joint features: vascular partial volume effect, deep iliac ligament insertion, fluid-filled bone cyst and lumbosacral transitional anomaly. Scans of TNF-treated spondyloarthritis patients served to mask readers. We analysed distribution and topography of BMO and SI joint features across eight anatomical SI joint regions (upper/lower ilium/sacrum, subdivided in anterior/posterior slices) descriptively, as concordantly recorded by ⩾2/3 readers on both MRI planes. BMO confirmed on both scans was compared with previous evaluation of semi-coronal MRI alone, which met the Assessment of SpondyloArthritis International Society definition for active sacroiliitis. Results Perpendicular semi-axial and semi-coronal MRI scans confirmed BMO in the SI joint of every fourth young athlete, preferentially in the anterior upper sacrum. BMO associated with four constitutional SI joint features was observed in 20–36% of athletes, clustering in the posterior lower ilium. The proportion of Assessment of SpondyloArthritis International Society-positive sacroiliitis recorded on the semi-coronal plane alone decreased by 33–56% upon amending semi-axial scans. Conclusion Semi-axial combined with standard semi-coronal scans in MRI protocols for sacroiliitis facilitated recognition of non-specific BMO, which clustered in posterior lower ilium/anterior upper sacrum. [ABSTRACT FROM AUTHOR]

If the assumption holds, we arrive at the representation: Graph HT ht where Graph HT ht and Graph HT ht ; this motivates their regression extrapolation approach for estimating Graph HT ht . [Extracted from the article]

Personalised oncology, whereby patients are given therapies based on their molecular tumour profile, is rapidly becoming an essential part of optimal clinical care, at least partly facilitated by recent advances in next-generation sequencing-based technology using liquid- and tissue-based biopsies. Consequently, clinical trials have shifted in approach, from traditional studies evaluating cytotoxic chemotherapy in largely histology-based populations to modified, biomarker-driven studies (e.g. basket, umbrella, platform) of molecularly guided therapies and cancer immunotherapies in selected patient subsets. Such modified study designs may assess, within the same trial structure, multiple cancer types and treatments, and should incorporate a multistakeholder perspective. This is key to generating complementary, fit-for-purpose and timely evidence for molecularly guided therapies that can be used as proof-of-concept to inform further study designs, lead to approval by regulatory authorities and be used as confirmation of clinical benefit for health technology assessment bodies. In general, the future of cancer clinical trials requires a framework for the application of innovative technologies and dynamic design methodologies, in order to efficiently transform scientific discoveries into clinical utility. Next-generation, modified studies that involve the joint efforts of all key stakeholders will offer individualised strategies that ultimately contribute to globalised knowledge and collective learning. In this review, we outline the background and purpose of such modified study designs and detail key aspects from a multistakeholder perspective. We also provide methodological considerations for designing the studies and highlight how insights from already-ongoing studies may address current challenges and opportunities in the era of personalised oncology. • Personalised oncology is rapidly becoming a key part of optimal clinical care. • Traditional clinical trials of tailored therapies are not always feasible. • Modified, multistakeholder study designs can support decision-making. • Ongoing studies may provide insights into methodological considerations. [ABSTRACT FROM AUTHOR]

Objective: Low‐grade bone marrow edema (BME) has been reported in the sacroiliac (SI) joints of 25% of healthy individuals and patients with nonspecific mechanical back pain, thus challenging the specificity and predictive value of magnetic resonance imaging (MRI) for the discrimination of early spondyloarthritis (SpA). It is unknown whether stress injury in competition sports may trigger BME. This study sought to explore the frequency and anatomic distribution of SI joint MRI lesions in recreational and elite athletes. Methods: After pretest calibration, semicoronal MRI scans of the SI joints of 20 recreational runners before and after running and 22 elite ice hockey players were assessed for BME and structural lesions. Three readers assessed the MRI scans in a blinded manner, using an SI joint quadrant–based module; scans from tumor necrosis factor inhibitor–treated patients with SpA served for masking. The readers recorded subjects who met the Assessment of SpondyloArthritis international Society (ASAS) definition of active sacroiliitis. For descriptive analysis, the frequency of SI joint quadrants exhibiting BME and structural lesions, as concordantly recorded by ≥2 of 3 readers, and their distribution in 8 anatomic SI joint regions (the upper and lower ilium and sacrum, subdivided in anterior and posterior slices) were determined. Results: The proportions of recreational runners and elite ice hockey players fulfilling the ASAS definition of active sacroiliitis, as recorded concordantly by ≥2 of 3 readers, were 30–35% and 41%, respectively. In recreational runners before and after running, the mean ± SD number of SI joint quadrants showing BME was 3.1 ± 4.2 and 3.1 ± 4.5, respectively, while in elite ice hockey players, it was 3.6 ± 3.0. The posterior lower ilium was the single most affected SI joint region, followed by the anterior upper sacrum. Erosion was virtually absent. Conclusion: In recreational and elite athletes, MRI revealed BME in an average of 3–4 SI joint quadrants, meeting the ASAS definition of active sacroiliitis in 30–41% of subjects. The posterior lower ilium was the single most affected SI joint region. These findings in athletes could help refine data‐driven thresholds for defining sacroiliitis in early SpA. [ABSTRACT FROM AUTHOR]

Objective To evaluate the baseline characteristics of patients with radiographic axial spondyloarthritis (SpA; ankylosing spondylitis [AS]) and patients with nonradiographic axial SpA, to investigate determinants of anti-tumor necrosis factor (anti-TNF) agent prescription on the background of a nonrestrictive reimbursement policy, and to assess the response to TNF inhibition. Methods We compared the characteristics of radiographic axial SpA and nonradiographic axial SpA in 1,070 patients from the Swiss Clinical Quality Management (SCQM) Cohort who fulfilled the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial SpA. By taking advantage of the situation that patients who are eligible for anti-TNF treatment are preferentially enrolled in the SCQM Cohort for patients with AS/axial SpA, we explored parameters leading to the initiation of anti-TNF treatment in single and multiple regression models and assessed treatment responses. Results We confirmed a similar burden of disease (as determined by self-reported disease activity, impaired function, and quality of life) in patients with nonradiographic axial SpA (n = 232) and those with radiographic axial SpA (n = 838). Patients with radiographic axial SpA had higher median levels of acute-phase reactants and higher median AS Disease Activity Scores (ASDAS; 3.2 versus 3.0). Anti-TNF treatment was initiated in 363 patients with radiographic axial SpA and 102 patients with nonradiographic axial SpA, preferentially in those with sacroiliitis on magnetic resonance imaging, peripheral arthritis, a higher C-reactive protein (CRP) level, a higher ASDAS, and a higher Bath Ankylosing Spondylitis Disease Activity Index level. The ASAS criteria for 40% improvement responses at 1 year were higher in patients with radiographic axial SpA compared with those with nonradiographic axial SpA (48.1% versus 29.6%; odds ratio [OR] 2.2, 95% confidence interval [95% CI] 1.12-4.46, P = 0.02). The difference was smaller in the subgroups of patients with elevated baseline CRP levels (51.6% in patients with radiographic axial SpA versus 38.5% in those with nonradiographic axial SpA; OR 1.7, 95% CI 0.68-4.48, P = 0.29). Conclusion The indications for treatment with anti-TNF agents were comparable for patients with radiographic axial SpA and those with nonradiographic axial SpA. With the exception of patients with elevated CRP levels at baseline, higher rates of response to TNF inhibition were achieved in the group of patients with radiographic axial SpA than in the group with nonradiographic axial SpA. [ABSTRACT FROM AUTHOR]

Objective To evaluate the baseline characteristics of patients with radiographic axial spondyloarthritis (SpA; ankylosing spondylitis [AS]) and patients with nonradiographic axial SpA, to investigate determinants of anti-tumor necrosis factor (anti-TNF) agent prescription on the background of a nonrestrictive reimbursement policy, and to assess the response to TNF inhibition. Methods We compared the characteristics of radiographic axial SpA and nonradiographic axial SpA in 1,070 patients from the Swiss Clinical Quality Management (SCQM) Cohort who fulfilled the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial SpA. By taking advantage of the situation that patients who are eligible for anti-TNF treatment are preferentially enrolled in the SCQM Cohort for patients with AS/axial SpA, we explored parameters leading to the initiation of anti-TNF treatment in single and multiple regression models and assessed treatment responses. Results We confirmed a similar burden of disease (as determined by self-reported disease activity, impaired function, and quality of life) in patients with nonradiographic axial SpA (n = 232) and those with radiographic axial SpA (n = 838). Patients with radiographic axial SpA had higher median levels of acute-phase reactants and higher median AS Disease Activity Scores (ASDAS; 3.2 versus 3.0). Anti-TNF treatment was initiated in 363 patients with radiographic axial SpA and 102 patients with nonradiographic axial SpA, preferentially in those with sacroiliitis on magnetic resonance imaging, peripheral arthritis, a higher C-reactive protein (CRP) level, a higher ASDAS, and a higher Bath Ankylosing Spondylitis Disease Activity Index level. The ASAS criteria for 40% improvement responses at 1 year were higher in patients with radiographic axial SpA compared with those with nonradiographic axial SpA (48.1% versus 29.6%; odds ratio [OR] 2.2, 95% confidence interval [95% CI] 1.12-4.46, P = 0.02). The difference was smaller in the subgroups of patients with elevated baseline CRP levels (51.6% in patients with radiographic axial SpA versus 38.5% in those with nonradiographic axial SpA; OR 1.7, 95% CI 0.68-4.48, P = 0.29). Conclusion The indications for treatment with anti-TNF agents were comparable for patients with radiographic axial SpA and those with nonradiographic axial SpA. With the exception of patients with elevated CRP levels at baseline, higher rates of response to TNF inhibition were achieved in the group of patients with radiographic axial SpA than in the group with nonradiographic axial SpA. [ABSTRACT FROM AUTHOR]

Background: Percutaneous mitral valve repair (MVR) using the MitraClip system has become a valid alternative for patients with severe mitral regurgitation (MR) and high operative risk. Objective: To identify clinical and periprocedural factors that may have an impact on clinical outcome. Design: Multi-centre longitudinal cohort study. Setting: Tertiary referral centres. Patients: Here we report on the first 100 consecutive patients treated with percutaneous MVR in Switzerland between March 2009 and April 2011. All of them had moderate-severe (3+) or severe (4+) MR, and 62% had functional MR. 82% of the patients were in New York Heart Association (NYHA) class III/IV, mean left ventricular ejection fraction was 48% and the median European System for Cardiac Operative Risk Evaluation was 16.9%. Interventions: MitraClip implantation performed under echocardiographic and fluoroscopic guidance in general anaesthesia. Main outcome measures: Clinical, echocardiographic and procedural data were prospectively collected. Results: Acute procedural success (APS, defined as successful clip implantation with residual MR grade ≤2+) was achieved in 85% of patients. Overall survival at 6 and 12 months was 89.9% (95% CI 81.8 to 94.6) and 84.6% (95% CI 74.7 to 91.0), respectively. Univariate Cox regression analysis identified APS (p=0.0069) and discharge MR grade (p=0.03) as significant predictors of survival. Conclusions: In our consecutive cohort of patients, APS was achieved in 85%. APS and residual discharge MR grade are important predictors of mid-term survival after percutaneous MVR. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the influence of additional (MRI) compared with computed tomography (CT) alone for the classification of traumatic spinal injuries using the Arbeitsgemeinshaft für Osteosynthesefragen (AO) system and the Thoraco-Lumbar Injury Classification and Severity (TLICS) scale. Materials and methods: Images from 100 consecutive patients with at least one fracture on CT were evaluated retrospectively by three radiologists with regard to the AO and TLICS classification systems in 2 steps. First, all images from the initial CT examination were analyzed. Second, 6 weeks later, CT and MR images were analyzed together. Descriptive statistics and Wilcoxon tests were performed to identify changes in the number of fractures and ligamentous lesions detected and their corresponding classification. Results: CT and MRI together revealed a total of 196 fractures (CT alone 162 fractures). The AO classification changed in 31 %, the TLICS classification changed in 33 % of the patients compared with CT alone. Based on CT and MRI together, the TLICS value changed from values < 5 (indication for conservative therapy) to values ≥ 5 (indication for surgical therapy) in 24 %. Conclusion: MRI of patients with thoracolumbar spinal trauma considerably improved the detection of fractures and soft tissue injuries compared with CT alone and significantly changed the overall trauma classification. [ABSTRACT FROM AUTHOR]