Causality assessment of adverse drug reaction reports using an expert-defined Bayesian network

In pharmacovigilance, reported cases are considered suspected adverse drug reactions (ADR). Health authorities have thus adopted structured causality assessment methods, allowing the evaluation of the likelihood that a drug was the causal agent of an adverse reaction. The aim of this work was to develop and validate a new causality assessment support system used in a regional pharmacovigilance centre. A Bayesian network was developed, for which the structure was defined by experts while the parameters were learnt from 593 completely filled ADR reports evaluated by the Portuguese Northern Pharmacovigilance Centre medical expert between 2000 and 2012. Precision, recall and time to causality assessment (TTA) was evaluated, according to the WHO causality assessment guidelines, in a retrospective cohort of 466 reports (April–September 2014) and a prospective cohort of 1041 reports (January–December 2015). Additionally, a simplified assessment matrix was derived from the model, enabling its preliminary direct use by notifiers. Results show that the network was able to easily identify the higher levels of causality (recall above 80%), although struggling to assess reports with a lower level of causality. Nonetheless, the median (Q1:Q3) TTA was 4 (2:8) days using the network and 8 (5:14) days using global introspection, meaning the network allowed a faster time to assessment, which has a procedural deadline of 30 days, improving daily activities in the centre. The matrix expressed similar validity, allowing an immediate feedback to the notifiers, which may result in better future engagement of patients and health professionals in the pharmacovigilance system.     

The ten most common adverse drug reactions (ADRs) in oncology patients: do they matter to you?

Aims To assess incidence, predictability, preventability and severity of adverse drug reactions (ADRs) in hospitalised oncology patients.Patients and methods Patients hospitalised at Peter MacCallum Cancer Centre from 28 February to 2 June 2000 were selected for interviews about symptoms related to their drug therapy. Medical records were also reviewed. Causality, predictability, preventability and severity were assessed for each ADR.Results One hundred and sixty-seven patients associated with 171 admissions were interviewed. Four hundred and fifty-four ADRs were identified in 127 (74.3%) separate admissions (mean ADRs per admission 2.7; range 0–18). Eighty-eight percent of ADRs were predictable. Of these, 1.6% was classified as definitely preventable and 46.1% probably preventable. The ten most common ADRs were constipation, nausea ± vomiting, fatigue, alopecia, drowsiness, myelosuppression, skin reactions, anorexia, mucositis and diarrhoea. These ADRs have high-documented incidence rates and were also the ten most predictable ADRs in this study. Common reasons for ADRs to be assessed as definitely or probably preventable were omission or inadequate/inappropriate use of preventative measures. The results also showed a discrepancy between clinical severity and patients perception of the impact of ADRs on well being.Conclusions ADRs are common in hospitalised oncology patients and are predictable and at least probably preventable in many instances. Improved use of preventative measures has the potential to contribute to reducing the incidence and severity of ADRs. Recognition and understanding of the discrepancy that exists between clinical severity and patient-perceived severity of ADRs will enable specific areas to be identified and targeted for vigourous intervention.     

Diffusion of responsibility attenuates altruistic punishment: A functional magnetic resonance imaging effective connectivity study

Humans altruistically punish violators of social norms to enforce cooperation and pro‐social behaviors. However, such altruistic behaviors diminish when others are present, due to a diffusion of responsibility. We investigated the neural signatures underlying the modulations of diffusion of responsibility on altruistic punishment, conjoining a third‐party punishment task with event‐related functional magnetic resonance imaging and multivariate Granger causality mapping. In our study, participants acted as impartial third‐party decision‐makers and decided how to punish norm violations under two different social contexts: alone (i.e., full responsibility) or in the presence of putative other third‐party decision makers (i.e., diffused responsibility). Our behavioral results demonstrated that the diffusion of responsibility served as a mediator of context‐dependent punishment. In the presence of putative others, participants who felt less responsible also punished less severely in response to norm violations. Our neural results revealed that underlying this behavioral effect was a network of interconnected brain regions. For unfair relative to fair splits, the presence of others led to attenuated responses in brain regions implicated in signaling norm violations (e.g., AI) and to increased responses in brain regions implicated in calculating values of norm violations (e.g., vmPFC, precuneus) and mentalizing about others (dmPFC). The dmPFC acted as the driver of the punishment network, modulating target regions, such as AI, vmPFC, and precuneus, to adjust altruistic punishment behavior. Our results uncovered the neural basis of the influence of diffusion of responsibility on altruistic punishment and highlighted the role of the mentalizing network in this important phenomenon. Hum Brain Mapp 37:663–677, 2016. © 2015 Wiley Periodicals, Inc .     

成人肥厚型鲜红斑痣82例肥厚相关因素分析

目的：分析肥厚型鲜红斑痣患者的临床特点及导致皮损肥厚的相关因素。方法2010年1月至2014年8月，安徽省立医院和安徽医科大学第一附属医院皮肤科门诊成人鲜红斑痣患者纳入研究。分析肥厚型鲜红斑痣患者临床特点，并采用单因素和多因素非条件 Logistic 回归分析导致皮损肥厚的相关因素。结果共收集资料完整的成年鲜红斑痣患者262例，其中肥厚型鲜红斑痣82例，男30例，女52例，年龄18~54岁，中位年龄32.5岁；66例（80.48%）表现为斑块样肥厚型，9例（10.98%）为丘疹/结节型，7例（8.54%）为混合型。肥厚型鲜红斑痣患者年龄≥30岁者占56.10%（46/82），皮损面积以11~30 cm2为主（41.46%，34/82），皮损颜色以紫红色为主（85.36%，70/82），与扁平型鲜红斑痣相比，两组差异有统计学意义（χ2=25.559、10.580、90.630， P <0.05），而性别、Fitzpatrick 皮肤分型、皮损部位及皮损分布与肥厚无关。多因素非条件 Logistic 回归分析显示，年龄≥30岁（OR =2.889，95% CI：1.459~5.721）、皮损呈紫红色（OR =19.984，95% CI：5.704~70.023）是鲜红斑痣肥厚的相关因素。结论年龄≥30岁和皮损颜色呈紫红色是肥厚型鲜红斑痣患者肥厚的相关因素。     

Drug- and Herb-Induced Liver Injury in Clinical and Translational Hepatology: Causality Assessment Methods,Quo Vadis?

Drug-induced liver injury (DILI) and herb-induced liver injury (HILI) are typical diseases of clinical and translational hepatology. Their diagnosis is complex and requires an experienced clinician to translate basic science into clinical judgment and identify a valid causality algorithm. To prospectively assess causality starting on the day DILI or HILI is suspected, the best approach for physicians is to use the Council for International Organizations of Medical Sciences (CIOMS) scale in its original or preferably its updated version. The CIOMS scale is validated, liver-specific, structured, and quantitative, providing final causality grades based on scores of specific items for individual patients. These items include latency period, decline in liver values after treatment cessation, risk factors, co-medication, alternative diagnoses, hepatotoxicity track record of the suspected product, and unintentional re-exposure. Provided causality is established as probable or highly probable, data of the CIOMS scale with all individual items, a short clinical report, and complete raw data should be transmitted to the regulatory agencies, manufacturers, expert panels, and possibly to the scientific community for further refinement of the causality evaluation in a setting of retrospective expert opinion. Good-quality case data combined with thorough CIOMS-based assessment as a standardized approach should avert subsequent necessity for other complex causality assessment methods that may have inter-rater problems because of poor-quality data. In the future, the CIOMS scale will continue to be the preferred tool to assess causality of DILI and HILI cases and should be used consistently, both prospectively by physicians, and retrospectively for subsequent expert opinion if needed. For comparability and international harmonization, all parties assessing causality in DILI and HILI cases should attempt this standardized approach using the updated CIOMS scale.     

抗结核药品对肠道菌群的改变及其对机体的影响

肠道菌群的结构和代谢产物与人体互相作用,维持肠道屏障稳态,促进全身营养代谢与免疫平衡,参与多种系统及组织、器官的病理生理过程,在结核感染、发病、治疗及转归过程中发挥重要作用,但是抗结核药品对肠道菌群的影响研究刚刚起步。作者综述肠道菌群在肠道屏障稳态中的作用,进而梳理和总结抗结核药品对肠道菌群影响的研究成果,并最终扩展至相关临床问题,讨论肠道菌群改变对机体的广泛影响。     

肺结核患者临床特征与外周血流式细胞亚群的相关性分析

目的 了解肺结核患者临床特征与外周血流式细胞亚群[T淋巴细胞亚群及自然杀伤 (NK)细胞]的相关性。方法 连续性收集2019年1月1日至5月25日期间同济大学附属上海市肺科医院肺结核住院患者1000例的临床资料进行回顾性分析。将患者各临床特征数据与外周血流式细胞亚群的检测值采用Eviews 8.0软件分别建立多元线性逐步回归模型,以明确各临床特征与外周血流式细胞亚群的检测值之间的相关性。结果 (1)肺结核患者的肺部病灶范围及呼吸道标本抗酸染色涂片结果与CD3⁺T细胞表达有关:肺部病灶范围越大、呼吸道标本抗酸染色涂片阳性程度越高,CD3⁺ T细胞数量越低(回归系数分别为-0.255、-0.499, P值分别为0.021、0.027)。(2)患者的年龄、性别、结核分子生物学检测结果与CD4⁺ T细胞表达有关: 0~<20岁年龄段患者CD4⁺ T细胞数量低于其他年龄段患者(回归系数-4.710,P=0.031);男性CD4⁺ T细胞数量低于女性患者(回归系数-2.150, P=0.001);分子生物学检测阳性的患者CD4⁺ T细胞数量高于检测阴性的患者(回归系数1.433, P=0.030)。(3)初治患者CD8⁺ T细胞数量高于复治患者(回归系数1.247, P=0.029);呼吸道标本抗酸染色涂片阳性程度越高CD8⁺ T细胞数量越高(回归系数0.442, P=0.033)。(4)并发肺外结核者的NK细胞低于未并发肺外结核者(回归系数0.375, P=0.030)。结论 肺结核患者的肺部病灶累及范围、呼吸道标本抗酸染色阳性与外周血流式细胞亚群CD3⁺ T细胞具有相关性;年龄、性别、结核分子生物学检测结果与CD4⁺ T细胞具有相关性;是否初治、呼吸道标本抗酸染色阳性与CD8⁺ T细胞具有相关性;是否并发肺外结核与NK细胞表达水平具有相关性。     

慢性心力衰竭病人血清高密度脂蛋白胆固醇、高敏肌钙蛋白T水平与心功能指标的相关性

目的 分析血清高密度脂蛋白胆固醇(HDL-C)、高敏肌钙蛋白T(Hs-cTnT)水平在慢性心力衰竭发生、发展中的价值。方法 选取2013年2月至2016年6月新疆维吾尔自治区人民医院收治的慢性心力衰竭住院病人(慢性心衰组,n=200)以及健康体检者(健康对照组,n=86)为研究对象,并根据美国心脏病协会(NYHA)心功能分级将慢性心衰组进一步分为Ⅱ级(n=43)、Ⅲ级(n=111)、Ⅳ级(n=46) 3个亚组。比较四组受试者间血清HDL-C、Hs-cTnT水平,所有受试对象均行超声心动图检查,测定左室射血分数(LVEF),采用Spearman等级相关分析慢性心力衰竭病人心功能分级、LVEF与血清HDL-C、Hs-cTnT水平的相关性。结果 慢性心衰组病人血清HDL-C(0.98±0.64)mmol/L低于健康对照组(1.59±0.58)mmol/L(t=7.256,P<0.001),血清Hs-cTnT(0.34±0.12)ng/mL高于健康对照组(0.04±0.02)ng/mL(t=8.978,P<0.001)。慢性心衰组病人血清HDL-C水平、LVEF由低到高依次为Ⅳ级、Ⅲ级、Ⅱ级;而血清Hs-cTnT水平由高到低依次为Ⅳ级、Ⅲ级、Ⅱ级。不同心功能分级病人血清HDL-C、Hs-cTnT水平以及LVEF均差异有统计学意义(F=33.451,P=0.000;F=37.302,P=0.000;F=53.701,P=0.000)。Spearman相关分析结果显示,慢性心衰组病人血清HDL-C水平与心功能分级呈负相关(r_s=-0.483,P=0.000),与LVEF呈正相关(r_s=0.221,P=0.002);血清Hs-cTnT水平与心功能分级呈正相关(r_s=0.693,P=0.000),与LVEF呈负相关(r_s=-0.433,P=0.000);慢性心衰组病人血清HDL-C水平与血清Hs-cTnT水平呈负相关(r_s=-0.284,P=0.000)。结论 慢性心力衰竭病人HDL-C水平降低、Hs-cTnT水平增高,且其血清水平与病人心功能状态显著相关,测定血清HDL、Hs-cTnT水平有利于慢性心力衰竭疾病的预防、治疗及预后评估。