Innovative Thinking on Endpoint Selection in Clinical Trials

ABSTRACT

In 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.     

Fundamentals about onset and progressive disease character of type 2 diabetes mellitus

ResearchGate is a world wide web for scientists and researchers to share papers, ask and answer questions, and find collaborators. As one of the more than 15 million members, the author uploads research output and reads and responds to some of the questions raised, which are related to type 2 diabetes. In that way, he noticed a serious gap of knowledge of this disease among medical professionals over recent decades. The main aim of the current study is to remedy this situation through providing a comprehensive review on recent developments in biochemistry and molecular biology, which can be helpful for the scientific understanding of the molecular nature of type 2 diabetes. To fill up the shortcomings in the curricula of medical education, and to familiarize the medical community with a new concept of the onset of type 2 diabetes, items are discussed like: Insulin resistance, glucose effectiveness, insulin sensitivity, cell membranes, membrane flexibility, unsaturation index (UI; number of carbon-carbon double bonds per 100 acyl chains of membrane phospholipids), slow-down principle, effects of temperature acclimation on phospholipid membrane composition, free fatty acids, energy transport, onset of type 2 diabetes, metformin, and exercise. Based on the reviewed data, a new model is presented with proposed steps in the development of type 2 diabetes, a disease arising as a result of a hypothetical hereditary anomaly, which causes hyperthermia in and around the mitochondria. Hyperthermia is counterbalanced by the slow-down principle, which lowers the amount of carbon-carbon double bonds of membrane phospholipid acyl chains. The accompanying reduction in the UI lowers membrane flexibility, promotes a redistribution of the lateral pressure in cell membranes, and thereby reduces the glucose transporter protein pore diameter of the transmembrane glucose transport channel of all Class I GLUT proteins. These events will set up a reduction in transmembrane glucose transport. So, a new blood glucose regulation system, effective in type 2 diabetes and its prediabetic phase, is based on variations in the acyl composition of phospholipids and operates independent of changes in insulin and glucose concentration. UI assessment is currently arising as a promising analytical technology for a membrane flexibility analysis. An increase in mitochondrial heat production plays a pivotal role in the existence of this regulation system.     

Dry eye signs and symptoms in aromatase inhibitor treatment and the relationship with pain

PurposeAromatase inhibitors (AIs) limit the synthesis of oestrogen in peripheral tissues thus lowering levels of oestrogen. The primary aim was to evaluate whether women treated with AIs have altered dry eye symptoms and signs. A sub-aim was to investigate whether symptoms of dry eye in postmenopausal women were associated with symptoms of non-eye pain, ocular pain and self-rated pain perception.MethodsThis cross-sectional, observational, single visit study recruited 56 postmenopausal women (mean age 64.1 + 7.9 years) and 52 undergoing AI treatment (mean age 66.6 + 9.0). Ocular symptoms (OSDI, MGD14) and pain questionnaires (PSQ, OPAS) were administered and signs of dry eye and meibomian gland dysfunction were evaluated.ResultsAlmost half of each group reported dry eye symptoms, defined as OSDI>12 (48% control, 46% AI). The PSQ score was significantly higher in the AI group (p = 0.04). Neither frequency or severity of dry eye (or MGD) symptoms scores were significantly different between groups. In the AI group, meibomian gland expressibility score was worse (p = 0.003); there were no differences in any other signs. Higher OSDI scores were associated with higher OPAS eye-pain scores (r = 0.49, p < 0.001), but not OPAS non-eye pain (r = 0.09, p = 0.35). Pain perception (PSQ) showed a moderate positive association with OPAS eye-pain (r = 0.30, p = 0.003).ConclusionsIn this study elevated ocular symptoms were observed in both the AI treated and the untreated groups, with no difference between the groups. Women undergoing AI treatment for early stage breast cancer had worse meibum expressibility score and increased pain perception compared to an untreated group of women.     

Gaining weight through retirement? Results from the SHARE survey

This paper estimates the causal impact of retirement on the Body Mass Index (BMI) of adults aged 50–69 years old, on the probability of being either overweight or obese and on the probability of being obese. Based on the 2004, 2006 and 2010–2011 waves of the Survey of Health, Ageing and Retirement in Europe (SHARE), our identification strategy exploits variation in European Early Retirement Ages (ERAs) and stepwise increases in ERAs in Austria and Italy between 2004 and 2011 to examine an exogenous shock to retirement behavior. Our results show that retirement induced by discontinuous incentives in early retirement schemes causes a 12-percentage point increase in the probability of being obese among men within a two- to four-year period. We find that the impact of retirement is highly non-linear and mostly affects the right-hand side of the male BMI distribution. Additional results show that this pattern is driven by men retiring from strenuous jobs and by those who were already at risk of obesity. In contrast, no significant results are found among women.     

西药联合穴位贴敷中西医结合治疗复治肺结核疗效观察

目的评价西药联合穴位贴敷中西医结合治疗复治肺结核的临床疗效。方法选择本院2017年1月～2018年1月收治的60例复治肺结核患者进行分组研究,全部患者根据治疗方法不同随机分为两组,每组各30例。两组均采取西药进行治疗,采用2HRZE/6HRZ标准化疗方案,实验组同时联合穴位贴敷中西医结合进行治疗,治疗后对比分析两组病灶吸收情况及两组临床症状改善情况。结果实验组病灶恶化9例,其病灶显著吸收率达50.0%,总有效率达70.0%,对照组病灶恶化6例,不变5例,其病灶显著吸收率达33.3%,总有效率达63.3%,两组病灶吸收总有效率组间比较,差异具有显著性(P0.05);实验组的疗效指数治疗6个月后显著高于对照组,组间比较,差异具有显著性(P0.05)。结论西药联合穴位贴敷中西医结合治疗复治肺结核疗效确切,可以显著促进病灶吸收,改善临床症状,安全性好,且还可以扶助人体正气,提高机体免疫力,调节全身状态,以达到治疗目的,是治疗复治肺结核的有效方法之一,值得临床广泛推广和应用。     

Lower body mass index and higher height are correlated with increased varicocele risk

To evaluate the anthropometric indexes in subjects with varicocele compared to controls and the incidence of varicocele in different body mass index (BMI) groups for the purpose of exploring the association between varicocele and anthropometric indexes. A comprehensive literature search was conducted by using PubMed, MEDLINE, EMBASE databases and Cochrane Library up to February 2019. A systematic review and meta‐analysis was conducted by STATA, and Newcastle–Ottawa Scale was utilised for assessing risk of bias. Ultimately, 13 articles containing seven case–control studies and six cross‐sectional studies with 1,385,630 subjects were involved in our study. Pooled results demonstrated that varicocele patients had a lower BMI (WMD = ?0.77, 95% CI = ?1.03 to ?0.51) and a higher height than nonvaricocele participants, especially in grade 3 varicocele patients. Subgroup analyses showed that normal BMI individuals had a higher risk of varicocele than obese or overweight individuals and a lower risk than underweight individuals. In conclusion, this study indicates that varicocele patients have a lower BMI and a higher height than nonvaricocele participants. Moreover, men with excess bodyweight have a lower incidence of varicocele compared to normal weight or underweight people. That is to say, high BMI and adiposity protect against varicocele and high BMI is associated with a decreased risk of varicocele.     

High-intensity interval exercise lowers postprandial glucose concentrations more in obese adults than lean adults

AimsTo compare postprandial glucose responses to high-intensity interval exercise (HIE) between obese and lean individuals.MethodsThirty healthy young adult males (15 obese, 15 lean) ate a standardised meal, then performed HIE (4 × 30-s Wingate cycling/4-min rest) or a no-exercise control trial (CON). Blood glucose was measured preprandially and up to 150 min postprandially.ResultsCompared to CON, HIE reduced postprandial glucose concentrations at 120–150 min in obese (p < 0.001) and lean men (p < 0.05), with greater reductions in obese than lean subjects at 120 (−27.0% vs. −8.3%), 135 (−31.9% vs. −15.7%), and 150 min (−21.8% vs. −10.6%). The total glucose area under the curve (AUC) for the testing period was lower with HIE than CON among obese men (p < 0.05), but not lean men (p > 0.05). We found moderate correlations between body mass and postprandial glucose changes (r = 0.39–0.44, p < 0.05), and between glucose AUC and body mass and fat free mass (r = 0.39–0.48, p < 0.05).ConclusionsOur findings suggest that HIE may act as a time-efficient lifestyle intervention strategy for improving obesity-related diabetes risk factors, and might play a role in primary diabetes prevention for the healthy but sedentary population.