利奈唑胺相关血小板减少的危险因素分析

目的探讨利奈唑胺相关血小板减少的危险因素。方法收集2011年1月至2012年7月在复旦大学附属中山医院因感染应用利奈唑胺的162例住院患者的临床资料并进行回顾性分析,根据用药后是否出现血小板减少,将患者分为血小板减少组和血小板正常组。主要分析指标为患者性别、年龄、体重,应用利奈唑胺前血小板计数、血清肌酐清除率(Ccr)、白蛋白、血红蛋白、丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)水平,应用利奈唑胺的剂量、给药途径和持续时间,以及合并用药情况等。对影响血小板计数的相关变量分别进行t检验、Mann-Whitney U检验和Kruskal-Wallis H检验,对筛选出的危险因素进行逐步Logistic回归统计分析,计算比值比(OR)及95%置信区间(CI)。结果 162例患者中男113例,女49例,年龄19～96岁,平均年龄(57.2±16.1)岁;用药方法均为静脉滴注,600 mg/次,2次/d。应用利奈唑胺的时间为1～46 d,中位时间6 d。血小板正常组115例,血小板减少组47例。47例患者用药后出现血小板减少的中位时间为4.5 d,血小板计数平均为(53±29)×109/L,其中轻、中、重度分别为25、10、12例。逐步Logistic回归分析显示,用药前Ccr<50 ml/min的OR为6.75,95%CI为2.93～15.58,P=0.000;血小板计数<100×109/L的OR为4.54,95%CI为1.53～13.50,P=0.006;应用利奈唑胺时间>14 d的OR为4.00,95%CI为1.40～11.39,P=0.009;用药前AST>75 U/L的OR为2.73,95%CI为1.07～6.99,P=0.036。结论应用利奈唑胺前Ccr、血小板计数低于正常、AST高于正常和应用利奈唑胺时间>14 d可能为利奈唑胺相关血小板减少的危险因素。     

Adverse events following statin–fenofibrate therapy versus statin alone: A meta‐analysis of randomized controlled trials

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Risk factors for linezolid-induced thrombocytopenia in adult inpatients

Background Previous reports about risk factors for linezolid-induced thrombocytopenia have been insufficient, often due to the variability in study design and population, and some factors have not yet been studied. Aim The aims of this study are to determine potential risk factors for linezolid-induced thrombocytopenia, and to analyze the influencing factors of different thrombocytopenia definitions. Method This retrospective study involved patients who were administered intravenous linezolid for?≥?1 day between January 1, 2015 and January 1, 2021. Their demographic and clinical data were extracted from electronic medical records. Thrombocytopenia was defined as: ①thrombocytopenia with platelet count?<?100?×?10⁹/L and a decrease in 25% or more from baseline of the platelet count (criterion 1); ②thrombocytopenia due to a platelet count drop decrease of 25% or more from baseline (criterion 2). Risk factors were determined via binary logistic regression analysis. Results This study included 320 patients. Binary logistic regression analysis indicated that baseline platelet count (p?<?0.001), linezolid therapy duration (p?=?0.001) and shock (patients require vasoactive medications) (p?=?0.019) were independent risk factors for criterion-1thrombocytopenia, while linezolid therapy duration (p?<?0.001) and shock (p?=?0.015) were independent risk factors for criterion-2 thrombocytopenia. There was also a significant correlation between shock and early-onset thrombocytopenia (p?=?0.005 and 0.019 for criterion 1 and criterion 2, respectively). Conclusion Linezolid therapy duration and shock were common causes of different thrombocytopenia definitions; shock was correlated with early-onset thrombocytopenia. Platelet count should be monitored during linezolid therapy especially during long-duration therapy and in shock patients.

     

Retrospective analysis of the risk factors for linezolid-induced thrombocytopenia in adult Japanese patients

Background Thrombocytopenia is a major side effect of linezolid therapy. However, there are few reports about the risk factors for linezolid-induced thrombocytopenia. Objective The aim of this study is to evaluate the risk factors for thrombocytopenia in patients who undergo linezolid therapy. Setting Aomori Prefectural Central Hospital in Japan, a tertiary 695 beds hospital. Method A retrospective review was performed using the hospital’s medical records. From January 2010 to August 2012, 75 adult patients who received linezolid therapy were enrolled in this study. Main outcome measure Linezolid-induced thrombocytopenia was defined as a decrease in the patient’s platelet count to <10 × 10⁴/μL or a reduction of ≥30 % from their baseline value. Odds ratios (OR) for thrombocytopenia were analyzed using multivariate stepwise logistic regression analysis. Results Thrombocytopenia occurred in 29 patients (38.6 %), seven of whom required platelet transfusions. The patients who developed thrombocytopenia were significantly older, displayed a significantly higher frequency of renal insufficiency, and received linezolid therapy for significantly longer than the patients without thrombocytopenia. Stepwise logistic regression analysis suggested that receiving linezolid therapy for ≥14 days was a significant risk factor for thrombocytopenia [OR 13.3, 95 % confidence interval (CI) 3.2–55.6, p < 0.01], whereas the creatinine clearance rate exhibited a significant negative correlation with the incidence of the condition [OR 0.98, 95 % CI 0.96–0.99, p = 0.037]. The incidence of thrombocytopenia among the patients who demonstrated creatinine clearance rates of <30 mL/min was 60 % (12/20), which was significantly higher than that observed among the patients who displayed creatinine clearance rates of more than 60 mL/min (26.4 %, 9/34, p = 0.014). Conclusion Receiving linezolid therapy for ≥14 days and a low creatinine clearance rate were suggested to be risk factors for linezolid-induced thrombocytopenia. The platelet counts of patients with these risk factors should be closely monitored.     

Non‐alcoholic fatty liver disease (NAFLD) fibrosis score predicts 6.6‐year overall mortality of Chinese patients with NAFLD

The non‐alcoholic fatty liver disease (NAFLD) fibrosis score (NFS) has emerged as a useful predictor of long‐term outcome in NAFLD patients. We evaluated the predictive performance of the NFS for overall mortality in a Chinese population with NAFLD. All NAFLD patients diagnosed ultrasonographically at Xixi Hospital of Hangzhou between 1996 and 2011 were retrospectively recruited to the study. Outcome was determined by interview and causes of death were confirmed by medical records. The area under the receiver operating characteristic curve (AUC_ROC) was used to determine the predictive accuracy of the NFS, BARD (body mass index, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, diabetes) score, FIB‐4 index and the AST/platelet ratio index (APRI) for mortality. Data from a total of 180 eligible patients (median age 39 years; 96 men) were analysed, with 12 deaths over a median follow‐up period of 6.6 years (range 0.5–14.8 years). Using Cox model analysis, the NFS as a continuous variable was identified as the only predictor for all‐cause mortality (hazard ratio 2.743, 95% confidence interval (CI) 1.670–4.504). The NFS yielded the highest AUC_ROC of 0.828 (95% CI 0.728–0.928, P < 0.05), followed by the FIB‐4 index, APRI and BARD score (AUC_ROC 0.806 (P < 0.05), 0.732 (P < 0.05) and 0.632, respectively). The data indicated that the NFS is a useful predictor of 6.6‐year all‐cause mortality for Chinese patients with NAFLD.     

Clopidogrel‐associated genetic variants on inhibition of platelet activity and clinical outcome for acute coronary syndrome patients

Acute coronary syndrome (ACS) has become a vital disease with high mortality worldwide. A combined antiplatelet therapy (aspirin and a P2Y₁₂ antagonist) is commonly used to prevent re‐infarction in ACS patients who have undergone percutaneous coronary intervention (PCI). Clopidogrel, a P2Y₁₂ antagonist, plays an important role in the inhibition of platelet aggregation (IPA). However, it is a pro‐drug requiring biotransformation by cytochrome P450 (CYP450). The aim of this study is to unravel the effect of clopidogrel‐associated genetic variants on inhibition of platelet activity and clinical outcomes in ACS patients. In our study, a total of 196 patients with metabolic gene polymorphism of clopidogrel were enrolled, and their antiplatelet effect as well as their cardiovascular events were collected. Approximately 2 mL of venous blood samples were used for genotype detection and another 4 mL were collected for platelet reactivity with thrombelastography. The primary clinical end‐point was defined as a combination of cardiovascular mortality and revascularization for targeted vascular lesion. Based on the results of IPA, the prevalence of high on‐treatment platelet reactivity (HPR) was 17.3% and the majority of patients (82.7%) obtained normal on‐treatment platelet reactivity (NPR). The HPR group had significantly higher body mass index (BMI) and lower arachidonic acid (AA) induced IPA (P < 0.05). Therapy including Glycoprotein (GP) IIb/IIIa antagonist increased IPA (P < 0.05). ADP‐induced IPA effect was lower with the presence of CYP2C19*2, *3 and paraoxonase (PON)1 Q192R loss‐of‐function (LOF) alleles, respectively (P < 0.05). Multivariate logistic regression analysis demonstrated that aspirin resistance (AA‐induced IPA < 50%) had a greater risk of the occurrence of major adverse cardiovascular events (MACE) (OR = 3.817; 95% CI: 1.672‐8.700; P = 0.002). CYP2C19*2 LOF alleles were associated with high risk of MACE in 1‐year post PCI operations (OR = 2.571; 95% CI: 1.143‐5.780; P = 0.030). For the ACS patients, the presence of CYP2C19*2 and PON1 Q192R LOF alleles were the major drivers of HPR.     

Associations of glycated haemoglobin A1c and glycated albumin with subclinical atherosclerosis in middle‐aged and elderly Chinese population with impaired glucose regulation

The aim of this study was to investigate the correlations of glycated haemoglobin A1c (HbA1c) and glycated albumin (GA) with subclinical atherosclerosis in middle‐aged and elderly Chinese populations with impaired glucose regulation (IGR). In total, 640 subjects with IGR and no history of cardiovascular disease or carotid artery plaque were recruited for this study (256 men, 384 women; age range, 40–70 years). The carotid intima‐media thickness (C‐IMT) measured by carotid ultrasonography was used as an indicator of subclinical atherosclerosis. Increased C‐IMT was defined as ≥ 0.70 mm (upper quartile). HbA1c and GA were measured with high‐performance liquid chromatography and enzymatic method, respectively. The average HbA1c and GA among all 640 subjects were 5.7 ± 0.3% and 14.0 ± 1.1%, respectively. HbA1c and GA were higher in subjects with increased C‐IMT than in subjects with normal C‐IMT (5.8 ± 0.3% vs 5.7 ± 0.3% and 14.2 ± 1.0% vs 13.9 ± 1.1%, respectively; both P < 0.01). Correlation analysis showed that both HbA1c and GA were positively correlated with C‐IMT (r = 0.135 and 0.112, respectively; both P < 0.01). Logistic regression analysis revealed that both HbA1c (odds ratio (OR), 2.630; 95% confidence interval (95% CI), 1.401–4.935; P = 0.003) and GA OR, 1.215; 95% CI, 1.008–1.466; P = 0.041) were independent risk factors for increased C‐IMT. Both HbA1c and GA reflect the risk of subclinical atherosclerosis in middle‐aged and elderly Chinese populations with IGR.     

Effectiveness and safety of direct oral anticoagulants in atrial fibrillation patients switched from vitamin K antagonists: A systematic review and meta‐analysis

A substantial proportion of atrial fibrillation patients initiating direct oral anticoagulants (DOAC) are vitamin K antagonists (VKA)‐experienced, for example switchers from VKA to DOAC. With this study, we aimed to summarize available evidence on the effectiveness and safety of DOAC vs VKA in real‐life VKA‐experienced atrial fibrillation patients. We searched EMBASE, MEDLINE and Cochrane Library systematically for English‐language studies indexed any time before October 2018. We included studies of VKA‐experienced atrial fibrillation patients initiating DOAC therapy, with continued VKA therapy as comparator. Outcomes included arterial thromboembolism and bleeding. When appropriate, meta‐analysis was performed by calculating pooled, weighted and adjusted hazard ratios (aHR) with 95% confidence intervals (CI). Eight cohort studies comparing VKA‐experienced DOAC (dabigatran or rivaroxaban) users with continued VKA users were included. When comparing DOAC to VKA, an increased risk of ischaemic stroke and myocardial infarction was found for dabigatran (pooled aHR of 1.61 [95% CI 1.19‐2.19, I² = 65%] and 1.29 [95% CI 1.10‐1.52, I² = 0%], respectively), but not for rivaroxaban. The use of dabigatran in VKA‐experienced users was associated with an increased risk of gastrointestinal bleeding (pooled aHR 1.63 [95% CI 1.36‐1.94, I² = 30%]), but a decreased risk of intracranial bleeding (pooled aHR 0.45 [95% CI 0.32‐0.64, I² = 0%]). In conclusion, the use of dabigatran in prior VKA users in clinical practice was associated with a slightly increased risk of arterial thromboembolism and gastrointestinal bleeding, but a decreased risk of intracranial bleeding. Importantly, observational studies of real‐life VKA‐experienced oral anticoagulant users may be confounded by the reason for switching.     

Effects of JTV‐519 on stretch‐induced manifestations of mechanoelectric feedback

JTV‐519 is a 1,4‐benzothiazepine derivative with multichannel effects that inhibits Ca²⁺ release from the sarcoplasmic reticulum and stabilizes the closed state of the ryanodine receptor, preventing myocardial damage and the induction of arrhythmias during Ca²⁺ overload. Mechanical stretch increases cellular Na⁺ inflow, activates the reverse mode of the Na⁺/Ca²⁺ exchanger, and modifies Ca²⁺ handling and myocardial electrophysiology, favoring arrhythmogenesis. This study aims to determine whether JTV‐519 modifies the stretch‐induced manifestations of mechanoelectric feedback. The ventricular fibrillation (VF) modifications induced by acute stretch were studied in Langendorff‐perfused rabbit hearts using epicardial multiple electrodes under control conditions (n=9) or during JTV‐519 perfusion: 0.1 μmol/L (n=9) and 1 μmol/L (n=9). Spectral and mapping techniques were used to establish the baseline, stretch and post‐stretch VF characteristics. JTV‐519 slowed baseline VF and decreased activation complexity. These effects were dose‐dependent (baseline VF dominant frequency: control=13.9±2.2 Hz; JTV 0.1 μmol/L=11.1±1.1 Hz, P<.01; JTV 1 μmol/L=6.6±1.1 Hz, P<.0001). The stretch‐induced acceleration of VF (control=38.8%) was significantly reduced by JTV‐519 0.1 μmol/L (19.8%) and abolished by JTV 1 μmol/L (−1.5%). During stretch, the VF activation complexity index was reduced in both JTV‐519 series (control=1.60±0.15; JTV 0.1 μmol/L=1.13±0.3, P<.0001; JTV 1 μmol/L=0.57±0.21, P<.0001), and was independently related to VF dominant frequency (R=.82; P<.0001). The fifth percentile of the VF activation intervals, conduction velocity and wavelength entered the multiple linear regression model using dominant frequency as the dependent variable (R=−.84; P<.0001). In conclusion, JTV‐519 slowed and simplified the baseline VF activation patterns and abolished the stretch‐induced manifestations of mechanoelectric feedback.     

Meta‐analysis of the role of high‐dose statins administered prior to percutaneous coronary intervention in reducing major adverse cardiac events in patients with coronary artery disease

1. There is considerable evidence regarding the efficacy of statins for the primary and secondary prevention of coronary artery disease (CAD). However, due to lack of sufficient evidence, there is still doubt whether high‐dose statin therapy prior to percutaneous coronary intervention (PCI) is beneficial. In the present study, we performed a meta‐analysis to evaluate the effect of preoperative high‐dose statin therapy on the incidence of major adverse cardiac events (MACE) after successful PCI. 2. Trials were retrieved through Medline (1980–2009) and the reference files limited to English‐language articles. Data were abstracted using a standardized protocol and a meta‐analysis was performed. 3. Five studies of a total 1789 patients with CAD qualified for analysis. Administration of high‐dose statins in CAD patients before PCI was associated with a significant reduction in MACE 30 days after the procedure. The incidence of MACE in the high‐dose statin group (6.98%) was significantly lower than that in the placebo group (14.77%), with an odds ratio (OR) of 0.43 (95% confidence interval (CI) 0.31–0.59; P < 0.00001). The incidence of post‐PCI increases in creatine kinase MB in the high‐dose statin and placebo groups was 9.20%vs 18.83%, respectively (OR 0.43; 95% CI 0.33–0.58; P < 0.00001), whereas the incidence of increases in troponin I was 30.13%vs 44.53%, respectively (OR 0.53; 95% CI 0.43–0.67; P < 0.00001), respectively. 4. In conclusion, high‐dose statin therapy before PCI provides a significant benefit over placebo in preventing post‐PCI MACE. Findings from the present analysis strongly support a strategy of routine loading of high‐dose statins before interventional therapy.     

A 10‐Year Experience of Therapeutic Drug Monitoring (TDM) of Linezolid in a Hospital‐wide Population of Patients Receiving Conventional Dosing: Is there Enough Evidence for Suggesting TDM in the Majority of Patients?

A retrospective study was conducted to assess our 10‐year experience of therapeutic drug monitoring (TDM) of linezolid in a large patient population to establish whether conventional dosing may result in adequate drug exposure in the majority of patients. Patients included in this study underwent TDM of linezolid trough concentration (C_min) during treatment with conventional doses of 600 mg every 12 hr in the period between January 2007 and June 2016. The desired range of C_min was set between 2 and 7 mg/L (underexposure, C_min < 2 mg/L; overexposure, C_min > 7 mg/L). Multivariate logistic regression analysis investigated variables potentially correlated with linezolid C_min. One thousand and forty‐nine patients had 2484 linezolid C_min assessed during treatment with conventional doses. Median (IQR) linezolid C_min was 5.08 mg/L (2.78–8.52 mg/L). Linezolid C_min was within the desired range in 50.8% of cases (1262/2484). Overexposure (n = 821; 33%) occurred much more frequently than underexposure (n = 401; 16.2%) and was severe (>20 mg/L) in 3.9% of cases (98/2484). Linezolid overexposure was significantly associated with CrCL_C‐G estimates ≤40 mL/min. (OR 1.463; 95% CI 1.124–1.904, p = 0.005). Linezolid underexposure was significantly associated with CrCL_C‐G estimates >100 mL/min. (OR 3.046; 95% CI 2.234–4.152, p < 0.001). Linezolid C_min was not correlated linearly with CrCL_C‐G (R² = 0.061). Variability in renal function explained only partially the very wide interindividual linezolid C_min variability. Our study suggests that TDM could represent a valuable approach in optimizing linezolid exposure in the majority of patients.     

Meta‐analysis: proton pump inhibitor use and the risk of community‐acquired pneumonia

Aliment Pharmacol Ther 31 , 1165–1177

Summary

Background Observational studies examining the association between proton pump inhibitor (PPI) use and risk of community‐acquired pneumonia are conflicting. Aim To assess systematically the association between risk of community‐acquired pneumonia and PPI use in adults. Methods We searched MEDLINE, EMBASE and CINAHL databases between 1988 and January 2010. Two reviewers independently selected studies based on eligibility criteria and extracted data. Included studies evaluated adults (≥18 years) who took PPIs as an out‐patient. The primary outcome was community‐acquired pneumonia. Only observational studies with a comparison arm were included. Results Over 2600 citations were reviewed. Six studies were included. All were nested case‐control studies. Meta‐analysis found an increased risk of community‐acquired pneumonia associated with PPI use [OR 1.36 (95% CI 1.12–1.65)]; significant heterogeneity remained (I² 92%, P < 0.001). In exploratory subgroup analysis, short duration of use was associated with an increased odds of community‐acquired pneumonia [OR 1.92 (95% CI 1.40–2.63), I² 75%, P = 0.003], whereas chronic use was not [OR 1.11 (95% CI 0.90–1.38), I² 91%, P < 0.001], a significant interaction (P < 0.005). Conclusions Heterogeneity precluded interpretation of the summary statistic. Exploratory analysis revealed that duration of PPI use may impact the risk of community‐acquired pneumonia, a finding that should be explored in future studies.     

Octreotide‐Associated Neutropenia

Drug‐induced neutropenia and agranulocytosis are rare adverse events but can be fatal. Neutropenia can be induced by a myriad of drugs from almost every pharmacologic class. Octreotide is a somatostatin analog that has been used to treat variceal bleeding, acromegaly, and severe diarrhea associated with metastatic tumors, and to reduce symptoms in the setting of malignant bowel obstruction and pseudoobstruction. The most common adverse effects associated with octreotide include pain at the injection site and gastrointestinal effects such as loose stools, cramping, and nausea; neutropenia is not currently listed as an adverse effect of the drug. We describe the case of an 87‐year‐old man who developed neutropenia immediately after administration of three doses of subcutaneous octreotide. He presented to the hospital with a history of constipation and straining for 3 days. He was admitted, and laxatives, suppositories, and enemas were administered over the next 3 days to induce a bowel movement; however, they were ineffective. Bowel obstruction secondary to a mass was confirmed by computed tomography; the mass was eventually diagnosed as colon cancer. Octreotide 100 µg subcutaneously every 8 hours was started for the obstruction on the evening of hospital day 4. After the patient had received 3 doses of octreotide, his white blood cell count (WBC) had decreased from 4.1 × 10³/mm³ (neutrophils 75.4%, absolute neutrophil count [ANC] 3.1 × 10³/mm³) on admission to 1.6 × 10³/mm³ (neutrophils 62%, ANC 0.99 × 10³/mm³) on day 5. Given the temporal relationship of octreotide and neutropenia as well as the lack of a reasonable alternative cause, it was suspected that octreotide was the most likely culprit of the patient's neutropenia. Octreotide was subsequently discontinued, and his WBC increased to 4.9 × 10³/mm³ (neutrophils 66.3%, ANC 3.2 × 10³/mm³) the next day. The remainder of the patient's hospitalization was not significant for any further hematologic abnormalities. His WBC and ANC (WBC 6.7 × 10³/mm³, neutrophils 83.2%, ANC 5.6 × 10³/mm³) remained stable 30 days after the incident. Use of the Naranjo Adverse Drug Reaction Probability Scale indicated a probable relationship (score of 5) between the patient's development of neutropenia and octreotide therapy. To our knowledge, this report highlights the first case of octreotide‐associated neutropenia. Although the frequency of drug‐induced neutropenia remains rare outside of cytotoxic chemotherapy, the importance of recognizing this adverse effect cannot be understated given the mortality risks for neutropenic patients.     

住院患者使用利奈唑胺致相关性血小板减少症的危险因素分析

目的 研究住院患者使用利奈唑胺致血小板减少的发生率及危险因素.方法 采用回顾性横断面研究,以解放军总医院2011年1月至2011年5月间使用利奈唑胺的住院患者为研究对象,通过医院信息系统记录患者一般资料、病生理情况、用药情况并动态监测血小板计数变化.定义血小板减少症为低于正常值下限(即血小板计数＜100×109/L),并根据排除标准控制混杂因素,对纳入病例使用利奈唑胺致血小板减少症的观察指标进行逐步逻辑回归筛选危险因素,并绘制ROC曲线预测发生特征.结果 获得用药病例345例,按入排标准纳入有效病例208例,其中男性129(62.02％)例,女性79( 37.98％)例,平均年龄为62.67±18.66(16～ 98)a,用药时间平均为9.68±6.07(3～39)天.使用利奈唑胺致相关性血小板减少症的有59例(28.37％),发生血小板低于正常值或基础值的25％的有106例(50.96％),其中有20人(9.62％)发生了Ⅲ度和Ⅳ度血小板下降,需要输血或输注血小板.单因素分析显示年龄、肌酐清除率、基础血小板值、总胆红素、血清白蛋白对血小板减少症的影响具有统计学意义,逐步逻辑回归多因素分析显示基础血小板值和年龄与血小板减少症密切相关.绘制血ROC曲线Youden指数最大时(0.3855),曲线下面积为0.739时,对应切点的敏感度为62.71％,特异度为75.84％.结论 基础血小板值、年龄是利奈唑胺致相关性血小板减少症的独立危险因素,对基础血小板值≤204×109/L、年龄≥82岁的患者,容易发生明显血小板减少症甚至出血风险,应加强血常规监测频率.低肌酐清除率、低血清白蛋白水平也是发生血小板减少的重要危险因素,提示利奈唑胺致相关性血小板减少症呈浓度依赖性,并与免疫机制相关.此外,可尝试使用ROC曲线筛选预测利奈唑胺相关性血小板减少的风险特征,并在易感人群中调整合适剂量以兼顾有效性和安全性.     

Eltrombopag dose predictors in thrombocytopenic subjects with hepatitis C virus infection

This study aims to identify patient characteristics that predict effective eltrombopag dosage for the treatment of Hepatitis C virus (HCV)‐related thrombocytopenia. Demographic, clinical and genetic data collected from thrombocytopenic patients (n = 1463, age ≥ 18 years) with chronic HCV infection who were able to achieve a target platelet count of > 90 × 10⁹/L following eltrombopag treatment. Patients were categorized into four groups (25, 50, 75, and 100 mg) based on the eltrombopag dose needed to achieve the target platelet count. Eltrombopag dose predictors were identified using a two stage approach. First, bivariate analysis, using anova for continuous variables and Chi‐square test for categorical variables, was performed to identify possible predictors of eltrombopag dose (P < 0.05). Second, ordinal logistic regression with stepwise addition followed by backward deletion was then performed using predictors identified in bivariate analysis step to produce final model containing independent predictors at P < 0.05. Ordinal logistic model identified several predictors of eltrombopag dose. Predictors of higher eltrombopag dose include: having a HCV genotype 2 or 3, being Central/South Asian, being White (Caucasian or European heritage), increased weight, and increased spleen length. Predictors of lower eltrombopag dose include: female gender, increased age, having a higher ALP plasma concentration, increased creatinine clearance, increased baseline lymphocytes count, and increased baseline platelet count. In conclusion, this study identified patient characteristics that predict effective eltrombopag dose for the treatment of HCV‐related thrombocytopenia. Early selection of the optimal eltrombopag dose expedites the initiation of antiviral therapy. This is expected to improve the antiviral therapy outcome before the patient progress into liver decompensation.     

Prevalence and determinants of uptake of folic acid in peri‐conceptional period in a rural lower‐middle‐income country,Ghana

Folate is a vitamin B‐related substance needed by expectant mothers during the period right before and after conception (peri‐conceptional period) to help protect foetuses against neural tube defects (NTDs). Despite efforts to promote the peri‐conceptional uptake of folic acid (FA), adherence remains low. The aim of this study was to assess the prevalence and determinants of peri‐conceptional FA uptake among childbearing women in northern Ghana. In a cross‐sectional study, data from 303 women accessing antenatal care services in the Upper East Region of Ghana between February and July 2017 were collected and analysed in Stata (Version 12.1). Chi‐square and logistic regression analysis were used to identify the independent determinants of peri‐conceptional uptake of FA. The mean age of the study population was 27.4 (±5.73) years. The prevalence of uptake of peri‐conceptional FA was 28.7% (95% confidence interval: 26.7%‐34.2%); 66% of the women were aware of FA and 52% had acceptable knowledge about FA. Initiating ANC after 3 months of pregnancy was associated with 91% less chance of peri‐conceptional FA use [adjusted odds ratio (AOR) 0.09; 95% confidence interval (CI) 0.04‐0.22; P < .001]. Not knowing the frequency of dosing of FA was associated with a 58% less likelihood of uptake of peri‐conceptional FA (AOR 0.42; 95% CI 0.23‐0.76; P = .004). There is low uptake of peri‐conceptional FA among women of childbearing age accessing antenatal services in Northern Ghana, and this uptake is determined by the time of initiation of ANC visit and knowledge of dosage regimen of FA.     

The effects of anaesthetics on postoperative physiological reactions: a meta‐analysis

This study aimed to systematically investigate the effects of different anaesthetics on postoperative physiological reactions compared with placebo. The literature search was conducted using three databases: PubMed, EMBASE, and the Cochrane Library. Studies published from January 1990 to January 2015 were screened. The language was restricted to English. Heterogeneity was analyzed by the Q test and I² statistic. A fixed‐effect model was used for homogenous data and a random‐effects model for heterogeneous data. The odds ratio (OR) and 95% confidence interval (CI) were calculated to monitor the incidences of overall adverse events, arterial blood pressure, and cardiac abnormalities. Sensitivity analysis was performed to estimate the strength of the meta‐analysis, and publication bias was analyzed using Egger's test. A total of 24 articles were included in this meta‐analysis. There were 1,810 and 1,806 cases in the anaesthetic group and the placebo group, respectively. The incidence of overall adverse events was significantly lower in the anaesthetic group compared with the placebo group (OR = 0.57; 95% CI, 0.38–0.84). No publication bias was observed, and no inverse estimates were calculated using sensitivity analysis. There was no significant difference for the incidence of arterial blood pressure (OR = 4.62; 95% CI, 0.90–23.70) and cardiac abnormalities (OR = 1.18; 95% CI, 0.53–2.63) between the two groups. Although the incidence of overall adverse events was decreased in the anaesthetic group, it is impossible to determine whether the use of anaesthetics during surgical operation has a protective effect on postoperative physiological reactions.     

Characteristics of drugs safety signals that predict safety related product information update

Purpose

Investigation of drug safety signals is one of the major tasks in pharmacovigilance. Among many potential signals identified, only a few reflect adverse drug reactions requiring regulatory actions, such as product information (PI) update. Limited information is available regarding the signal characteristics that might predict PI update following signal evaluation. The objective of this study was to identify signal characteristics associated with PI updates following signal evaluation by the European Medicines Agency Pharmacovigilance Risk Assessment Committee during 2012 to 2016.

Methods

A comparative study was performed based on data from 172 safety signals. Characteristics of signals were extracted from the European Pharmacovigilance Issues Tracking Tool database. Multivariable logistic regression analysis was used to assess the relationship between signal characteristics and the decision to update the PI.

Results

Multivariable logistic regression analysis showed that the presence of evidence in multiple types of data sources (adjusted odds ratio [OR] 7.8 95% CI [1.5, 40.1]); mechanistic plausibility of the drug‐event association (adjusted OR 3.9 95% CI [1.9, 8.0]); seriousness of the event (adjusted OR 4.2 95% CI [1.3, 13.9]); and age of drugs ≤5 years (adjusted OR 3.9 95% CI [1.2, 12.7]) were associated with the decision to change the PI (P < 0.05).

Conclusions

This study identified 4 characteristics of drug safety signals that have shown to be associated with PI changes as outcome of signal evaluation. These characteristics may be used as criteria for selection and prioritization of potential signals that are more likely to necessitate product information updates.     

Additional role of serum 25‐hydroxyvitamin D3 levels in atherosclerosis in Chinese middle‐aged and elderly men

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