Rethinking intercurrent events in defining estimands for tuberculosis trials.

BACKGROUND/AIMS: Tuberculosis remains one of the leading causes of death from an infectious disease globally. Both choices of outcome definitions and approaches to handling events happening post-randomisation can change the treatment effect being estimated, but these are often inconsistently described, thus inhibiting clear interpretation and comparison across trials. METHODS: Starting from the ICH E9(R1) addendum's definition of an estimand, we use our experience of conducting large Phase III tuberculosis treatment trials and our understanding of the estimand framework to identify the key decisions regarding how different event types are handled in the primary outcome definition, and the important points that should be considered in making such decisions. A key issue is the handling of intercurrent (i.e. post-randomisation) events (ICEs) which affect interpretation of or preclude measurement of the intended final outcome. We consider common ICEs including treatment changes and treatment extension, poor adherence to randomised treatment, re-infection with a new strain of tuberculosis which is different from the original infection, and death. We use two completed tuberculosis trials (REMoxTB and STREAM Stage 1) as illustrative examples. These trials tested non-inferiority of new tuberculosis treatment regimens versus a control regimen. The primary outcome was a binary composite endpoint, 'favourable' or 'unfavourable', which was constructed from several components. RESULTS: We propose the following improvements in handling the above-mentioned ICEs and loss to follow-up (a post-randomisation event that is not in itself an ICE). First, changes to allocated regimens should not necessarily be viewed as an unfavourable outcome; from the patient perspective, the potential harms associated with a change in the regimen should instead be directly quantified. Second, handling poor adherence to randomised treatment using a per-protocol analysis does not necessarily target a clear estimand; instead, it would be desirable to develop ways to estimate the treatment effects more relevant to programmatic settings. Third, re-infection with a new strain of tuberculosis could be handled with different strategies, depending on whether the outcome of interest is the ability to attain culture negativity from infection with any strain of tuberculosis, or specifically the presenting strain of tuberculosis. Fourth, where possible, death could be separated into tuberculosis-related and non-tuberculosis-related and handled using appropriate strategies. Finally, although some losses to follow-up would result in early treatment discontinuation, patients lost to follow-up before the end of the trial should not always be classified as having an unfavourable outcome. Instead, loss to follow-up should be separated from not completing the treatment, which is an ICE and may be considered as an unfavourable outcome. CONCLUSION: The estimand framework clarifies many issues in tuberculosis trials but also challenges trialists to justify and improve their outcome definitions. Future trialists should consider all the above points in defining their outcomes

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

Robust P-H∞Integrated Controller for Flexible Link Manipulator System in the Presence of Disturbance

Flexible link manipulators have recently high attention in research due to the numerous advantages over traditional manipulators. However, flexible link manipulators still have critical problem of less position accuracy due to the tip vibration. Thus, this research contributes by developing a robust P-H∞ integrated controller for a flexible link manipulator (FLM). The P-H∞ integrated controller is a combination of Proportional (p ) controller and H∞ controller which helps of possession several advantages such as optimal position tracking, effective vibration repression, and robust to reject disturbances. The proposed P-H∞ integrated controller has been simulated to control the FLM system using MATLAB/Simulink toolbox. The results have demonstrated satisfactory performance of the proposed P-H∞ integrated controller in terms of position tracking, vibration repression, and disturbance rejection

Dynamic Modelling and Intelligent Hybrid Optimal Controller of Hybrid Manipulator for Vibration Suppression and Tracking Control

Flexible links possess numerous advantages over rigid links which impose the research attention towards employing flexible links in robotics. However, flexible links have a tip vibration that has the difficulty of being presented in dynamic models. Furthermore, the tip vibration leads to the control difficulty as a controller must control a system for the position and the tip elastic vibration. This research proposes a dynamic model and an intelligent hybrid optimal controller of a hybrid manipulator, the hybrid manipulator has a rigid link, a flexible link, and a variable payload. The proposed dynamic model is obtained using a combined technique of the finite element method and the Lagrangian method. The proposed dynamic model is compared with a SimMechanics model in terms of their open-loop responses, and both models have close match responses which indicates that the novel dynamic model is accurate. The intelligent hybrid optimal controller is also proposed based on the integration of an optimal linear quadratic regulator and a fuzzy logic controller. The integration of the fuzzy control and the linear quadratic regulator controller achieves 39.5% reduction of the fuzzy rules which assists to solve the explosion of the fuzzy rules problem since the hybrid manipulator is a multi-input system. The proposed intelligent optimal controller demonstrates improved position control, effective tip vibration suppression, better tip trajectory tracking, and better robustness to overcome the impact of the payload uncertainty compared to the linear quadratic regulator controller based on the simulation validation of the Simulink in MATLA

Treatment estimands in clinical trials of patients hospitalised for COVID-19: ensuring trials ask the right questions

When designing a clinical trial, explicitly defining the treatment estimands of interest (that which is to be estimated) can help to clarify trial objectives and ensure the questions being addressed by the trial are clinically meaningful. There are several challenges when defining estimands. Here, we discuss a number of these in the context of trials of treatments for patients hospitalised with COVID-19 and make suggestions for how estimands should be defined for key outcomes. We suggest that treatment effects should usually be measured as differences in proportions (or risk or odds ratios) for outcomes such as death and requirement for ventilation, and differences in means for outcomes such as the number of days ventilated. We further recommend that truncation due to death should be handled differently depending on whether a patient- or resource-focused perspective is taken; for the former, a composite approach should be used, while for the latter, a while-alive approach is preferred. Finally, we suggest that discontinuation of randomised treatment should be handled from a treatment policy perspective, where non-adherence is ignored in the analysis (i.e. intention to treat)

A review of mathematical methods for flexible robot dynamics modeling and simulation

In recent decades, lots of robots are designed and produced all over the world because of their important applications. Nowadays, using the robot is more and more popular in many different fields. In practice, the modeling and control of most of the robots are performed with an important assumption that all links of a robot are rigid bodies. This is to simplify the modeling, analysis, and control for a robot. The elastic deformation of a link always exists during a robot’s operation. This elastic deformation of a flexible robot has significant effects on several characterizations and specifications of the robot such as the robot strength, the accuracy of the robot motion, the robot control, etc. In the literature, there have been many studies addressing the dynamics modeling and control of flexible robots. This paper presents an overview of the mathematical methods which have been used for the kinematic and dynamic modeling of the flexible manipulators

A Review of Mathematical Methods for Flexible Robot Dynamics Modeling and Simulation

In recent decades, lots of robots are designed and produced all over the world because of their important applications. Nowadays, using the robot is more and more popular in many different fields. In practice, the modeling and control of most of the robots are performed with an important assumption that all links of a robot are rigid bodies. This is to simplify the modeling, analysis, and control for a robot. The elastic deformation of a link always exists during a robot’s operation. This elastic deformation of a flexible robot has significant effects on several characterizations and specifications of the robot such as the robot strength, the accuracy of the robot motion, the robot control, etc. In the literature, there have been many studies addressing the dynamics modeling and control of flexible robots. This paper presents an overview of the mathematical methods which have been used for the kinematic and dynamic modeling of the flexible manipulators

Rethinking intercurrent events in defining estimands for tuberculosis trials.

Background/aimsTuberculosis remains one of the leading causes of death from an infectious disease globally. Both choices of outcome definitions and approaches to handling events happening post-randomisation can change the treatment effect being estimated, but these are often inconsistently described, thus inhibiting clear interpretation and comparison across trials.MethodsStarting from the ICH E9(R1) addendum's definition of an estimand, we use our experience of conducting large Phase III tuberculosis treatment trials and our understanding of the estimand framework to identify the key decisions regarding how different event types are handled in the primary outcome definition, and the important points that should be considered in making such decisions. A key issue is the handling of intercurrent (i.e. post-randomisation) events (ICEs) which affect interpretation of or preclude measurement of the intended final outcome. We consider common ICEs including treatment changes and treatment extension, poor adherence to randomised treatment, re-infection with a new strain of tuberculosis which is different from the original infection, and death. We use two completed tuberculosis trials (REMoxTB and STREAM Stage 1) as illustrative examples. These trials tested non-inferiority of new tuberculosis treatment regimens versus a control regimen. The primary outcome was a binary composite endpoint, 'favourable' or 'unfavourable', which was constructed from several components.ResultsWe propose the following improvements in handling the above-mentioned ICEs and loss to follow-up (a post-randomisation event that is not in itself an ICE). First, changes to allocated regimens should not necessarily be viewed as an unfavourable outcome; from the patient perspective, the potential harms associated with a change in the regimen should instead be directly quantified. Second, handling poor adherence to randomised treatment using a per-protocol analysis does not necessarily target a clear estimand; instead, it would be desirable to develop ways to estimate the treatment effects more relevant to programmatic settings. Third, re-infection with a new strain of tuberculosis could be handled with different strategies, depending on whether the outcome of interest is the ability to attain culture negativity from infection with any strain of tuberculosis, or specifically the presenting strain of tuberculosis. Fourth, where possible, death could be separated into tuberculosis-related and non-tuberculosis-related and handled using appropriate strategies. Finally, although some losses to follow-up would result in early treatment discontinuation, patients lost to follow-up before the end of the trial should not always be classified as having an unfavourable outcome. Instead, loss to follow-up should be separated from not completing the treatment, which is an ICE and may be considered as an unfavourable outcome.ConclusionThe estimand framework clarifies many issues in tuberculosis trials but also challenges trialists to justify and improve their outcome definitions. Future trialists should consider all the above points in defining their outcomes

Can myocardial remodeling be a useful surrogate predictor of myocardial iron load? A 3D echocardiographic multicentric study

The relationship between myocardial iron load and eccentric myocardial remodeling remains an under-investigated area; it was thought that remodeling is rather linked to fibrosis. This study aims to determine whether or not measures of remodeling can be used as predictors of myocardial iron. For this purpose, 60 patients with thalassemia were studied with 3D echocardiography and myocardial relaxometry (T2*) by Cardiac MRI. 3D derived sphericity index was significantly higher in patients with myocardial iron load. It was correlated with T2* with a 100% sensitivity and specificity (cut-off value of 0.34) to discriminate between patients with and without myocardial iron overload