Exploring interaction effects in small samples increases rates of false-positive and false-negative findings: results from a systematic review and simulation study

ObjectiveTo give a comprehensive comparison of the performance of commonly applied interaction tests.MethodsA literature review and simulation study was performed evaluating interaction tests on the odds ratio (OR) or the risk difference (RD) scales: Cochran Q (Q), Breslow–Day (BD), Tarone, unconditional score, likelihood ratio (LR), Wald, and relative excess risk due to interaction (RERI)-based tests.ResultsReview results agreed with results from our simulation study, which showed that on the OR scale, in small sample sizes (eg, number of subjects ≤ 250) the type 1 error rates of the LR test was 0.10; the BD and Tarone tests showed results around 0.05. On the RD scale, the LR and RERI tests had error rates around 0.05. On both scales, tests did not differ regarding power. When exposure prevented the outcome RERI-based tests were relatively underpowered (eg, N = 100; RERI power = 5% vs. Wald power = 18%). With increasing sample size, difference decreased.ConclusionIn small samples, interaction tests differed. On the OR scale, the Tarone and BD tests are recommended. On the RD scale, the LR and RERI-based tests performed best. However, RERI-based tests are underpowered compared with other tests, when exposure prevents the outcome, and sample size is limited.     

The influence of Gelatin/PCL ratio and 3-D construct shape of electrospun membranes on cartilage regeneration

Scaffolds play an important role in directing three-dimensional (3-D) cartilage regeneration. Our recent study reported the potential advantages of electrospun gelatin/polycaprolactone (GT/PCL) membranes in regenerating 3-D cartilage. However, it is still unknown whether the changes of GT/PCL ratio have significant influence on 3-D cartilage regeneration. To address this issue, the current study prepared three kinds of electrospun membranes with different GT/PCL ratios (70:30, 50:50, 30:70). Adhesion and proliferation of chondrocytes on the membranes were examined to evaluate biocompatibility of the membranes. Cartilage with different 3-D shapes was engineered to further evaluate the influences of GT/PCL ratio on cartilage regeneration. The current results demonstrated that all the membranes with different GT/PCL ratios presented good biocompatibility with chondrocytes. Nevertheless, the high PCL content in the membranes significantly hampered early 3-D cartilage formation at 3 weeks in vivo. Unexpectedly, at 12 weeks, all the cylinder-shaped constructs formed mature cartilage-like tissue with no statistical differences among groups. To our surprise, ear-shaped cartilage regeneration obtained quite different results again: the high PCL content completely disrupted cartilage regeneration even at 12 weeks, and only the least PCL content group formed homogeneous and continuous cartilage with a satisfactory shape and elasticity similar to human ear. All these results indicated that the high PCL content was unfavorable for 3-D cartilage regeneration, especially for the cartilage with a complicated shape, and that GT/PCL 70:30 might be a relatively suitable ratio for ear-shaped cartilage regeneration. The research models established in the current study provide detailed information for cartilage and other tissue regeneration based on electrospun GT/PCL membranes.     

Relation between HbA1c and incident cardiovascular disease over a period of 6 years in the Hong Kong population

Aim

The current trend on diabetes management advocates replacing the paradigm from a uniform to an individualized patient-centered haemoglobin A_1c (HbA_1c) target, but there is no consensus on the optimal HbA_1c level. The study aimed at examining the association between HbA_1c and the risk of cardiovascular diseases (CVD) for diabetic patients with different characteristics, in order to identify patient-centered treatment targets.

肝脏疾病患者血清脂类及载脂蛋白含量变化的意义

本文对不同类型肝脏疾病病人110例和36例健康人的血清脂类、载脂蛋白测定及相关比值进行计算,结果发现:肝硬化(LC)及肝癌(HCC)时,TG明显升高;慢活肝(CAH)、LC及重症肝炎(FH)时TC明显降低;各类肝脏疾病均表现为HDL-C显著降低;APOAI与HDL-C相类似,APOB与LDL-C变化一致;利用比值测定则更能反映出各类肝病患者血清脂类及载脂蛋白变化规律,提示多项血清脂类测定并进行综合分析,对了解肝脏疾病的动态变化和预后判断具有重要意义。     

COVID-19 mortality,excess mortality,deaths per million and infection fatality ratio,Belgium, 9 March 2020 to 28 June 2020

BackgroundCOVID-19 mortality, excess mortality, deaths per million population (DPM), infection fatality ratio (IFR) and case fatality ratio (CFR) are reported and compared for many countries globally. These measures may appear objective, however, they should be interpreted with caution.AimWe examined reported COVID-19-related mortality in Belgium from 9 March 2020 to 28 June 2020, placing it against the background of excess mortality and compared the DPM and IFR between countries and within subgroups.MethodsThe relation between COVID-19-related mortality and excess mortality was evaluated by comparing COVID-19 mortality and the difference between observed and weekly average predictions of all-cause mortality. DPM were evaluated using demographic data of the Belgian population. The number of infections was estimated by a stochastic compartmental model. The IFR was estimated using a delay distribution between infection and death.ResultsIn the study period, 9,621 COVID-19-related deaths were reported, which is close to the excess mortality estimated using weekly averages (8,985 deaths). This translates to 837 DPM and an IFR of 1.5% in the general population. Both DPM and IFR increase with age and are substantially larger in the nursing home population.DiscussionDuring the first pandemic wave, Belgium had no discrepancy between COVID-19-related mortality and excess mortality. In light of this close agreement, it is useful to consider the DPM and IFR, which are both age, sex, and nursing home population-dependent. Comparison of COVID-19 mortality between countries should rather be based on excess mortality than on COVID-19-related mortality.     

Hepatotoxicity reports in the FDA adverse event reporting system database: A comparison of drugs that cause injury via mitochondrial or other mechanisms

Drug-induced liver injury (DILI) is a leading reason for preclinical safety attrition and post-market drug withdrawals. Drug-induced mitochondrial toxicity has been shown to play an essential role in various forms of DILI, especially in idiosyncratic liver injury. This study examined liver injury reports submitted to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) for drugs associated with hepatotoxicity via mitochondrial mechanisms compared with non-mitochondrial mechanisms of toxicity. The frequency of hepatotoxicity was determined at a group level and individual drug level. A reporting odds ratio (ROR) was calculated as the measure of effect. Between the two DILI groups, reports for DILI involving mitochondrial mechanisms of toxicity had a 1.43 (95% CI 1.42–1.45; P < 0.0001) times higher odds compared to drugs associated with non-mitochondrial mechanisms of toxicity. Antineoplastic, antiviral, analgesic, antibiotic, and antimycobacterial drugs were the top five drug classes with the highest ROR values. Although the top 20 drugs with the highest ROR values included drugs with both mitochondrial and non-mitochondrial injury mechanisms, the top four drugs (ROR values > 18: benzbromarone, troglitazone, isoniazid, rifampin) were associated with mitochondrial mechanisms of toxicity. The major demographic influence for DILI risk was also examined. There was a higher mean patient age among reports for drugs that were associated with mitochondrial mechanisms of toxicity [56.1 ± 18.33 (SD)] compared to non-mitochondrial mechanisms [48 ± 19.53 (SD)] (P < 0.0001), suggesting that age may play a role in susceptibility to DILI via mitochondrial mechanisms of toxicity. Univariate logistic regression analysis showed that reports of liver injury were 2.2 (odds ratio: 2.2, 95% CI 2.12–2.26) times more likely to be associated with older patient age, as compared with reports involving patients less than 65 years of age. Compared to males, female patients were 37% less likely (odds ratio: 0.63, 95% CI 0.61–0.64) to be subjects of liver injury reports for drugs associated with mitochondrial toxicity mechanisms. Given the higher proportion of severe liver injury reports among drugs associated with mitochondrial mechanisms of toxicity, it is essential to understand if a drug causes mitochondrial toxicity during preclinical drug development when drug design alternatives, more clinically relevant animal models, and better clinical biomarkers may provide a better translation of drug-induced mitochondrial toxicity risk assessment from animals to humans. Our findings from this study align with mitochondrial mechanisms of toxicity being an important cause of DILI, and this should be further investigated in real-world studies with robust designs.     

大手术后MODS患者血清sgp130/lL-6比值变化及意义

目的：探讨大手术后MODS患者血清可溶性糖蛋白130（sgp130）和白细胞介素6(IL-6)比值的变化及临床意义。方法将56例大手术后MODS患者按MODS评分（Marshall标准）[1]分为轻、中、重三组,再采用双抗体夹心酶联免疫吸附（ELISA）法检测各组患者和30例健康体检者（对照组）血清sgp130、IL-6的水平以及sgp130/IL-6比值,并观察各组sgp130/IL-6比值间的关系。结果三组MODS患者sgp130、IL-6的水平均明显升高,与健康对照组比较差异有显著性（P<0.01）,并且sgp130、IL-6的水平有随MODS严重程度增加而逐渐升高;三组MODS患者sgp130/IL-6比值均明显降低,与健康对照组比较差异有显著性（P<0.01）,并且sgp130/IL-6比值有随MODS严重程度增加而逐渐降低,且各组间差异显著（P<0.01）。结论血清sgp130、IL-6参与MODS的发生、发展,sgp130/IL-6比值可作为评估大手术后MODS患者病情严重程度的有效指标。