Pro-Arrhythmic Potential of Oral Antihistamines (H1): Combining Adverse Event Reports with Drug Utilization Data across Europe

Background

There is appreciable utilisation of antihistamines (H₁) in European countries, either prescribed by physician and purchased by patients for self-medication. Terfenadine and astemizole underwent regulatory restrictions in ’90 because of their cardiac toxicity, but only scarce clinical data are available on other antihistamines.

Aim

To investigate the pro-arrhythmic potential of antihistamines by combining safety reports of the FDA Adverse Event Reporting System (FAERS) with drug utilization data from 13 European Countries.

Methods

We identified signals of antihistamine arrhythmogenic potential by analyzing FAERS database for all cases of Torsades de Pointes (TdP), QT abnormalities (QTabn), ventricular arrhythmia (VA) and sudden cardiac death/cardiac arrest (SCD/CA). Number of cases ≥3 and disproportionality were used to define alert signals: TdP and QTabn identified stronger signals, whereas SCD/CA identified weaker signals. Drug utilization data from 2005 to 2010 were collected from administrative databases through health authorities and insurance.

Results

Antihistamines were reported in 109 cases of TdP/QT prolongation, 278 VA and 610 SCD/CA. Five agents resulted in stronger signals (cetirizine, desloratadine, diphenhydramine, fexofenadine, loratadine) and 6 in weaker signals (alimemazine, carbinoxamine, cyclizine, cyproeptadine, dexchlorpheniramine and doxylamine). Exposure to antihistamines with stronger signal was markedly different across European countries and was at least 40% in each Country. Cetirizine was >29 Defined Daily Doses per 1000 inhabitants per day (DID) in Norway, desloratadine >11 DID in France and loratadine >9 DID in Sweden and Croatia. Drugs with weaker signals accounted for no more than 10% (in Sweden) and in most European countries their use was negligible.

Conclusions

Some second-generation antihistamines are associated with signal of torsadogenicity and largely used in most European countries. Although confirmation by analytical studies is required, regulators and clinicians should consider risk-minimisation activities. Also antihistamines without signal but with peculiar use in a few Countries (e.g., levocetirizine) or with increasing consumption (e.g., rupatadine) deserve careful surveillance.     

医疗不良事件报告系统利用现状调查

目的 了解我国医疗不良事件报告系统的利用现状。方法 采用分层随机抽样的方法,调查山东省6个样本市30家二、三级医院对原卫生部和中国医院协会报告系统的利用上报情况。结果 有41.38%的医院表示利用过卫生部的报告系统,13.79%的医院表示原卫生部的2个报告系统都利用过,只有10.34%的表示原卫生部的2个报告系统和中国医院协会的报告系统都用过;报告的数量也十分有限,基本都是在个位数。结论 现有的不良事件报告系统利用率不足,可以通过完善报告系统和反馈机制、加强政策执行力等方式,提高不良事件报告系统利用率和不良事件报告率。     

154例药品不良反应监测报告分析

目的:分析我院2009和2010年收集的154例药品不良反应(ADR)报告,以期了解不良反应发生的特点和规律,减少或避免不良反应的重复发生,为临床科室合理用药提供参考。方法:采用回顾性分类统计方法,对我院2009和2010两年上报的154例报告就ADR分布与年龄、给药途径、药物分类、累及系统及器官等方面的关系进行统计分析。结果:154例不良反应报告中以抗微生物药物和中药注射剂为主,分别占44.81%和20.78%。ADR临床表现以变态反应为主,其中儿童和老年患者居多(33.12%和48.05%),以静脉滴注方式为主(91.55%),临床表现主要以皮肤及其附件损伤最常见(75.97%)。结论:应加强ADR监测上报工作,并及时向临床科室反馈,提高临床安全用药意识,确保临床用药安全。     

154例药品不良反应监测报告分析

目的：分析我院2009和2010年收集的154例药品不良反应（ADR）报告,以期了解不良反应发生的特点和规律,减少或避免不良反应的重复发生,为临床科室合理用药提供参考。方法：采用回顾性分类统计方法,对我院2009和2010两年上报的154例报告就ADR分布与年龄、给药途径、药物分类、累及系统及器官等方面的关系进行统计分析。结果：154例不良反应报告中以抗微生物药物和中药注射剂为主,分别占44．81％和20．78％。ADR临床表现以变态反应为主,其中儿童和老年患者居多（33．12％和48．05％）,以静脉滴注方式为主（91．55％）,临床表现主要以皮肤及其附件损伤最常见（75．97％）。结论：应加强ADR监测上报工作,并及时向临床科室反馈,提高临床安全用药意识,确保临床用药安全。     

Development and Validation of a Risk Model for Predicting Adverse Drug Reactions in Older People during Hospital Stay: Brighton Adverse Drug Reactions Risk (BADRI) Model

Background

Older patients are at an increased risk of developing adverse drug reactions (ADR). Of particular concern are the oldest old, which constitute an increasingly growing population. Having a validated clinical tool to identify those older patients at risk of developing an ADR during hospital stay would enable healthcare staff to put measures in place to reduce the risk of such an event developing. The current study aimed to (1) develop and (2) validate an ADR risk prediction model.

Methods

We used a combination of univariate analysis and multivariate binary logistic regression to identify clinical risk factors for developing an ADR in a population of older people from a UK teaching hospital. The final ADR risk model was then validated in a European population (European dataset).

Results

Six-hundred-ninety patients (median age 85 years) were enrolled in the development stage of the study. Ninety-five reports of ADR were confirmed by independent review in these patients. Five clinical variables were identified through multivariate analysis and included in our final model; each variable was attributed a score of 1. Internal validation produced an AUROC of 0.74, a sensitivity of 80%, and specificity of 55%. During the external validation stage the AUROC was 0.73, with sensitivity and specificity values of 84% and 43% respectively.

Conclusions

We have developed and successfully validated a simple model to use ADR risk score in a population of patients with a median age of 85, i.e. the oldest old. The model is based on 5 clinical variables (≥8 drugs, hyperlipidaemia, raised white cell count, use of anti-diabetic agents, length of stay ≥12 days), some of which have not been previously reported.     

Expert Opinions on Improving Femicide Data Collection across Europe: A Concept Mapping Study

Femicide, defined as the killings of females by males because they are females, is becoming recognized worldwide as an important ongoing manifestation of gender inequality. Despite its high prevalence or widespread prevalence, only a few countries have specific registries about this issue. This study aims to assemble expert opinion regarding the strategies which might feasibly be employed to promote, develop and implement an integrated and differentiated femicide data collection system in Europe at both the national and international levels. Concept mapping methodology was followed, involving 28 experts from 16 countries in generating strategies, sorting and rating them with respect to relevance and feasibility. The experts involved were all members of the EU-Cost-Action on femicide, which is a scientific network of experts on femicide and violence against women across Europe. As a result, a conceptual map emerged, consisting of 69 strategies organized in 10 clusters, which fit into two domains: “Political action” and “Technical steps”. There was consensus among participants regarding the high relevance of strategies to institutionalize national databases and raise public awareness through different stakeholders, while strategies to promote media involvement were identified as the most feasible. Differences in perceived priorities according to the level of human development index of the experts’ countries were also observed.     

Genetic Risk Score of NOS Gene Variants Associated with Myocardial Infarction Correlates with Coronary Incidence across Europe

Coronary artery disease (CAD) mortality and morbidity is present in the European continent in a four-fold gradient across populations, from the South (Spain and France) with the lowest CAD mortality, towards the North (Finland and UK). This observed gradient has not been fully explained by classical or single genetic risk factors, resulting in some cases in the so called Southern European or Mediterranean paradox. Here we approached population genetic risk estimates using genetic risk scores (GRS) constructed with single nucleotide polymorphisms (SNP) from nitric oxide synthases (NOS) genes. These SNPs appeared to be associated with myocardial infarction (MI) in 2165 cases and 2153 controls. The GRSs were computed in 34 general European populations. Although the contribution of these GRS was lower than 1% between cases and controls, the mean GRS per population was positively correlated with coronary incidence explaining 65–85% of the variation among populations (67% in women and 86% in men). This large contribution to CAD incidence variation among populations might be a result of colinearity with several other common genetic and environmental factors. These results are not consistent with the cardiovascular Mediterranean paradox for genetics and support a CAD genetic architecture mainly based on combinations of common genetic polymorphisms. Population genetic risk scores is a promising approach in public health interventions to develop lifestyle programs and prevent intermediate risk factors in certain subpopulations with specific genetic predisposition.     

Development of an Adverse Drug Reaction Risk Assessment Score among Hospitalized Patients with Chronic Kidney Disease

Background

Adverse drug reactions (ADRs) represent a major burden on the healthcare system. Chronic kidney disease (CKD) patients are particularly vulnerable to ADRs because they are usually on multiple drug regimens, have multiple comorbidities, and because of alteration in their pharmacokinetics and pharmacodynamic parameters. Therefore, one step towards reducing this burden is to identify patients who are at increased risk of an ADR.

Objective

To develop a method of identifying CKD patients who are at increased risk for experiencing ADRs during hospitalisation.

Materials and Methods

Factors associated with ADRs were identified by using demographic, clinical and laboratory variables of patients with CKD stages 3 to 5 (estimated glomerular filtration rate, 10–59 ml/min/1.73 m²) who were admitted between January 1, 2012, and December 31, 2012, to the renal unit of Dubai Hospital. An ADR risk score was developed by constructing a series of logistic regression models. The overall model performance for sequential models was evaluated using Akaike Information Criterion for goodness of fit. Odd ratios of the variables retained in the best model were used to compute the risk scores.

Results

Of 512 patients (mean [SD] age, 60 [16] years), 62 (12.1%) experienced an ADR during their hospitalisation. An ADR risk score included age 65 years or more, female sex, conservatively managed end-stage renal disease, vascular disease, serum level of C-reactive protein more than 10 mg/L, serum level of albumin less than 3.5 g/dL, and the use of 8 medications or more during hospitalization. The C statistic, which assesses the ability of the risk score to predict ADRs, was 0.838; 95% CI, 0.784–0.892).

Conclusion

A score using routinely available patient data can be used to identify CKD patients who are at increased risk of ADRs.     

Knowledge and Theme Discovery across Very Large Biological Data Sets Using Distributed Queries: A Prototype Combining Unstructured and Structured Data

As the discipline of biomedical science continues to apply new technologies capable of producing unprecedented volumes of noisy and complex biological data, it has become evident that available methods for deriving meaningful information from such data are simply not keeping pace. In order to achieve useful results, researchers require methods that consolidate, store and query combinations of structured and unstructured data sets efficiently and effectively. As we move towards personalized medicine, the need to combine unstructured data, such as medical literature, with large amounts of highly structured and high-throughput data such as human variation or expression data from very large cohorts, is especially urgent. For our study, we investigated a likely biomedical query using the Hadoop framework. We ran queries using native MapReduce tools we developed as well as other open source and proprietary tools. Our results suggest that the available technologies within the Big Data domain can reduce the time and effort needed to utilize and apply distributed queries over large datasets in practical clinical applications in the life sciences domain. The methodologies and technologies discussed in this paper set the stage for a more detailed evaluation that investigates how various data structures and data models are best mapped to the proper computational framework.     

熵权法在药品不良反应信号筛选及综合风险评价中的应用

目的：在运用经典方法对药品不良反应信号进行检测后,对信号进行再筛选并评价药品的综合风险。方法：以江苏省药品不良反应监测网络数据库为资料来源,SQL server 为后台数据库,Matlab 为算法主要实现工具,运用熵权法结合专家评分,对BCPNN 方法检测出的信号进行再调整和评级。结果：运用综合权重进行调整后,发现不同药品不良反应信号的强弱发生了一定的变化。其中,氟喹诺酮类药品中的加替沙星导致低血糖、呼吸困难等药品不良反应的风险较信号评级之前有所增加,需要专家在评审时更为留意。结论：将熵权法运用在药品不良反应信号的监测中,可使信号更接近客观筛选和主观判断的平衡值,部分罕发但严重的药品不良反应信号得到发现和重视,并能方便地研究药物引起的多种药品不良反应的综合风险。     

Adverse Events Associated with Yoga: A Systematic Review of Published Case Reports and Case Series

While yoga is gaining increased popularity in North America and Europe, its safety has been questioned in the lay press. The aim of this systematic review was to assess published case reports and case series on adverse events associated with yoga. Medline/Pubmed, Scopus, CAMBase, IndMed and the Cases Database were screened through February 2013; and 35 case reports and 2 case series reporting a total of 76 cases were included. Ten cases had medical preconditions, mainly glaucoma and osteopenia. Pranayama, hatha yoga, and Bikram yoga were the most common yoga practices; headstand, shoulder stand, lotus position, and forceful breathing were the most common yoga postures and breathing techniques cited. Twenty-seven adverse events (35.5%) affected the musculoskeletal system; 14 (18.4%) the nervous system; and 9 (11.8%) the eyes. Fifteen cases (19.7%) reached full recovery; 9 cases (11.3%) partial recovery; 1 case (1.3%) no recovery; and 1 case (1.3%) died. As any other physical or mental practice, yoga should be practiced carefully under the guidance of a qualified instructor. Beginners should avoid extreme practices such as headstand, lotus position and forceful breathing. Individuals with medical preconditions should work with their physician and yoga teacher to appropriately adapt postures; patients with glaucoma should avoid inversions and patients with compromised bone should avoid forceful yoga practices.     

Current management of patients hospitalized with community-acquired pneumonia across Europe: outcomes from REACH

Background

Data describing real-life management and treatment of community-acquired pneumonia (CAP) in Europe are limited. REACH (http://{"type":"clinical-trial","attrs":{"text":"NCT01293435","term_id":"NCT01293435"}}NCT01293435) was a retrospective, observational study collecting data on the management of EU patients hospitalized with CAP.The purpose of this study was to understand patient and disease characteristics in patients hospitalized with CAP and to review current clinical practices and outcomes.

Methods

Patients were aged ≥18 years, hospitalized with CAP between March 2010 and February 2011, and requiring in-hospital treatment with intravenous antibiotics. An electronic Case Report Form was used to collect patient, disease and treatment variables, including type of CAP, medical history, treatment setting, antibiotics administered and clinical outcomes.

Results

Patients (N = 2,039) were recruited from 128 centres in ten EU countries (Belgium, France, Germany, Greece, Italy, the Netherlands, Portugal, Spain, Turkey, UK). The majority of patients were aged ≥65 years (56.4%) and had CAP only (78.8%). Initial antibiotic treatment modification occurred in 28.9% of patients and was more likely in certain groups (patients with comorbidities; more severely ill patients; patients with healthcare-associated pneumonia, immunosuppression or recurrent episodes of CAP). Streamlining (de-escalation) of therapy occurred in 5.1% of patients. Mean length of hospital stay was 12.6 days and overall mortality was 7.2%.

Conclusion

These data provide a current overview of clinical practice in patients with CAP in EU hospitals, revealing high rates of initial antibiotic treatment modification. The findings may precipitate reassessment of optimal management regimens for hospitalized CAP patients.     

论沼气及其综合利用与现代农业相结合

论及沼气及其综合利用的６个方面,这些内容涉及到农林牧副渔工各个方面;沼气综合利用的全面开展,有力地促进了能源、经济、生态和社会四者的协调发展,为现代农业的多元化发展起到了极其重要的纽带作用．     

The spatial distribution of soils across Europe: A fractal approach

In this work we investigate the applicability of fractal modeling to the soil surface system in Europe, as described by the European Soil Database (V2.0) and the soil classification of the World Reference Base [FAO, 1999. World Reference Base for Soil Resources. ISSS–ISRIC–FAO, Rome, World Soil Resources Report No. 84]. Firstly, we observe the power law patterns of the distribution of pedotaxa as well as their pedorichness–area relationships. After this, we consider the 45 most abundant soils that cover 92% of the surface of Europe and estimate the box-counting fractal dimension of the areas covered by each of the pedotaxa within three orders of magnitude. Our analysis shows a remarkable scaling behavior of soil distribution and strongly suggests the fractal nature of pedotaxa distribution across Europe. These findings lead us to propose that considering the pedotaxa fractal dimension could play an important role in the analysis of the complexity of European soil systems.     

Multi-Indication Carbamazepine and the Risk of Severe Cutaneous Adverse Drug Reactions in Korean Elderly Patients: A Korean Health Insurance Data-Based Study

Objective

To evaluate the risk of severe cutaneous adverse drug reactions (SCAR) after exposure to multi-indication antiepileptic drugs for in Korean elderly patients.

Methods

We used a nationwide database from the Korean Health Insurance Review and Assessment Service claims constructed for the monitoring of drug utilization among the entire Korean elderly population from January 2005 to June 2006. We identified cases of SCARs among inpatients aged ≥65 years and those newly diagnosed with erythema multiforme according to the International Classification of Diseases, 10th revision code (L51). Each case was matched to four controls for gender, age, and the first hospitalization date as the index date. The use of carbamazepine, gabapentin, lamotrigine, topiramate, phenobarbital, phenytoin, and valproate during a 60-day period before the index date was compared. A conditional logistic regression analysis was performed to calculate the odds ratios (OR) and 95% confidence intervals (CI) of SCARs for antiepileptic drug.

Results

We identified 286 cases of SCAR and 1,144 matched controls. Among the 25 patients who were prescribed antiepileptic drugs within 60 days of the index date. There were 11 cases (3.8%) of severe ocular manifestations, and most elderly patients were first-time or short-term users of antiepileptic drugs. Among the 10 cases of carbamazepine use, only 2 cases were prescribed carbamazepine for seizure. All antiepileptic drugs were associated with an increased SCAR risk (adjusted OR = 3.42, 95% CI: 1.75–6.63). The SCAR risk was highest in patients treated with carbamazepine (adjusted OR = 10.39, 95% CI: 2.64–40.86, for multi-indication; adjusted OR = 6.84, 95% CI: 1.55–30.10, for neuropathic pain).

Conclusion

Carbamazepine use was associated with a nearly 10-fold increase in severe cutaneous drug reactions in Korean elderly patients. This association was consistently high with SCAR patients who received carbamazepine for neuropathic pain.     

Carbon profiles of typical forest types across Europe assessed with CO2FIX

This paper presents for 16 typical forest types across Europe a standard carbon sequestration profile. The study was carried out with the model CO2FIX which was parameterised with local yield table data and additional required parameters. CO2FIX quantifies the carbon of the forest ecosystem–soil–wood products chain at the stand level. To avoid misleading results annual net sequestration rates are not presented here, because these strongly fluctuate in time. Therefore, only its advancing mean is presented as a more reliable indicator. This avoids a great deal of uncertainty for policy makers. The variation between forest types is large, but mean sequestration rates mostly peak after some 38 years (with a net source lasting up to 15 years after afforestation) at an average value of 2.98 Mg C ha⁻¹ per year (ranging between forest types from 4.1 to 1.15). After 200 years, the net sequestration rate saturates to a value of 0.8 Mg C ha⁻¹ per year (ranging from 1.4 to 0.13). The long-term mean carbon stock in tree biomass and products amounts on average to 114 Mg C ha⁻¹ (ranging from 52 to 196).     

Joint Models of Longitudinal Data and Recurrent Events with Informative Terminal Event

This article presents semiparametric joint models to analyze longitudinal data with recurrent events (e.g. multiple tumors, repeated hospital admissions) and a terminal event such as death. A broad class of transformation models for the cumulative intensity of the recurrent events and the cumulative hazard of the terminal event is considered, which includes the proportional hazards model and the proportional odds model as special cases. We propose to estimate all the parameters using the nonparametric maximum likelihood estimators (NPMLE). We provide the simple and efficient EM algorithms to implement the proposed inference procedure. Asymptotic properties of the estimators are shown to be asymptotically normal and semiparametrically efficient. Finally, we evaluate the performance of the method through extensive simulation studies and a real-data application.