ABSTRACTIn clinical trials, selection of appropriate study endpoints is critical for an accurate and reliable evaluation of safety and effectiveness of a test treatment under investigation. In practice, however, there are usually multiple endpoints available for measurement of disease status and/or therapeutic effect of the test treatment under study. For example, in cancer clinical trials, overall survival, response rate, and/or time to disease progression are usually considered as primary clinical endpoints for evaluation of safety and effectiveness of the test treatment under investigation. Once the study endpoints have been selected, sample size required for achieving a desired power is then determined. It, however, should be noted that different study endpoints may result in different sample sizes. In practice, it is usually not clear which study endpoint can best inform the disease status and measure the treatment effect. Moreover, different study endpoints may not translate one another although they may be highly correlated one another. In this article, we intend to develop an innovative endpoint namely therapeutic index based on a utility function to combine and utilize information collected from all study endpoints. Statistical properties and performances of the proposed therapeutic index are evaluated theoretically. A numerical example concerning a cancer clinical trial is given to illustrate the use of the proposed therapeutic index. 相似文献
In addition to providing pathogen-specific immunity, vaccines can also confer nonspecific effects (NSEs) on mortality and morbidity unrelated to the targeted disease. Immunisation with live vaccines, such as the BCG vaccine, has generally been associated with significantly reduced all-cause infant mortality. In contrast, some inactivated vaccines, such as the diphtheria, tetanus, whole-cell pertussis (DTPw) vaccine, have been controversially associated with increased all-cause mortality especially in female infants in high-mortality settings. The NSEs associated with BCG have been attributed, in part, to the induction of trained immunity, an epigenetic and metabolic reprograming of innate immune cells, increasing their responsiveness to subsequent microbial encounters. Whether non-live vaccines such as DTPw induce trained immunity is currently poorly understood. Here, we report that immunisation of mice with DTPw induced a unique program of trained immunity in comparison to BCG immunised mice. Altered monocyte and DC cytokine responses were evident in DTPw immunised mice even months after vaccination. Furthermore, splenic cDCs from DTPw immunised mice had altered chromatin accessibility at loci involved in immunity and metabolism, suggesting that these changes were epigenetically mediated. Interestingly, changing the order in which the BCG and DTPw vaccines were co-administered to mice altered subsequent trained immune responses. Given these differences in trained immunity, we also assessed whether administration of these vaccines altered susceptibility to sepsis in two different mouse models. Immunisation with either BCG or a DTPw-containing vaccine prior to the induction of sepsis did not significantly alter survival. Further studies are now needed to more fully investigate the potential consequences of DTPw induced trained immunity in different contexts and to assess whether other non-live vaccines also induce similar changes. 相似文献
ObjectiveThe aim of this systematic review and meta-analysis was to evaluate the effect of surface conditioning methods on the bond strength of industrial indirect composite blocks (ICs).MethodsBased on the PICOS strategy, the Medline via PubMed, Embase and Web of Science (ISI – Web of Knowledge) electronic databases were searched for peer-reviewed articles in both English and Chinese, with no publication year limit. In vitro studies evaluating the effects of surface conditioning on the bond strength of ICs were selected. The meta-analysis was conducted to calculate the mean difference between surface-conditioned ICs and unconditioned controls. Subgroup analysis was performed to evaluate the different surface conditioning methods, separately for polymer-infiltrated ceramic network (PICN) material and the ICs with dispersed fillers (ICDFs). Meta-analyses were performed with a random-effects model at a significance level of 0.05.Results and SignificanceFrom 802 relevant studies, 25 were selected for full-text analysis. Nineteen studies were eligible for inclusion in this systematic review, whereas 9 studies were included in the meta-analysis. A manual search of the principal periodicals specific to the area resulted in no additional articles. The meta-analysis indicated a significant difference in bond strength between the surface-conditioned ICs and controls under both non-aged and aged conditions. The combination of mechanical and chemical conditioning yielded the highest bond strength of ICs. This meta-analysis suggests that chemical etching followed by a universal primer and alumina air abrasion followed by a silane coupling agent could be considered the best strategy for optimizing the bond strength of PICN materials and ICDFs under aged conditions, respectively. 相似文献
Introduction: Effective treatment of rheumatoid arthritis (RA) requires suppression of the underlying inflammation. Measurement of such inflammation, the disease activity, is mandatory to target treatment and maximize outcomes. However, this is not as straightforward as it may seem.
Areas covered: The many tools developed to measure disease activity in RA, from composite scores and patient-reported outcomes, to laboratory markers and imaging are discussed, with a focus on their utility in guiding therapy and assessing response. The complex issues in measuring disease activity in RA, whether in clinical trials or normal clinical practice, and in the context of national guidelines and recommendations, available time, and resources are considered.
Expert commentary: The key to effective management of RA is the rapid suppression of inflammation, ideally to remission, with maintenance of such remission. The aim is to prevent disability and maximize quality of life. Central to this is the ability to determine disease activity (potentially open to suppression) as opposed to damage (irreversible). A variety of measures are currently available, allowing better assessment of response to treatment. In the future, the development of predictive biomarkers allowing targeting of drugs may revolutionize this field and render the tools of today redundant. 相似文献
Sudden death in childhood and adolescence is fortunately rare. However, when it occurs, it can have a devastating effect on the family. Therefore, these cases should be thoroughly investigated, including a complete post mortem examination by a specialist in paediatric pathology. The aim is to identify the cause of death, and potentially prevent future deaths. This review will provide an overview of the epidemiology of sudden death in childhood and adolescence and will outline the wide range of causes of death identified. Certain aspects of the paediatric post mortem examination will be discussed, and will finish with a section on deaths in children with chronic medical conditions. 相似文献