Intention‐to‐treat analysis with treatment discontinuation and missing data in clinical trials

Motivated by a recent National Research Council study, we discuss three aspects of the analysis of clinical trials when participants prematurely discontinue treatments. First, we distinguish treatment discontinuation from missing outcome data. Data collection is often stopped after treatment discontinuation, but outcome data could be recorded on individuals after they discontinue treatment, as the National Research Council study recommends. Conversely, outcome data may be missing for individuals who do not discontinue treatment, as when there is loss to follow up or missed clinic visits. Missing outcome data is a standard missing data problem, but treatment discontinuation is better viewed as a form of noncompliance and treated using ideas from the causal literature on noncompliance. Second, the standard intention to treat estimand, the average effect of randomization to treatment, is compared with three alternative estimands for the intention to treat population: the average effect when individuals continue on the assigned treatment after discontinuation, the average effect when individuals take a control treatment after treatment discontinuation, and a summary measure of the effect of treatment prior to discontinuation. We argue that the latter choice of estimand has advantages and should receive more consideration. Third, we consider when follow‐up measures after discontinuation are needed for valid measures of treatment effects. The answer depends on the choice of primary estimand and the plausibility of assumptions needed to address the missing data. Ideas are motivated and illustrated by a reanalysis of a past study of inhaled insulin treatments for diabetes, sponsored by Eli Lilly. Copyright © 2014 John Wiley & Sons, Ltd.     

Erythrophagocytosis of Lead-Exposed Erythrocytes by Renal Tubular Cells: Possible Role in Lead-Induced Nephrotoxicity

Background: Nephrotoxicity associated with lead poisoning has been frequently reported in epidemiological studies, but the underlying mechanisms have not been fully described.Objectives: We examined the role of erythrocytes, one of the major lead reservoirs, in lead-associated nephrotoxicity.Methods and results: Co-incubation of lead-exposed human erythrocytes with HK-2 human renal proximal tubular cells resulted in renal tubular cytotoxicity, suggesting a role of erythrocytes in lead-induced nephrotoxicity. Morphological and flow cytometric analyses revealed that HK-2 cells actively phagocytized lead-exposed erythrocytes, which was associated with phosphatidylserine (PS) externalization on the erythrocyte membrane and generation of PS-bearing microvesicles. Increased oxidative stress and up-regulation of nephrotoxic biomarkers, such as NGAL, were observed in HK-2 cells undergoing erythrophagocytosis. Moreover, TGF-β, a marker of fibrosis, was also significantly up-regulated. We examined the significance of erythrophagocytosis in lead-induced nephrotoxicity in rats exposed to lead via drinking water for 12 weeks. We observed iron deposition and generation of oxidative stress in renal tissues of lead-exposed rats, as well as the histopathological alterations such as tubulointerstitial lesions, fibrosis, and up-regulation of KIM-1, NGAL, and TGF-β.Conclusions: Our data strongly suggest that erythrophagocytosis and subsequent iron deposition in renal tubular cells could significantly enhance nephrotoxicity following lead exposure, providing insight on lead-associated kidney damages.Citation: Kwon SY, Bae ON, Noh JY, Kim K, Kang S, Shin YJ, Lim KM, Chung JH. 2015. Erythrophagocytosis of lead-exposed erythrocytes by renal tubular cells: possible role in lead-induced nephrotoxicity. Environ Health Perspect 123:120–127; http://dx.doi.org/10.1289/ehp.1408094     

Magnetic surface molecularly imprinted poly(3-aminophenylboronic acid) for selective capture and determination of diethylstilbestrol

Diethylstilbestrol (DES) is considered a representative example of an exogenous endocrine disrupting compound (EDC). It can retard development in infants, lead to serious metabolic regulation disorders, and even result in distortion and cancer in the reproductive system. Therefore, achieving rapid and accurate analysis of trace amounts of DES in complex environments is of great importance to human health and for environmental protection. Novel magnetic molecularly imprinted polymers (MIPs) with excellent molecular recognition ability and super water-compatibility were developed for the selective capture of DES in water samples. Fe₃O₄@SiO₂ magnetic nanoparticles (NPs) were synthesized and used as support cores. Molecularly imprinted poly(3-aminophenylboronic acid) (poly(APBA)), synthesized on magnetic cores based on a surface-imprinting strategy, can preferentially bind DES molecules in water samples. The magnetic core–shell MIPs (denoted as Fe₃O₄@SiO₂@APBA/MIPs) exhibited high binding capacity and favorable recognition specificity for DES in water. The adsorption kinetics and experimental isotherm data of DES on magnetic MIPs can be well described by the pseudo-second-order kinetic model and the Langmuir isotherm, respectively. The imprinted nanoparticles were subjected to magnetic solid-phase extraction (MSPE) of DES from water samples. The DES content in the samples was determined by high-performance liquid chromatography (HPLC). The peak area increased linearly with increasing DES concentration over the range 0.08–150 μg L⁻¹, with a detection limit of 0.03 μg L⁻¹. The recoveries for spiked lake water samples were in the range 97.1–103.2%, with relative standard deviation (RSD) of 2.8–4.3% (n = 6).

Imprinted poly(APBA) nanoshell on Fe₃O₄@SiO₂ surface was first synthesized and used for MSPE of diethylstilbestrol followed by HPLC determination.     

环形激光治疗下肢静脉曲张的手术护理配合

目的 总结环形激光治疗下肢静脉曲张的手术护理配合体会。 方法 对2017年1月至2017年7月期间,如皋市人民医院收治的52例下肢静脉曲张患者采用新型SJVF-2015优福通半导体激光仪配合环形激光光纤行腔内环形激光闭合术,采用个性化环激光护理配合方法。结果 手术时间30～50 min,出血量10～20 ml,平均住院4.8 d,无手术并发症发生。结论 环形激光性能特殊,熟练掌握其有别于普通激光手术的护理配合要领,是保证手术成功的重要环节。     

Clinical Outcomes in Critically Ill Patients Associated With the Use of Complex vs Weight‐Only Predictive Energy Equations

Background: The energy intake goal is important to achieving energy intake in critically ill patients, yet clinical outcomes associated with energy goals have not been reported. Methods: This secondary analysis used the Improving Nutrition Practices in the Critically III International Nutrition Surveys database from 2007–2009 to evaluate whether mortality or time to discharge alive is related to use of complex energy prediction equations vs weight only. The sample size was 5672 patients in the intensive care unit (ICU) ≥4 days and a subset of 3356 in the ICU ≥12 days. Mortality and time to discharge alive were compared between groups by regression, controlling for age, sex, admission type, Acute Physiology and Chronic Health Evaluation II score, ICU geographic region, actual energy intake, and obesity. Results: There was no difference in mortality between the use of complex and weight‐only equations (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.86–1.15), but obesity (OR, 0.83; 95% CI, 0.71–0.96) and higher energy intake (OR, 0.65; 95% CI, 0.56–0.76) had lower odds of mortality. Time to discharge alive was shorter in patients fed using weight‐only equations (hazard ratio [HR], 1.11; 95% CI, 1.01–1.23) in patients staying ≥4 days and with greater energy intake (HR, 1.19; 95% CI, 1.06–1.34) in patients in the ICU ≥12 days. Conclusion: These data suggest that higher energy intake is important to survival and time to discharge alive. However, the analysis was limited by actual energy intake <70% of goal. Delivery of full goal intake will be needed to determine the relationship between the method of determining energy goal and clinical outcomes.     

脂多糖诱导成骨细胞增殖的Notch信号通路研究

目的:探讨脂多糖(LPS)对成骨细胞增殖的Notch信号通路的诱导激活作用.方法:以MC3T3-E1细胞为模型,设计正常对照组、LPS浓度梯度组(5、10μg组)、DAPT组(先加入DAPT,随后加入10μg LPS)和DMSO组(先加入DMSO,随后加入10μg LPS).分别于OBDM培养基中诱导分化5d和15d时加入不同浓度的脂多糖、DAPT和DMSO,培养3d后进行MTT实验,随后采用PCR检测各组细胞中HES1mRNA表达量.结果:与对照组相比,加入脂多糖5μg组第5天,脂多糖10 μg组第5、6、7天时细胞吸光度显著降低(P＜0.01);与正常对照组相比,5μg组和10 μg组脂多糖均能够使MC3T3-E1细胞和成骨细胞前体细胞增殖能力降低(P＜0.01),而仅5μg组LPS能够使成骨细胞增殖分化能力降低(P＜0.01);不同浓度LPS均能够诱导HES1mRNA的表达,与对照组相比,差异有统计学意义(P＜0.01);随着LPS浓度增加,HES1mRNA表达量显著增加(P＜0.01);与对照组相比,DM-SO组HES1mRNA量显著较高,差异具有统计学差异(P＜0.05).结论:脂多糖抑制骨头发育和愈合,可能是通过激活经典的Notch信号通路,诱导HES1mRNA的表达,抑制成骨细胞及其前体细胞的增殖分化造成.     

Risk factors for latent tuberculosis infection in children in South Korea

Objectives: In South Korea, latent tuberculosis infection (LTBI) screening is a critical strategy associated with efforts to reduce the incidence of tuberculosis (TB). Currently, only children with a known history of TB contact are considered as pediatric high-risk groups for LTBI, and consequently, LTBI screening is only provided to these children. However, to reduce the incidence of TB, the high-risk groups that undergo LTBI screening should be expanded. This study aimed to assess the risk factors for LTBI among children living in South Korea with no known history of TB contact for the identification of additional high-risk groups. We investigated the risk factors for LTBI among US visa applicant children, who undergo LTBI screening regardless of their TB contact history.

Methods: We obtained data on demographic characteristics, medical history, Bacillus Calmette–Guerin (BCG) vaccination history, and results of LTBI screening for children aged 2–14 years. A tuberculin skin test was used for the diagnosis of LTBI, and an induration of 10 mm or greater was used to define a positive test. Adjusted odds ratios and 95% confidence intervals were calculated to determine the association between clinical and demographic variables and LTBI.

Results: Of the 1,664 study participants, 91 (5.5%) had LTBI. The binary logistic regression analysis showed that children born in high TB burden foreign countries had the highest odds of LTBI when considering all the risk factors investigated. Increasing age, absence of BCG vaccination, and a previous diagnosis of asthma were also significant risk factors for LTBI.

Conclusion: These results indicate that children born in high TB burden foreign countries should be considered a high-risk group for LTBI in South Korea; the inclusion of these children in LTBI screening should be considered.