Background rates of 41 adverse events of special interest for COVID-19 vaccines in 10 European healthcare databases - an ACCESS cohort study.

BACKGROUND: In May 2020, the ACCESS (The vACCine covid-19 monitoring readinESS) project was launched to prepare real-world monitoring of COVID-19 vaccines. Within this project, this study aimed to generate background incidence rates of 41 adverse events of special interest (AESI) to contextualize potential safety signals detected following administration of COVID-19 vaccines. METHODS: A dynamic cohort study was conducted using a distributed data network of 10 healthcare databases from 7 European countries (Italy, Spain, Denmark, The Netherlands, Germany, France and United Kingdom) over the period 2017 to 2020. A common protocol (EUPAS37273), common data model, and common analytics programs were applied for syntactic, semantic and analytical harmonization. Incidence rates (IR) for each AESI and each database were calculated by age and sex by dividing the number of incident cases by the total person-time at risk. Age-standardized rates were pooled using random effect models according to the provenance of the events. FINDINGS: A total number of 63,456,074 individuals were included in the study, contributing to 211.7 million person-years. A clear age pattern was observed for most AESIs, rates also varied by provenance of disease diagnosis (primary care, specialist care). Thrombosis with thrombocytopenia rates were extremely low ranging from 0.06 to 4.53/100,000 person-years for cerebral venous sinus thrombosis (CVST) with thrombocytopenia (TP) and mixed venous and arterial thrombosis with TP, respectively. INTERPRETATION: Given the nature of the AESIs and the setting (general practitioners or hospital-based databases or both), background rates from databases that show the highest level of completeness (primary care and specialist care) should be preferred, others can be used for sensitivity. The study was designed to ensure representativeness to the European population and generalizability of the background incidence rates. FUNDING: The project has received support from the European Medicines Agency under the Framework service contract nr EMA/2018/28/PE.

Empowering knowledge generation through international data network: the IMeCCHI-DATANETWORK.

INTRODUCTION: The International Methodology Consortium for Coded Health Information (IMeCCHI) is a collaboration of health services researchers who promote methodological advances in coded health information. The IMeCCHI-DATANETWORK initiative focuses on developing a multi-purpose distributed data infrastructure and common data model (CDM) to enable cross-border data sharing and international comparisons. METHODS: IMeCCHI consortium partners from six different countries - Canada, Denmark, Italy, New Zealand, South Korea, and Switzerland - used a questionnaire to describe their original databases which differ in size, structure, content and coding systems. To standardize these data, they agreed on a CDM and mapped their population-based databases to meet the CDM specifications. At the end of this process, local data had a more homogenous content and structure, which made them syntactically and semantically interoperable. Data transformation was performed using a common data management software called TheMatrix. RESULTS: The CDM encompasses four tables of structured data (person characteristics, hospitalizations, outpatient prescription medication and death), linked at the individual level through a person identifier. It can be used to answer research questions across countries using locally converted databases, which facilitates study replication in a distributed fashion. As a proof-of-concept study, an initial research question was addressed using an agreed protocol. Local data were transformed in csv files in the CDM structure and TheMatrix was tested to transform the standardized data from each partner into local analytical datasets. This allowed results to be shared between countries, whilst maintaining local control over each region's data. CONCLUSION: The IMeCCHI-DATANETWORK, a model of a distributed data network, demonstrated that it is feasible to analyze international data using standardized analytical methods that enable independent analyses by regions, without relocating datasets thereby protecting local confidentiality obligations. The distributed data infrastructure can produce results that can be generalized to several countries, while facilitating cross-border data sharing and international comparisons. KEYWORDS: Common data model, international comparison, cross-border data sharing, interoperability, observational data.

Evidence of ß-blockers drug repurposing for the treatment of triple negative breast cancer: A systematic review.

Triple negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer (BC) for which limited therapeutic options are available. Recently, ß-blockers (BBs) have been suggested to have favorable effects in the treatment of BC. The aim of this systematic review was to collect evidence from preclinical and clinical studies concerning the scientific evidence for the repurposing of BBs in TNBC treatment. PubMed database was searched to retrieve studies of interest published up to 30/01/2018. All preclinical studies using TNBC in vitro and in vivo models and assessing the effect of any molecule with sympatholytic or sympathomimetic activity on adrenergic receptors were included. Clinical studies concerning BBs were considered eligible. The Newcastle-Ottawa scale was used for the quality assessment of clinical studies. A total of 614 study references were retrieved. Forty-six preclinical studies were included. In in vitro studies, propranolol, a non-selective BB, significantly decreased proliferation, migration and invasion of TNBC cells. Consistently, in in vivo studies, propranolol inhibited metastasis, angiogenesis and tumor growth. Clinical studies, reporting evidence from a total of four distinct retrospective observational cohort studies, showed a beneficial effect of BBs in TNBC treatment. The overall quality of the clinical evidence collected was low. Preclinical evidence collected in this systematic review are in line with the results reported in the clinical studies retrieved, pointing towards a beneficial effect of BB in the treatment of TNBC. However, given the overall low quality of available evidence, no definite conclusion may be drawn.

The limitations of some European healthcare databases for monitoring the effectiveness of pregnancy prevention programmes as risk minimisation measures.

PURPOSE: Pregnancy prevention programmes (PPPs) exist for some medicines known to be highly teratogenic. It is increasingly recognised that the impact of these risk minimisation measures requires periodic evaluation. This study aimed to assess the extent to which some of the data needed to monitor the effectiveness of PPPs may be present in European healthcare databases. METHODS: An inventory was completed for databases contributing to EUROmediCAT capturing pregnancy and prescription data in Denmark, Norway, the Netherlands, Italy (Tuscany/Emilia Romagna), Wales and the rest of the UK, to determine the extent of data collected that could be used to evaluate the impact of PPPs. RESULTS: Data availability varied between databases. All databases could be used to identify the frequency and duration of prescriptions to women of childbearing age from primary care, but there were specific issues with availability of data from secondary care and private care. To estimate the frequency of exposed pregnancies, all databases could be linked to pregnancy data, but the accuracy of timing of the start of pregnancy was variable, and data on pregnancies ending in induced abortions were often not available. Data availability on contraception to estimate compliance with contraception requirements was variable and no data were available on pregnancy tests. CONCLUSION: Current electronic healthcare databases do not contain all the data necessary to fully monitor the effectiveness of PPP implementation, and thus, special data collection measures need to be instituted.

Risk of cardiac valvulopathy with use of bisphosphonates: a population-based, multi-country case-control study.

UNLABELLED: Analyses of healthcare data from 30 million individuals in three countries showed that current use of bisphosphonates may be associated with a small increased risk of cardiac valvulopathy (vs. those not exposed within the previous year), although confounding cannot be entirely ruled out. The observed tendency for decreased valvulopathy risk with cumulative duration of bisphosphonate use >6 months may even indicate a protective effect with prolonged use. Further studies are still needed to evaluate whether bisphosphonates increase or decrease the risk of valvulopathy. INTRODUCTION: A signal of cardiac valve disorders with use of bisphosphonates was identified in the literature and EudraVigilance database, which contains reports of suspected adverse drug reactions from worldwide sources. The aim of this study was to evaluate the association using population-based healthcare data. METHODS: This was a case-control study among users of bisphosphonates and other drugs for osteoporosis in six healthcare databases covering over 30 million individuals in Italy, Netherlands and the UK from 1996 to 2012. Prescriptions/dispensations were used to assess drug exposure. Newly diagnosed cases of cardiac valvulopathy were identified via disease codes/free-text search. Controls were matched to each case by age, sex, database and index date. Adjusted odds ratios (ORs) were estimated using conditional logistic regression for the pooled data and meta-analysis of individual database risk estimates. RESULTS: A small but statistically significant association was found between exposure to bisphosphonates as a class and risk of valvulopathy. Overall risk was 18 % higher (95 % CI 12-23 %) in those currently exposed to any bisphosphonate (mainly alendronate and risedronate) vs. those not exposed within the previous year. Risk of valve regurgitation was 14 % higher (95 % CI 7-22 %). Decreased valvulopathy risk was observed with longer cumulative duration of bisphosphonate use, compared to use of less than 6 months. Meta-analyses of database-specific estimates confirmed results from pooled analyses. CONCLUSIONS: The observed increased risks of cardiac valvulopathy with bisphosphonate use, although statistically significant, were quite small and unlikely to be clinically significant. Further studies are still needed to evaluate whether bisphosphonates increase or decrease the risk of valvulopathy and to investigate possible mechanisms for the association.

Selective serotonin reuptake inhibitor prescribing before, during and after pregnancy: a population-based study in six European regions.

OBJECTIVE: To explore the prescribing patterns of selective serotonin reuptake inhibitors (SSRIs) before, during and after pregnancy in six European population-based databases. DESIGN: Descriptive drug utilisation study. SETTING: Six electronic healthcare databases in Denmark, the Netherlands, Italy (Emilia Romagna/Tuscany), Wales and the rest of the UK. POPULATION: All women with a pregnancy ending in a live or stillbirth starting and ending between 2004 and 2010. METHODS: A common protocol was implemented across databases to identify SSRI prescriptions issued (UK) or dispensed (non-UK) in the year before, during or in the year following pregnancy. MAIN OUTCOME MEASURES: The percentage of deliveries in which the woman received an SSRI prescription in the year before, during or in the year following pregnancy. We also compared the choice of SSRIs and changes in prescribing over the study period. RESULTS: In total, 721 632 women and 862,943 deliveries were identified. In the year preceding pregnancy, the prevalence of SSRI prescribing was highest in Wales [9.6%; 95% confidence interval (CI95 ), 9.4-9.8%] and lowest in Emilia Romagna (3.3%; CI95 , 3.2-3.4%). During pregnancy, SSRI prescribing had dropped to between 1.2% (CI95 , 1.1-1.3%) in Emilia Romagna and 4.5% (CI95 , 4.3-4.6%) in Wales. The higher UK pre-pregnancy prescribing rates resulted in higher first trimester exposures. After pregnancy, SSRI prescribing increased most rapidly in the UK. Paroxetine was more commonly prescribed in the Netherlands and Italian regions than in Denmark and the UK. CONCLUSIONS: The higher SSRI prescribing rates in the UK, compared with other European regions, raise questions about differences in the prevalence and severity of depression and its management in pregnancy across Europe.

Does alcohol consumption exacerbate the mental health consequences of interpersonal violence?

Although studies show that interpersonal violence is associated with poorer mental health, few studies specify the conditions under which victimization can be more or less detrimental to psychological well-being. Building on previous research, the authors test whether the association between interpersonal violence and psychological distress is moderated by alcohol consumption. Our analysis of longitudinal data from the Welfare, Children, and Families project suggests that interpersonal violence is more strongly associated with psychological distress in the context of more frequent intoxication. Programs designed to treat the combination of victimization and heavy alcohol consumption may make unique contributions to the well-being of women.

[Burden of disease of occupational asthma in Tuscany: methodological aspects and preliminary results]. / Il calcolo del Burden of disease dell'asma da lavoro in Toscana: aspetti metodologici e risultati preliminari.

In Italy, unlike in other European countries, the public health burden of work-related asthma (WRA) has not yet be defined by means of a standardized validated epidemiological metric. The aim of the present study is to describe the methodology for the calculation of the Burden of Disease of WRA in Tuscany on the grounds of available healthcare and health survey data. The paper is particularly intended to illustrate the methodological approach to estimate the prevalence of the disease.

First Report of Botryosphaeria dothidea on Sycamore, Red Oak, and English Oak in Northwestern Italy.

The Parco Nord Milano, Italy is a 600-ha green area (45°53'71″N, 9°20'97″E). Since the spring of 2002, extensive and unknown decline was observed on 20-year-old sycamore (Acer pseudoplatanus), red oak (Quercus rubra), and English oak (Q. robur) plantations. The trees showed branch and twig dieback associated with bark cankering along the whole stem and an irregular to wilted crown. A closer inspection of the inner part of the symptomatic trunk and roots revealed a dark bluish tissue discoloration. From the symptomatic trunk and root tissue, a dark gray abundant mycelium was consistently isolated on potato dextrose agar (PDA). The sequenced internal transcribed spacer (ITS) regions of rDNA (GenBank Accession Nos. DQ198265, DQ198266, and DQ198267) showed 99% identity to Botryosphaeria dothidea strain CBS110302 (GenBank Accession No. AY259092). A Fusicoccum sp. with black pycnidia was consistently collected from the cankers. The conidia were hyaline, aseptate, fusiform to narrowly ellipsoidal, with a truncate base (22 × 4.5 µm), referred to as Fusicoccum aesculi (CBS identification), the anamorph of B. dothidea (2). Pathogenicity tests were conducted for all three hosts by stem inoculation on 18-month-old seedlings growing in plastic pots containing a 2:1 turf/sand mixture. Two experiments were conducted using two inoculation techniques. In the first trial, 6-mm-diameter mycelial plugs of B. dothidea were applied to 6-mm-long bark wounds. The same inoculation method was used for application to bark without wounding. Control seedlings were inoculated with sterile agar plugs in a similar fashion as above. Inoculated and control seedlings were kept in a growth chamber and watered once per week. In the second trial, segments of branches 15-cm long were inoculated with 6-mm-diameter B. dothidea plugs (1), with and without any wounding. Control segments of branches were treated with sterile agar plugs in place of fungal mycelium. The branches were incubated at 23°C in moist chambers. For both experiments, the inoculated stem portions were wrapped with Parafilm to prevent desiccation. There were three replicate seedlings per inoculation technique, experiment, and plant species. After 2 months, all seedlings showed bark cankers and pycnidial formation, while the controls were symptomless. An inner dark bluish stem tissue discoloration was observed. The symptoms were more abundant on the segment of branches where the inoculum was applied to the wounded bark. B. dothidea was successfully reisolated, confirming Koch's postulates. To our knowledge, although it is accepted as synonymous of B. berengeriana (2), this is the first report of B. dothidea on sycamore, red oak, and English oak in Italy. The fungus was previously reported in Italy to cause canker on Platanus spp. References: (1) M. E. Sanchez et al. Plant Dis. 87:1515, 2003. (2) B. Slippers et al. Mycologia 96:83, 2004.

Tratamiento de la hipertension arterial esencial con acebutolol en dosis unica diaria. / Treatment of essential arterial hipertension with acebutolol in daily single dose

Se estudio la accion antihipertensiva de acebutolol en dosis unica en 26 enfermos hipertensos tratados en la Primera Catedra de Medicina. El acebutolol fue administrado en dosis unicas de 200 a 400 mg. Quince pacientes normalizaron sus cifras tensionales, ocho las mejoraron y en tres no se obtuvo mejoria. No se registraron efectos secundarios en ningun caso