Prognostic value of an inflammatory biomarker-based clinical algorithm in septic patients in the emergency department: An observational study

BackgroundTo develop an inflammatory biomarker-based, simple-to-use nomogram for the early identification of septic patients at high risk of mortality in the emergency department (ED).MethodsAll patients diagnosed with sepsis admitted to the intensive care unit (ICU) from the ED were screened from the Medical Information Mart for Intensive Care III database and divided into two cohorts: the primary cohort and the validation cohort. We used bivariate logistic regression analysis to determine independent risk factors and to construct a predictive nomogram and subsequently evaluated the calibration, discrimination and clinical usefulness of the nomogram. The gradient boosting machine (GBM) model was used to more accurately evaluate these variables.ResultsA total of 5663 admissions were enrolled, of which 3964 comprised the primary cohort and 1699 comprised the validation group, with 28-day mortality rates of 21.2% and 20.4%, respectively. Age > 69, neutrophil-to-lymphocyte ratio (NLR) > 9.8, platelet-to-lymphocyte ratio (PLR) > 249.89, lymphocyte-to-monocyte ratio (LMR) ≤ 2.18, and red cell distribution width (RDW) were detected as important determinants of 28-day mortality and included in the nomogram. The calibration plot revealed an adequate fit of the nomogram for predicting the risk of 28-day mortality. Regarding discriminative ability, receiver operating characteristic curve analysis showed that the nomogram had an area under the curve (AUC) of 0.826 (95% CI: 0.811–0.841, P < 0.001) in the primary cohort, which was greater than that of all individual parameters and other scores. Decision curve analysis also indicated that our nomogram was feasible in clinical practice, as the threshold probabilities were 0–0.62 for the primary cohort. The GBM model yielded a significantly greater AUC of up to 0.867.ConclusionsThis proposed simple-to-use nomogram based on age, NLR, PLR, LMR and RDW provides a relatively accurate mortality prediction for septic patients in the ED.     

Germline variant burden in multidrug resistance transporters is a therapy-specific predictor of survival in breast cancer patients

Multidrug resistance due to facilitated drug efflux mediated by ATP-binding cassette (ABC) transporters is a main cause for failure of cancer therapy. Genetic polymorphisms in ABC genes affect the disposition of chemotherapeutics and constitute important biomarkers for therapeutic response and toxicity. Here we correlated germline variability in ABC transporters with disease-specific survival (DSS) in 960 breast cancer (BRCA), 314 clear cell renal cell carcinoma and 325 hepatocellular carcinoma patients. We find that variant burden in ABCC1 is a strong predictor of DSS in BRCA patients, whereas candidate polymorphisms are not associated with DSS. This association is highly drug-specific for subgroups treated with the MRP1 substrates cyclophosphamide (log-rank p = 0.0011) and doxorubicin (log-rank p = 0.0088) independent of age and tumor stage, whereas no association was found in individuals treated with tamoxifen (log-rank p = 0.13). Structural mapping of significant variants revealed multiple variants at residues involved in protein stability, cofactor stabilization or substrate binding. Our results demonstrate that BRCA patients with high variant burden in ABCC1 are less prone to respond appropriately to pharmacological therapy with MRP1 substrates, thus incentivizing the consideration of genomic germline data for precision cancer medicine.     

美国新药技术成熟度评价研究

目的研究提出适合我国新药研发和药品安全管理的技术成熟度评价机制。方法借鉴美国新药研发技术成熟度等级(biomedical technology readiness level,BTRL)评价标准与方法,结合我国新药研发、监管和产业化特点,提出我国成熟度评价等级和指标,并在重大新药创制科技重大专项研发管理中开展探索分析。结果与结论探索建立我国化学药和生物制品技术成熟度评价等级标准,将为我国新药研发科研项目和保障药品安全提供管理与评估工具,为其他行业领域提供参考借鉴。     

全国名中医丁书文益气活血解毒法治疗心房颤动的处方用药规律挖掘＊

目的 丁书文教授创新性地提出了心系疾病热毒学说，运用益气活血解毒法治疗房颤疗效显著。本研究以丁教授多年的处方数据为基础，探讨丁教授益气活血解毒法治疗房颤的用药规律。方法 收集来自山东中医药大学附属医院门诊系统的丁书文教授处方数据，筛选出治疗房颤的372个处方，采用关联规则、点式互信息、复杂网络等数据挖掘方法对丁教授的药物配伍和处方进行分析。结果 本研究利用复杂网络分析方法获得了丁教授治疗房颤的核心处方，提示益气活血解毒法是其主要治则治法；利用处方相似性和社团分析方法，获得15组类方，其中3种类方与丁教授总结的三大治法高度符合；为探寻丁教授清热解毒配伍特点，结合关联规则和点式互信息算法，获得了10个丁教授清热解毒配伍药对。结论 数据挖掘技术提供了名医处方数据分析与提炼的可行方法，对丁教授经验的传承和临床应用提供直接可靠的依据。     

The risk of fractures,acute myocardial infarction,atrial fibrillation and ventricular arrhythmia in geriatric patients exposed to promethazine

ABSTRACT

Objectives: This study aimed to compare the risk of fractures, acute myocardial infarction, atrial fibrillation, and ventricular arrhythmia among Danish citizens aged ≥ 65 which were new users of promethazine or domperidone, triazolam, loratadine, and betahistine. Secondly, the study aimed to perform a risk stratification to identify the most relevant predictors for the study outcomes.

Methods: The study period was 01/01/2015 to 31/12/2016. The data sources were the Danish registers. Each patient was followed for 90 days. A logistic regression model was used to compute the unadjusted and adjusted odds ratios (OR), and a conditional inference tree was used to identify the most relevant predictors for the study outcomes.

Results: Promethazine had a higher risk of hospitalization for atrial fibrillation than loratadine and betahistine (OR 1.58; 95% CI 1.07–2.63 and OR 3.22; 95% CI 1.69–7.14, respectively). For fractures, acute myocardial infarction, and ventricular arrhythmia hospitalizations, no statistically significant differences were found among drugs under investigation. The medical history of cardiac arrhythmia (OR 4.14; 95% CI 2.94–5.78, p < 0.0001) was the most relevant predictor for atrial fibrillation hospitalizations.

Conclusion: This study found an increased risk of atrial fibrillation hospitalization among promethazine users, and the risk was higher among patients with prior cardiac arrhythmia.     

万古霉素药物暴露量阈值与肾毒性的相关性分析

目的探讨万古霉素药物暴露量与肾毒性发生的相关性,并确定其上限阈值。方法前瞻性收集2018年5月-2019年1月接受静脉注射万古霉素治疗的成人住院患者信息。使用贝叶斯最大后验概率法计算药时曲线下面积(AUC)并采用分类和回归树(CART)的方法分析和确定万古霉素初始剂量及与肾毒性相关的稳态AUC阈值。通过受试者工作特征(ROC)曲线评估上述方法所得AUC阈值的预测性能及对万古霉素相关肾毒性的诊断价值,并采用多因素logistic回归分析量化肾毒性发生风险因素。结果共纳入患者155例,其中发生肾毒性患者13例(8.39%)。经CART分析得到AUC0-24、AUC24-48、AUCss0-24对肾毒性预测的最佳阈值点分别为622 mg·h/L、617 mg·h/L、578 mg·h/L。经多因素logistic回归分析,AUC超过最佳阈值点时肾毒性发生率显著提高(P≤0.01),联合使用肾毒性药物与肾毒性发生独立相关,会提高约6倍的肾毒性发生率(P<0.01)。结论万古霉素暴露量超过阈值时会大幅提高肾毒性发生风险,提示AUC监测对预测肾毒性发生有很高的临床价值。     

Was It Worth Introducing Health Economic Evaluation of Innovative Drugs in the French Regulatory Setting? The Case of New Hepatitis C Drugs

Objective

This paper constitutes the first attempt to draw lessons from the recent uptake of health economic evaluation of innovative drugs in the French regulatory framework.

药品审评检查机构质量管理体系建设实践探索

目的:贯彻国务院强化质量管理、落实全国药监部门完善自身质量管理体系工作部署,梳理山东省药品审评检查机构质量管理体系建设情况,总结经验、查找不足,加强审评检查质量管理。方法:调研药品审评检查机构导入质量管理体系的现实意义,剖析山东省药品审评检查机构质量管理体系建设的实践经验,思考存在的问题。结果:行之有效的质量管理体系对药品审评检查机构规范化建设和药品审评检查发展起到了积极的推动作用。结论:药品审评检查机构推进质量管理体系建设,对规范自身建设、提高工作质量、降低业务风险、服务医药产业发展具有重要作用,也是必然要求,药品审评检查机构质量管理体系需要持续改进,逐渐与国际接轨。     

欧盟和美国对药品说明书【适应症】项目的撰写要求及启示

介绍欧盟和美国有关药品说明书[适应症]项目撰写的法规和指导原则，特别是最近欧洲药品管理局（EMA）发布的"治疗适应症的用语"。从这些管理文件得到的启示是相关法规规定不宜太粗糙，应具体、精准，应包括内容和格式的规定；而且要有指导原则伴随，以保证法规落到实处。熟悉掌握药品说明书[适应症]项目的撰写要求对规范撰写其他项目有普遍指导意义，对于药品说明书的监管也有裨益。     

The adverse-effect profile of lacosamide

ABSTRACT

Introduction: Lacosamide has been used in epilepsy patients in the United States, Europe and Asia since it was approved by the FDA in 2008. Many patients have benefited from this drug as a new generation of sodium channel blocker. With the worldwide use of this drug, its adverse effects have gradually emerged, especially some rare adverse events.

Areas covered: The present review aims to summarize the adverse effects of lacosamide reported in the literature in recent years to promote the safe clinical application of the drug.

Expert opinion: In more than 10 years of experience in drug usage, adverse reactions of lacosamide have also been gradually discovered. The review showed that lacosamide is safe and effective in antiepileptic treatment, and its common side effects are dizziness, headache, drowsiness, diplopia, and cardiovascular abnormalities. Skin rashes, hematotoxicity and heart damage, psychological symptoms and suicide risk have also been reported and emphasized.