Towards clinical data-driven eligibility criteria optimization for interventional COVID-19 clinical trials

ObjectiveThis research aims to evaluate the impact of eligibility criteria on recruitment and observable clinical outcomes of COVID-19 clinical trials using electronic health record (EHR) data.Materials and MethodsOn June 18, 2020, we identified frequently used eligibility criteria from all the interventional COVID-19 trials in ClinicalTrials.gov (n = 288), including age, pregnancy, oxygen saturation, alanine/aspartate aminotransferase, platelets, and estimated glomerular filtration rate. We applied the frequently used criteria to the EHR data of COVID-19 patients in Columbia University Irving Medical Center (CUIMC) (March 2020–June 2020) and evaluated their impact on patient accrual and the occurrence of a composite endpoint of mechanical ventilation, tracheostomy, and in-hospital death.ResultsThere were 3251 patients diagnosed with COVID-19 from the CUIMC EHR included in the analysis. The median follow-up period was 10 days (interquartile range 4–28 days). The composite events occurred in 18.1% (n = 587) of the COVID-19 cohort during the follow-up. In a hypothetical trial with common eligibility criteria, 33.6% (690/2051) were eligible among patients with evaluable data and 22.2% (153/690) had the composite event.DiscussionBy adjusting the thresholds of common eligibility criteria based on the characteristics of COVID-19 patients, we could observe more composite events from fewer patients.ConclusionsThis research demonstrated the potential of using the EHR data of COVID-19 patients to inform the selection of eligibility criteria and their thresholds, supporting data-driven optimization of participant selection towards improved statistical power of COVID-19 trials.     

An Embryonic Diapause-like Adaptation with Suppressed Myc Activity Enables Tumor Treatment Persistence

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基于知识图谱构建和定性访谈法探析张忠德教授辨治间质性肺病临床特征与方药规律＊

目的 构建个性化知识图谱技术和定性访谈法结合，进一步挖掘张忠德教授辨治间质性肺疾病临证特征与用药规律。方法 采用回顾性分析，系统收集张忠德教授广东省中医院门诊2010年8月至2020年8月治疗间质性肺疾病病历，按照诊断标准、纳入标准、排除标准，严格筛选后，通过广东省中医院大数据挖掘团队中医药大数据智能处理与知识服务系统进行数据挖掘分析，并通过多元化视觉定性访谈法，将定量与定性分析有效结合。结果 共筛选出347首方，共141味药物，常用药物频次 ≥ 84次的药物有10味，其中党参、麦芽、黄芪、紫菀、白术等为核心用药，通过症状与药物推理知识地图显示，党参、炒麦芽、黄芪、大枣、太子参、山萸肉、巴戟天等为主要治疗用药；临证遣方用药知识关联分析，得知咳嗽、耳鸣、心悸、水肿、头痛、胸闷、恶寒等为多见，针对咳嗽，首选紫苏子、橘红、桂枝等温肺降气通阳之品等；频繁聚集显示，常用药对炒麦芽-炒白术、黄芪-党参、黄精-菟丝子、前胡-紫菀、炙枇杷叶-浙贝母等；聚类分析结果得到4组关系密切的聚类新药物组合；以脾为中轴，肺肾共扶为主的“平调五脏论”，分期阶梯辨治间质性肺疾病。结论 张忠德教授认为间质性肺疾病，虚实夹杂为多见，应从肺、脾、肾着手，采用平调五脏论分期阶梯辨治，用药配伍精简，以和为贵，以平为期。     

The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength

Lgr5 was originally discovered as a common Wnt target gene in adult intestinal crypts and colon cancer. It was subsequently identified as an exquisite marker of multiple Wnt-driven adult stem cell types. Lgr5 and its homologs, Lgr4 and Lgr6, constitute the receptors for R-spondins, potent Wnt signal enhancers and stem cell growth factors. The Lgr5/R-spondin complex acts by neutralizing Rnf43 and Znrf3, two transmembrane E3 ligases that remove Wnt receptors from the stem cell surface. Rnf43/Znrf3 are themselves encoded by Wnt target genes and constitute a negative Wnt feedback loop. Thus, adult stem cells are controlled by an intricate interplay of potent Wnt agonists, antagonists, and anti-antagonists.     

Binocular form deprivation influences the visual cortex

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors are considered to play a crucial role in synaptic plasticity in the developing visual cortex. In this study, we established a rat model of binocular form deprivation by suturing the rat binocular eyelids before eye-opening at postnatal day 14. During development, the decay time of excitatory postsynaptic currents mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors of normal rats became longer after eye-opening; however, the decay time did not change significantly in binocular form deprivation rats. The peak value in the normal group became gradually larger with age, but there was no significant change in the binocular form deprivation group. These findings indicate that binocular form deprivation influences the properties of excitatory postsynaptic currents mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in the rat visual cortex around the end of the critical period, indicating that form stimulation is associated with the experience-dependent modification of neuronal synapses in the visual cortex.     

纳洛酮对缺氧诱导大鼠神经元损伤的抑制作用及其机制

目的探讨纳洛酮对缺氧诱导大鼠神经元损伤的作用及其可能的机制。方法体外培养大鼠神经元，将其分为正常对照组、缺氧诱导组、缺氧诱导＋纳洛酮干预组。应用流式细胞术测定大鼠神经元损伤；应用荧光探针2，7-二氯二氢荧光素乙酰乙酸（DCFDA）检测细胞内活性氧的变化；应用比色法检测超氧化物歧化酶（SOD）的活性；应用Westernblot检测NF—KB的活化。结果（1）纳洛酮抑制缺氧诱导的大鼠神经元凋亡，缺氧组大鼠神经元细胞凋亡明显增加，为对照组的3．54倍，纳洛酮干预组为对照组的1．35倍（均P〈0．05）。（2）纳洛酮抑制缺氧诱导的活性氧生成，缺氧诱导大鼠神经元活性氧生成，为对照组的2．66倍，纳洛酮干预组为对照组的1．24倍（均P〈0．05）。（3）纳洛酮抑制缺氧诱导的NF—KB活化（P〈0．05）。（4）抗氧化剂NAC抑制缺氧诱导的NF—KB活化，抑制率达49％（P〈0．05）。结论纳洛酮抑制缺氧诱导的活性氧生成，进而抑制NF—KB活化，从而抑制缺氧诱导的大鼠神经元凋亡。     

Eosinophilic otitis media diagnosis using flow cytometric immunophenotyping

Objectives: (1) To assess the ability of flow cytometric immunophenotyping to detect and quantitate eosinophils in patients with eosinophilic otitis media (EOM). (2) to evaluate the association of EOM to bronchial asthma.

Methods: Twenty-one patients with chronic otorrhea or middle ear effusion (MEE) were included in this prospective cohort study. Group I composed of 10 patients (14 ears) and associated to bronchial asthma. Group II included 11 patients (11 ears) without bronchial asthma. Samples of MEE were sent for flow cytometric analysis at initial presentation. Patients with positive eosinophils on flow cytometric immunophenotyping were analyzed after one-month course of dexamethasone eardrops.

Results: EOM was diagnosed in all patients of group I and in three patients of group II. The mean eosinophils percentage was 43.5% and 14.2% for group I and group II, respectively (p?=?.006). Those patients showed a significant response to dexamethasone eardrops, both on clinical examination and on flow cytometric analysis with a decrease in eosinophil levels post-treatment. However, this improvement was temporary and symptoms recurred after treatment cessation. Bronchial asthma was not associated to all patients with EOM.

Conclusion: Diagnosis of EOM remained mostly clinical; flow cytometry immunophenotyping of MEE may be helpful as an additional tool in diagnosis and monitoring the response to treatment, particularly in non-asthmatic patients.