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Background: Laparoscopic adrenalectomy is the preferred surgical approach for adrenal resection. The simultaneous presence of obesity and subsequent liver steatosis may complicate the procedure, increasing the risk of intra- and perioperative complications. This study explores the effectiveness of a preoperative very low-calorie ketogenic diet in improving surgical outcomes in patients with obesity undergoing laparoscopic adrenalectomy., Methods: A retrospective analysis was conducted on 70 patients from January 2021 to July 2024 at the Bariatric and Endocrine-Metabolic Surgery Unit, University of Naples "Federico II." Among these, 54 patients with a body mass index ≥30 kg/m 2 were divided into 2 groups: group A, which underwent a 4-week very low-calorie ketogenic diet, and group B, which did not receive any dietary intervention. Propensity score matching was used to balance the groups for confounding factors. Furthermore, a subanalysis between groups was performed according to right and left laparoscopic adrenalectomy., Results: Group A had a significantly reduced operative time (94.59 ± 54.11 minutes) compared with group B (129.22 ± 51.06 minutes, P = .01). Additionally, group A exhibited fewer perioperative complications (P = .01). The very low-calorie ketogenic diet was also associated with a significant reduction in body mass index from 31.74 ± 1.31 kg/m 2 to 29.05 ± 0.99 kg/m 2 (P = .001) before surgery., Conclusions: Our analysis suggests preoperative very low-calorie ketogenic diet can significantly improve surgical outcomes in patients with obesity scheduled to adrenal glands surgery. The study supports the integration of dietary interventions into the preoperative management of patients with obesity undergoing laparoscopic adrenalectomy. Future research with larger sample sizes and randomized controlled trials is recommended to validate these findings and optimize preoperative care protocols., Competing Interests: Conflict of Interest/Disclosure The authors have no relevant financial disclosures., (Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.)

Prostate cancer progression is driven by androgen receptor (AR) activity, which is a target for therapeutic approaches. Enzalutamide is an AR inhibitor that prolongs the survival of patients with advanced prostate cancer. However, resistance mechanisms arise and impair its efficacy. One of these mechanisms is the expression of AR-V7, a constitutively active AR splice variant. The Mediator complex is a multisubunit protein that modulates gene expression on a genome-wide scale. MED12 and cyclin-dependent kinase (CDK)8, or its paralog CDK19, are components of the kinase module that regulates the proliferation of prostate cancer cells. In this study, we investigated how MED12 and CDK8/19 influence cancer-driven processes in prostate cancer cell lines, focusing on AR activity and the enzalutamide response. We inhibited MED12 expression and CDK8/19 activity in LNCaP (AR+, enzalutamide-sensitive), 22Rv1 (AR-V7+, enzalutamide-resistant), and PC3 (AR-, enzalutamide-insensitive) cells. Both MED12 and CDK8/19 inhibition reduced cell proliferation in all cell lines, and MED12 inhibition reduced proliferation in the respective 3D spheroids. MED12 knockdown significantly inhibited c-Myc protein expression and signaling pathways. In 22Rv1 cells, it consistently inhibited the AR response, prostate-specific antigen (PSA) secretion, AR target genes, and AR-V7 expression. Combined with enzalutamide, MED12 inhibition additively decreased the AR activity in both LNCaP and 22Rv1 cells. CDK8/19 inhibition significantly decreased PSA secretion in LNCaP and 22Rv1 cells and, when combined with enzalutamide, additively reduced proliferation in 22Rv1 cells. Our study revealed that MED12 and CDK8/19 regulate AR activity and that their inhibition may modulate response to enzalutamide in prostate cancer., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

The objective was to perform a systematic review of those performance outcomes (HRD) tools that assess sensitivity in post-stroke subjects, as well as to know which of all is the most reliable and viable. The design was a systematic review. The following were included: HRD, developed in post-stroke subjects, of any etiology and period of evolution; 18 years of age or older and testing for sensitivity; results on psychometric properties. Excluded: self-reported results, the report of cross-cultural adaptation, designed through computerized means. 19 HRD were acquired. The psychometric properties analyzed were reliability, internal consistency, measurement error, construct validity, content validity, and sensitivity to change, the first being the most studied. Psychometric properties were identified, assessed, compared, and summarized. Of all of them, we recommend the use of the modified Erasmus Nottingham Sensory Assessment, as it presents the best degree of confidence in the evidence., (Copyright © 2024 Sociedad Española de Rehabilitación y Medicina Física. Publicado por Elsevier España, S.L.U. All rights reserved.)

Purpose: The COVID-19 pandemic has impacted medication needs and prescribing practices, including those affecting pregnant women. Our goal was to investigate patterns of medication use among pregnant women with COVID-19, focusing on variations by trimester of infection and location., Methods: We conducted an observational study using six electronic healthcare databases from six European regions (Aragon/Spain; France; Norway; Tuscany, Italy; Valencia/Spain; and Wales/UK). The prevalence of primary care prescribing or dispensing was compared in the 30-day periods before and after a positive COVID-19 test or diagnosis., Results: The study included 294,126 pregnant women, of whom 8943 (3.0%) tested positive for, or were diagnosed with, COVID-19 during their pregnancy. A significantly higher use of antithrombotic medications was observed particularly after COVID-19 infection in the second and third trimesters. The highest increase was observed in the Valencia region where use of antithrombotic medications in the third trimester increased from 3.8% before COVID-19 to 61.9% after the infection. Increases in other countries were lower; for example, in Norway, the prevalence of antithrombotic medication use changed from around 1-2% before to around 6% after COVID-19 in the third trimester. Smaller and less consistent increases were observed in the use of other drug classes, such as antimicrobials and systemic corticosteroids., Conclusion: Our findings highlight the substantial impact of COVID-19 on primary care medication use among pregnant women, with a marked increase in the use of antithrombotic medications post-COVID-19. These results underscore the need for further research to understand the broader implications of these patterns on maternal and neonatal/fetal health outcomes., (© 2024. The Author(s).)

Superiority trials are designed to test the hypothesis that a given diagnostic or therapeutic strategy is better than (i.e. "superior to") placebo or an active control. Conversely, non-inferiority trials test the hypothesis that a newer (i.e. alternative) strategy is not "unacceptably worse" than a control (i.e. "traditional", or "older") strategy. Non-inferiority trials are increasingly conducted in clinical medicine more often when a "newer" strategy is supposed to offer a relevant advantage in terms other than clinical efficacy (i.e. better tolerability, less cost, simpler regimen, etc.) versus a "gold standard" traditional strategy. The principle underlying non-inferiority trials is that the above advantage justifies the preferential use of the newer strategy in the clinical practice even if the clinical efficacy of the "new" appears to be a bit worse than that of the "old", albeit not unacceptably worse (i.e. not beyond a pre-specified value). The demonstration of non-inferiority requires that the confidence interval of the point estimate (e.g. the hazard ratio) does not cross a pre-specified limit. The definition of such pre-specified limit, the so called "non-inferiority margin", is a pivotal point when planning non-inferiority trials. It denotes the maximally tolerated worse effect of the alternative strategy, compared with the traditional one, required to conclude that an alternative strategy is non-inferior to the traditional "gold standard". The non-inferiority margin is derived from previous trials evaluating the efficacy of the traditional strategy vs placebo. We reviewed the principles and the practical aspects in the design and conduct of non-inferiority trials.

Background: A missed diagnosis of Crohn's disease (CD) can delay treatment initiation with consequences on disease course., Aims: To measure the possible impact of missed diagnoses on drug utilization and access to healthcare facilities in a real-world cohort of CD patients., Methods: This retrospective observational study has been conducted on the regional administrative databases of Tuscany (Italy). We included patients with a first record of CD diagnosis between 06/11/2011 and 06/30/2016. Possible missed diagnosis (exposure) was defined by hospital presentation for gastrointestinal symptoms consistent with CD diagnosis that occurred in the 7-60 months preceding CD diagnosis. We compared exposed and non-exposed patients by assessing time-free from biologic drugs and from Emergency Department (ED) or hospital access. Hazard ratio (HR) was calculated using Cox models., Results: Among 3342 CD patients, 584 (17.5%) had a possible missed diagnosis. A risk of being treated with biologic drugs [adjusted HR (aHR): 2.17, 95% CI: 1.75-2.71] and of access to ED or hospitalization (aHR: 1.59, 95% CI: 1.44-1.75) was observed in patients with a possible missed diagnosis as compared to those without., Conclusion: Tertiary care caregivers should be trained in the identification of early CD symptoms, to timely identify CD diagnosis and optimize pharmacological treatment and disease management., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: The disease activity associated with the drug-utilization patterns of biologic Disease Modifying Anti-Rheumatic Drugs (DMARDs) is poorly investigated in real-world studies on rheumatoid arthritis (RA) patients. To investigate the relationship between biologic DMARD initiation/discontinuations in RA patients identified in the healthcare administrative databases of Tuscany and the Disease Activity Score 28 (DAS28) reported in the medical charts. Methods: This retrospective population-based study included RA's first-ever biologic DMARD users of the Pisa University Hospital from 2014 to 2016. Patients were followed up until 31 December 2019. We evaluated the DAS28 recorded before (T0) and after (T1) the biologic DMARD initiation and before (TD0) and after (TD1) discontinuations. Patients were classified as "off-target" (DAS28 > 3.2) or "in-target" (DAS28 ≤ 3.2). We described the disease activity trends at initiation and discontinuation. Results: Ninety-five users were included (73 women, mean age 59.6). Among 70 patients (74%) with at least three DAS28 measures, 28 (40.0%) were off-target at T0 and 38 (54.3%) in-target at T1. Thirty-three (47%) patients had at least one discontinuation, among those with at least three DAS28 assessments. In the disease activity trend, disease stability or improvement was observed in 28 out of 37 (75.7%) patients at initiation and in 24 out of 37 (64.9%) at discontinuation. Discussion: Biologic DMARD discontinuations identified in the healthcare administrative databasese of Tuscany are frequently observed in situations of controlled RA disease. Further studies are warranted to confirm that these events can be used in studies using healthcare administrative databases as proxies of treatment effectiveness., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Convertino, Cazzato, Tillati, Giometto, Gini, Valdiserra, Cappello, Ferraro, Bonaso, Bartolini, Paoletti, Lorenzoni, Trieste, Filippi, Turchetti, Cristofano, Blandizzi, Mosca, Lucenteforte and Tuccori.)

Background: In March 2018, the European pregnancy prevention programme for oral retinoids was updated as part of risk minimisation measures (RMM), emphasising their contraindication in pregnant women. Objective: To measure the impact of the 2018 revision of the RMMs in Europe by assessing the utilisation patterns of isotretinoin, alitretinoin and acitretin, contraceptive measures, pregnancy testing, discontinuation, and pregnancy occurrence concomitantly with a retinoid prescription. Methods: An interrupted time series (ITS) analysis to compare level and trend changes after the risk minimisation measures implementation was conducted on a cohort of females of childbearing age (12-55 years of age) from January 2010 to December 2020, derived from six electronic health data sources in four countries: Denmark, Netherlands, Spain, and Italy. Monthly utilisation figures (incidence rates [IR], prevalence rates [PR] and proportions) of oral retinoids were calculated, as well as discontinuation rates, contraception coverage, pregnancy testing, and rates of exposed pregnancies to oral retinoids, before and after the 2018 RMMs. Results: From 10,714,182 females of child-bearing age, 88,992 used an oral retinoid at any point during the study period (mean age 18.9-22.2 years old). We found non-significant level and trend changes in incidence or prevalence of retinoid use in females of child-bearing age after the 2018 RMMs. The reason of discontinuation was unknown in >95% of cases. Contraception use showed a significant increase trend in Spain; for other databases this information was limited. Pregnancy testing was hardly recorded thus was not possible to model ITS analyses. After the 2018 RMM, rates of pregnancy occurrence during retinoid use, and start of a retinoid during a pregnancy varied from 0.0 to 0.4, and from 0.2 to 0.8, respectively. Conclusion: This study shows a limited impact of the 2018 RMMs on oral retinoids utilisation patterns among females of child-bearing age in four European countries. Pregnancies still occur during retinoid use, and oral retinoids are still prescribed to pregnant women. Contraception and pregnancy testing information was limited in most databases. Regulators, policymakers, prescribers, and researchers must rethink implementation strategies to avoid any pregnancy becoming temporarily related to retinoid use., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Durán, Riera-Arnau, Abtahi, Pajouheshnia, Hoxhaj, Gamba, Alsina, Martin-Perez, Garcia-Poza, Llorente-Garcia, Gonzalez-Bermejo, Ibánez, Sabaté, Vidal, Ballarín, Sanfélix-Gimeno, Rodríguez-Bernal, Peiró, García-Sempere, Sanchez-Saez, Ientile, Ingrasciotta, Guarneri, Tanaglia, Tari, Herings, Houben, Swart-Polinder, Holthuis, Huerta, Gini, Roberto, Bartolini, Paoletti, Limoncella, Girardi, Hyeraci, Andersen, Kristiansen, Hallgreen, Klungel and Sturkenboom.)

Introduction: Due to established teratogenicity of valproates, the EU risk minimisation measures (RMMs) with a pregnancy prevention programme (PPP) for valproate were updated in March 2018., Objectives: To investigate the effectiveness of the 2018 EU RMMs on valproate utilisation in five European countries/regions., Methods: A multi-database, times series study of females of childbearing potential (12-55 years) was conducted using electronic medical records from five countries/regions (01.01.2010-31.12.2020): Denmark, Tuscany (Italy), Spain, the Netherlands, and the UK. Clinical and demographic information from each database was transformed to the ConcePTION Common Data Model, quality checks were conducted and a distributed analysis was performed using common scripts. Incident and prevalent use of valproate, proportion of discontinuers and switchers to alternative medicine, frequency of contraception coverage during valproate use, and occurrence of pregnancies during valproate exposure were estimated per month. Interrupted time series analyses were conducted to estimate the level or trend change in the outcome measures., Results: We included 69,533 valproate users from 9,699,371 females of childbearing potential from the five participating centres. A significant decline in prevalent use of valproates was observed in Tuscany, Italy (mean difference post-intervention -7.7%), Spain (-11.3%), and UK (-5.9%) and a non-significant decline in the Netherlands (-3.3%), but no decline in incident use after the 2018 RMMs compared to the period before. The monthly proportion of compliant valproate prescriptions/dispensings with a contraceptive coverage was low (<25%), with an increase after the 2018 RMMs only in the Netherlands (mean difference post-intervention 12%). There was no significant increase in switching rates from valproates to alternative medicine after the 2018 intervention in any of the countries/regions. We observed a substantial number of concurrent pregnancies during valproate exposure, but with a declining rate after the 2018 RMMs in Tuscany, Italy (0.70 per 1000 valproate users pre- and 0.27 post-intervention), Spain (0.48 and 0.13), the Netherlands (0.34 and 0.00), and an increasing rate in UK (1.13 and 5.07)., Conclusion: There was a small impact of the 2018 RMMs on valproate use in the studied European countries/regions. The substantial number of concurrent pregnancies with valproate exposure warrants a careful monitoring of implementation of the existing PPP for valproate in clinical practice in Europe, to see if there is any need for additional measures in the future., (© 2023. The Author(s).)

Introduction: Italian administrative healthcare databases are frequently used for studies on real-world drug utilization. However, there is currently a lack of evidence on the accuracy of administrative data in describing the use of infusive antineoplastics. In this study, we used rituximab as a case study to investigate the validity of the regional administrative healthcare database of Tuscany (RAD) in describing the utilization of infusive antineoplastics., Methods: We identified patients aged 18 years or older who had received ≥1 rituximab administration between 2011 and 2014 in the onco-haematology ward of the University Hospital of Siena. We retrieved this information from the Hospital Pharmacy Database (HPD-UHS) and linked the person-level information to RAD. Patients who had received ≥1dispensing of rituximab, single administration episodes, and patients treated for non-Hodgkin Lymphoma (nHL) or Chronic Lymphocytic Leukemia (CLL) were identified in RAD and validated using HPD-UHS as the reference standard. We identified the indications of use using algorithms based on diagnostic codes (ICD9CM codes, nHL=200*, 202*; CLL=204.1). We tested 22 algorithms of different complexity for each indication of use and calculated sensitivity and positive predictive value (PPV), with 95% confidence intervals (95%CI), as measures of validity., Results: According to HPD-UHS, 307 patients received rituximab for nHL (N=174), CLL (N=21), or other unspecified indications (N=112) in the onco-haematology ward of the University Hospital of Siena. We identified 295 rituximab users in RAD (sensitivity=96.1%), but PPV could not be assessed due to missing information in RAD on dispensing hospital wards. We identified individual rituximab administration episodes with sensitivity=78.6% [95%CI: 76.4-80.6] and PPV=87.6% [95%CI: 86.1-89.2]. Sensitivity of algorithms tested for identifying nHL and CLL ranged from 87.7% to 91.9% for nHL and from 52.4% to 82.7% for CLL. PPV ranged from 64.7% to 66.1% for nHL and from 32.4% to 37.5% for CLL., Discussion: Our findings suggest that RAD is a very sensitive source of information for identifying patients who received rituximab for onco-haematological indications. Single administration episodes were identified with good-to-high accuracy. Patients receiving rituximab for nHL were identified with high sensitivity and acceptable PPV, while the validity for CLL was suboptimal., Competing Interests: CB, RG are employed and AG, GR are collaborator by ARS, a public health agency that conducts or participates in pharmacoepidemiology studies compliant with the ENCePP Code of Conduct. The budget of ARS is partially sustained by such studies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bartolini, Roberto, Girardi, Moscatelli, Spini, Barchielli, Bocchia, Fabbri, Donnini, Ziche, Monti and Gini.)

Several outcome-based prospective investigations have provided solid data which support the prognostic value of 24 h ambulatory blood pressure over and beyond cardiovascular traditional risk factors. Average 24 h, daytime, and nighttime blood pressures are the principal components of the ambulatory blood pressure profile that have improved cardiovascular risk stratification beyond traditional risk factors. Furthermore, several additional ambulatory blood pressure measures have been investigated. The correct interpretation in clinical practice of ambulatory blood pressure monitoring needs a standardization of methods. Several algorithms for its clinical use have been proposed. Implementation of the results of ambulatory blood pressure monitoring in the management of individual subjects with the aim of improving risk stratification is challenging. We suggest that clinicians should focus attention on ambulatory blood pressure components which have been proven to act as the main independent predictors of outcome (average 24 h, daytime, and nighttime blood pressure, pulse pressure, dipping status, BP variability).

This study is aimed at describing tofacitinib and baricitinib users by characterizing their prescription and healthcare histories, drug and healthcare utilization patterns, and direct costs from a healthcare system perspective. This retrospective cohort study was performed using Tuscan administrative healthcare databases, which selected two groups of Janus kinase inhibitors (JAKi) incident users (index date) from 1st January 2018 to 31 December 2019 and from 1 January 2018 to 30 June 2019. We included patients ≥18 years old, at least 10 years of data, and six months of follow-up. In the first analysis, we describe mean time, standard deviation (SD), from the first-ever disease-modifying antirheumatic drug (DMARD) to the JAKi, and costs of healthcare facilities and drugs in the 5 years preceding the index date. In the second analysis, we assessed Emergency Department (ED) accesses and hospitalizations for any causes, visits, and costs in the follow-up. In the first analysis, 363 incident JAKi users were included (mean age 61.5, SD 13.6; females 80.7%, baricitinib 78.5%, tofacitinib 21.5%). The time to the first JAKi was 7.2 years (SD 3.3). The mean costs from the fifth to the second year before JAKi increased from 4325 € (0; 24,265) to 5259 € (0; 41,630) per patient/year, driven by hospitalizations. We included 221 incident JAKi users in the second analysis. We observed 109 ED accesses, 39 hospitalizations, and 64 visits. Injury and poisoning (18.3%) and skin (13.8%) caused ED accesses, and cardiovascular (69.2%) and musculoskeletal (64.1%) caused hospitalizations. The mean costs were 4819 € (607.5; 50,493) per patient, mostly due to JAKi. In conclusion, the JAKi introduction in therapy occurred in compliance with RA guidelines and the increase in costs observed could be due to a possible selective prescription., Competing Interests: M.T., C.B., E.L., V.L., G.T., R.G. are involved as investigators of this observational study funded by Galapagos in compliance with the ENCEPP code of conduct. R.G., C.B., O.P. are employed by ARS, a public health agency that conducts or participates in pharmacoepidemiology studies compliant with the ENCePP Code of Conduct. The budget of ARS is partially sustained by such studies. I.C., S.B., S.F., G.V., E.C., E.F., M.B. have no relevant financial or non-financial interests to disclose.

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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Corinne Willame is conducting a PhD at the University Medical Center Utrecht, as part of which she coordinated this project from January 2021. She works full time for Janssen Pharmaceutica and allocated working-time to finalize this project, this should be considered an in-kind contribution. Janssen Pharmaceutica was not a member of the consortium or project. Rosa Gini, Claudia Bartolini and Olga Paoletti are employed by ARS Toscana, a public research center that conducts or participates in pharmacoepidemiology studies compliant with the ENCePP Code of Conduct. The budget of ARS is partially sustained by such studies. Nicolas Thurin works for Bordeaux PharmacoEpi, an independent research platform of the Bordeaux University and its subsidiary the ADERA SAS, which performs financially supported studies for public and private partners, in line with the ENCePP Code of Conduct. Lei Wang, Vera Ehrenstein and Johnny Kahlert are salaried employees of their organization, which receives institutional research funding from pharmaceutical companies and regulatory agencies, administered by Aarhus University. Miriam Sturkenboom, Daniel Weibel, Carlos E. Durán, Roel Elbers, are salaried employees by University Medical Center Utrecht, which receives institutional research funding from pharmaceutical companies and regulatory agencies, administered by University Medical Center Utrecht. All these studies follow the ENCePP code of conduct. Miriam Sturkenboom is a consultant to the Task Force for Global Health for the Safety Platform for Emergency vACcines (SPEAC) project. Caitlin Dodd currently works for Panalgo. Felipe Villalobos, Meritxell Pallejà-Millán and María Aragón are salaried employees at Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), which receives institutional research funding from public and private partners, pharmaceutical companies and regulatory agencies, administered by IDIAPJGol. Mar Martín-Pérez, Patricia García-Poza, Airam de Burgos, Maria Martínez-González and Verónica Bryant are employees at the Spanish Agency for Medicines and Medical Devices which fully finance the BIFAP database, a non-profit database for performing independent pharmacoepidemiologic research in the public research Spanish setting. Consuelo Huerta was employee at the Spanish Agency for Medicines during the time in which this study was performed. She is currently assistant professor of the Public Health Department of the Faculty of Medicine in the Complutense University of Madrid. Ulrike Haug and Tania Schink are working at an independent, non-profit research institute, the Leibniz Institute for Prevention Research and Epidemiology – BIPS. Unrelated to this study, BIPS occasionally conducts studies financed by the pharmaceutical industry. Almost exclusively, these are post-authorization safety studies (PASS) requested by health authorities. The design and conduct of these studies as well as the interpretation and publication are not influenced by the pharmaceutical industry and performed in line with the ENCePP Code of Conduct. All other authors have no conflict of interest.]., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: A high degree of adherence to direct oral anticoagulants is essential for reducing the risk of ischaemic stroke and systemic embolism in patients with atrial fibrillation, owing to the rapid decline in anticoagulation activity when doses are omitted (i.e. rebound effect)., Objective: We aimed to assess the relationship between non-adherence and non-persistence with direct oral anticoagulants and the incidence of ischaemic stroke in patients with atrial fibrillation., Methods: A nested case-control study was conducted in the Netherlands, Italy and Germany among patients with atrial fibrillation starting direct oral anticoagulants between the drug approval date and the end of database availability. Patients with an ischaemic stroke during the follow-up were selected as cases and compared with matched controls (matched on age ± 5 years, sex, year of cohort entry date and CHA 2 DS 2 -VASc-score at cohort entry date). The cohort entry date was the first dispensing date. Study patients were those aged ≥ 45 years, with ≥ 1 year database history, ≥ 1 year follow-up and at least two direct oral anticoagulant dispensings after the cohort entry date. Adherence and persistence to direct oral anticoagulant treatment were defined as the proportion of days covered ≥ 80% or direct oral anticoagulant continuous use between the cohort entry date and the index date (i.e. date of ischaemic stroke), respectively., Results: In The Netherlands, Italy and Germany, 105 cases and 395 controls, 1580 cases and 6248 controls, and 900 cases and 3570 controls were included, respectively. Odds ratios (ORs) for stroke among current users who were non-adherent compared to adherent users were 0.43 (95% confidence interval [CI] 0.09-1.96) in The Netherlands, 1.11 (95% CI 0.98-1.26) in Italy and 1.21 (95% CI 1.01-1.45) in Germany. The risk of stroke was significantly higher among non-persistent users compared with persistent users in all three databases [OR 1.56 (95% CI 1.00-2.44), OR 1.48 (1.32-1.65) and OR 1.91 (95% CI 1.64-2.22), respectively]. In The Netherlands and Germany, the risk of stroke was higher the longer a patient had stopped using direct oral anticoagulants., Conclusions: Both non-adherence (in Germany) and non-persistence increased the risk of stroke, either using a once-daily or twice-daily regime., (© 2022. The Author(s).)

Background: The European post-authorisation study (EU PAS) register is a repository launched in 2010 by the European Medicines Agency (EMA). All EMA-requested PAS, commonly observational studies, must be recorded in this register. Multi-database studies (MDS) leveraging secondary data have become an important strategy to conduct PAS in recent years, as reflected by the type of studies registered in the EU PAS register., Objectives: To analyse and describe PAS in the EU PAS register, with focus on MDS., Methods: Studies in the EU PAS register from inception to 31st December 2018 were described concerning transparency, regulatory obligations, scope, study type (e.g., observational study, clinical trial, survey, systematic review/meta-analysis), study design, type of data collection and target population. MDS were defined as studies conducted through secondary use of >1 data source not linked at patient-level. Data extraction was carried out independently by 14 centres with expertise in pharmacoepidemiology, using publicly available information in the EU PAS register including study protocol, whenever available, using a standardised data collection form. For validation purposes, a second revision of key fields for a 15% random sample of studies was carried out by a different centre. The inter-rater reliability (IRR) was then calculated. Finally, to identify predictors of primary data collection-based studies/versus those based on secondary use of healthcare databases) or MDS (vs. non-MDS), odds ratios (OR) and 95% confidence intervals (CI) were calculated fitting univariate logistic regression models., Results: Overall, 1426 studies were identified. Clinical trials (N = 30; 2%), systematic reviews/meta-analyses (N = 16; 1%) and miscellaneous study designs (N = 46; 3%) were much less common than observational studies (N = 1227; 86%). The protocol was available for 63% (N = 360) of 572 observational studies requested by a competent authority. Overall, 36% (N = 446) of observational studies were based fully or partially on primary data collection. Of 757 observational studies based on secondary use of data alone, 282 (37%) were MDS. Drug utilisation was significantly more common as a study scope in MDS compared to non-MDS studies. The overall percentage agreement among collaborating centres that collected the data concerning study variables was highest for study type (93.5%) and lowest for type of secondary data (67.8%)., Conclusions: Observational studies were the most common type of studies in the EU PAS register, but 30% used primary data, which is more resource-intensive. Almost half of observational studies using secondary data were MDS. Data recording in the EU PAS register may be improved further, including more widespread availability of study protocols to improve transparency., (© 2022 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Background: Direct oral anticoagulants are available for patients with atrial fibrillation., Objective: This study compared adherence and persistence of once-daily (QD) vs twice-daily (BID) direct oral anticoagulants in patients with atrial fibrillation., Methods: A cohort study was conducted in three databases in the Netherlands, Italy and Germany. Patients with AF starting direct oral anticoagulants after drug approval date were included. The index date was the date of first dispensing. Study patients were restricted to those aged ≥ 18 years, ≥ 1 year database history and ≥ 1 year follow-up. Adherence to treatment was defined as the proportion of days covered ≥ 80% between the index date and the date of last dispensing of the index regimen (i.e. exposure period). The proportion of days covered was also determined during the 12-month follow-up. Persistence was defined as continuous use from index to treatment discontinuation., Results: In the Netherlands, Italy and Germany, respectively, 6068, 32,260 and 167,445 patients were included. The mean age of the patients was 70, 77 and 74 years, and 31%, 40% and 61% were QD users, all respectively. Among QD/BID users, 93/90%, 88/86% and 77/58%, respectively were adherent during the exposure period. Persistence rates at 1 year in QD/BID users were 60/59%, 13/14% and 46/31%, respectively., Conclusions: Adherence to treatment was high. In Germany, adherence was markedly higher in QD users compared with BID users. In Italy and the Netherlands, these differences were marginal. Persistence was low in all countries, but discontinuation was temporary. Only in Germany, persistence was markedly lower in BID users vs QD users., (© 2022. The Author(s).)

Background: To verify whether, in patients on metformin (MET) monotherapy for type 2 diabetes (T2D), the add-on of a dipeptidyl peptidase inhibitor (DPP4i) compared to a sulfonylurea (SU) can delay the time to the subsequent treatment intensification (TI). Methods: Population-based administrative data banks from four Italian geographic areas were used. Patients aged ≥18 years on MET monotherapy receiving first DPP4i or SU dispensing between 2008 and 2015 (cohort entry) were followed up to the occurrence of TI (insulin dispensing or add-on of a third non-insulin hypoglicemic >180 days after cohort entry), treatment discontinuation, switch, cancer, death, TI occurrence within, end of data availability, end of study period (31 December 2016), whichever came first. Patients on MET + DPP4i were matched 1:1 with those on MET + SU by sex, age, year of cohort entry, and data bank. Hazard Ratio (HR) and 95% confidence intervals (95%CI) were estimated using multivariable Cox regression model including matching variables and potential confounders measured at baseline. Different sensitivity analyses were performed: i) matching at 180 days after cohort entry, ii) intent to treat (ITT) analysis, iii) matching by duration of MET monotherapy, iv) matching by propensity score. Results: The matched study cohort included 10,600 patients. Overall, 763 TI were observed (4.5/100 person-years; mean follow-up = 1.6 years). The primary analysis showed no difference in time to TI between the two groups (HR = 1.02; 95% CI = 0.88-1.19). Sensitivity analyses confirmed this result, except from the ITT analysis (HR = 1.27; 1.13-1.43). Conclusion: The use of a DPP4i rather than a SU as add-on to MET monotherapy was not associated with a delay in treatment intensification., Competing Interests: GR, AG, CB and RG are employed by Agenzia regionale di sanitá della Toscana (ARS), a public health agency that conducts or participates in pharmacoepidemiology studies compliant with the ENCePP Code of Conduct. The budget of ARS is partially sustained by such studies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Roberto, Girardi, Barone-Adesi, Pecere, Ientile, Bartolini, Da Cas, Spila-Alegiani, Ferrajolo, Francesconi, Trifirò, Poluzzi, Baccetti and Gini.)

In 2019, the Innovative Medicines Initiative (IMI) funded the ConcePTION project-Building an ecosystem for better monitoring and communicating safety of medicines use in pregnancy and breastfeeding: validated and regulatory endorsed workflows for fast, optimised evidence generation-with the vision that there is a societal obligation to rapidly reduce uncertainty about the safety of medication use in pregnancy and breastfeeding. The present paper introduces the set of concepts used to describe the European data sources involved in the ConcePTION project and illustrates the ConcePTION Common Data Model (CDM), which serves as the keystone of the federated ConcePTION network. Based on data availability and content analysis of 21 European data sources, the ConcePTION CDM has been structured with six tables designed to capture data from routine healthcare, three tables for data from public health surveillance activities, three curated tables for derived data on population (e.g., observation time and mother-child linkage), plus four metadata tables. By its first anniversary, the ConcePTION CDM has enabled 13 data sources to run common scripts to contribute to major European projects, demonstrating its capacity to facilitate effective and transparent deployment of distributed analytics, and its potential to address questions about utilization, effectiveness, and safety of medicines in special populations, including during pregnancy and breastfeeding, and, more broadly, in the general population., (© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Scanty information on clustering longitudinal real-world data is available in the medical literature about the adherence implementation phase in rheumatoid arthritis (RA). To identify and characterize trajectories by analyzing the implementation phase of adherence to biologic Disease-Modifying Anti-Rheumatic Drugs (DMARDs), we conducted a retrospective cohort drug-utilization study using Tuscan administrative databases. RA patients were identified by a validated algorithm, including the first biologic DMARD supply from 2010 to 2015, RA specialist visit in the year before or after the first supply date and RA diagnosis in the five years before or in the year after the first supply date. We observed users for three years or until death, neoplasia, or pregnancy. We evaluated adherence quarterly through the Medication Possession Ratio. Firstly, we identified adherence trajectories and described the baseline characteristics; then, we focused on the trajectory most populated to distinguish the related sub-trajectories. We identified 952 first ever-biologic DMARD users in RA (712 females, mean age 52.7 years old, standard deviation 18.8). The biologic DMARD mostly supplied was etanercept (387 users) followed by adalimumab (233). Among 935 users with at least 3 adherence values, we identified 49 fully-adherent users, 829 continuous users, and 57 early-discontinuing users. Significant differences were observed among the index drugs. After focusing on the continuous users, three sub-trajectories were identified: continuous-steady users (556), continuous-alternate users (207), and continuous-declining users (66). No relevant differences emerged at the baseline. The majority of first ever-biologic DMARD users showed a continuous adherence behavior in RA. The role of adherence potential predictors and the association with effectiveness and safety outcomes should be explored by further studies.

Background: Non-operative management is often the treatment of choice in cases of complicated appendicitis and routine interval appendectomy is not usually recommended. Actually, recent studies show an alarming number of appendiceal neoplasms following interval appendectomy. The aim of this study is to evaluate the prevalence of appendiceal neoplasms and their histological types after interval appendectomy for complicated appendicitis in adults., Methods: A comprehensive literature search of the PubMed, Scopus and Web of Science databases was conducted according to the PRISMA statement. Studies reporting appendiceal neoplasm rates after interval appendectomy and histopathological characteristics were included. The most recent World Health Organization (WHO) classification of malignant tumours was considered. A pooled prevalence analysis for both prevalence and pathology was performed., Results: A total of eight studies was included: seven retrospective series and one randomized controlled trial. The pooled prevalence of neoplasms after interval appendectomy was 11% (95% CI 7-15; I 2  = 37.5%, p = 0.13). Appendiceal mucinous neoplasms occurred in 43% (95% CI 19-68), adenocarcinoma in 29% (95% CI 6-51), appendiceal neuroendocrine neoplasm in 21% (95% CI 6-36), globet cell carcinoma in 13% (95% CI -2-28), adenoma or serrated lesions in 20% (95% CI -0-41) of cases., Conclusion: The risk of appendiceal neoplasm in patients treated with interval appendectomy for complicated appendicitis is 11%; mucinous neoplasm is the most common histopathological type. Further studies should investigate this association in order to clarify the biological pathway and clinical implications., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2021 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)

Validation of algorithms for selecting patients from healthcare administrative databases (HAD) is recommended. This PATHFINDER study section is aimed at testing algorithms to select rheumatoid arthritis (RA) patients from Tuscan HAD (THAD) and assessing RA diagnosis time interval between the medical chart date and that of THAD. A population was extracted from THAD. The information of the medical charts at the Rheumatology Unit of Pisa University Hospital represented the reference. We included first ever users of biologic disease modifying anti-rheumatic drugs (bDMARDs) between 2014 and 2016 (index date) with at least a specialist visit at the Rheumatology Unit of the Pisa University Hospital recorded from 2013 to the index date. Out of these, we tested four index tests (algorithms): (1) RA according to hospital discharge records or emergency department admissions (ICD-9 code, 714*); (2) RA according to exemption code from co-payment (006); (3) RA according to hospital discharge records or emergency department admissions AND RA according to exemption code from co-payment; (4) RA according to hospital discharge records or emergency department admissions OR RA according to exemption code from co-payment. We estimated sensitivity, specificity, positive and negative predicted values (PPV and NPV) with 95% confidence interval (95% CI) and the RA diagnosis median time interval (interquartile range, IQR). Two sensitivity analyses were performed. Among 277 reference patients, 103 had RA. The fourth algorithm identified 96 true RA patients, PPV 0.78 (95% CI 0.70-0.85), sensitivity 0.93 (95% CI 0.86-0.97), specificity 0.84 (95% CI 0.78-0.90), and NPV 0.95 (95% CI 0.91-0.98). The sensitivity analyses confirmed performance. The time measured between the actual RA diagnosis date recorded in medical charts and that assumed in THAD was 2.2 years (IQR 0.5-8.4). In conclusion, this validation showed the fourth algorithm as the best. The time interval elapsed between the actual RA diagnosis date in medical charts and that extrapolated from THAD has to be considered in the design of future studies., (© 2021. The Author(s).)

Routinely collected electronic healthcare data (rcEHD) have a tremendous potential for enriching pre-marketing evidence on target- and immunotherapies used to treat lung cancer (LC). A scoping review was performed to provide a structured overview of available rcEHD-based studies on this topic and to support the execution of future research by facilitating access to pertinent literature both for study design and benchmarking. Eligible studies published between 2016 and 2020 in PubMed and ISI Web of Science were searched. Data source and study characteristics, as well as evidence on drug utilization and survival were extracted. Thirty-two studies were included. Twenty-six studies used North American data, while three used European data only. Thirteen studies linked ≥1 data source types among administrative/claims data, cancer registries and medical/health records. Twenty-nine studies retrieved cancer-related information from medical records/cancer registries and 31 studies retrieved information on drug utilization or survival from medical records or administrative/claim data. Most part of studies concerned non-small-cell-LC patients (29 out of 32) while none focused on small-cell-LC. Study cohorts ranged between 85 to 81,983 patients. Only two studies described first-line utilization of immunotherapies. Results from this review will serve as a starting point for the execution of future rcEHD-based studies on innovative LC pharmacotherapies.

To investigate the association of the 2019-2020 influenza vaccine with prognosis of patients positive for SARS-CoV-2A, a large multi-database cohort study was conducted in four Italian regions (i.e., Lazio, Lombardy, Veneto, and Tuscany) and the Reggio Emilia province (Emilia-Romagna). More than 21 million adults were residing in the study area (42% of the population). We included 115,945 COVID-19 cases diagnosed during the first wave of the pandemic (February-May, 2020); 34.6% of these had been vaccinated against influenza. Three outcomes were considered: hospitalization, death, and intensive care unit (ICU) admission/death. The adjusted relative risk (RR) of being hospitalized in the vaccinated group when compared with the non-vaccinated group was 0.87 (95% CI: 0.86-0.88). This reduction in risk was not confirmed for death (RR = 1.04; 95% CI: 1.01-1.06), or for the combined outcome of ICU admission or death. In conclusion, our study, conducted on the vast majority of the population during the first wave of the pandemic in Italy, showed a 13% statistically significant reduction in the risk of hospitalization in some geographical areas and in the younger population. No impact of seasonal influenza vaccination on COVID-19 prognosis in terms of death and death or ICU admission was estimated.

Background: The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private collaboration aiming to develop and test a system for rapid benefit-risk (B/R) monitoring of vaccines using European healthcare databases. Event misclassification can result in biased estimates. Using different algorithms for identifying cases of Bordetella pertussis (BorPer) infection as a test case, we aimed to describe a strategy to quantify event misclassification, when manual chart review is not feasible., Methods: Four participating databases retrieved data from primary care (PC) setting: BIFAP: (Spain), THIN and RCGP RSC (UK) and PEDIANET (Italy); SIDIAP (Spain) retrieved data from both PC and hospital settings. BorPer algorithms were defined by healthcare setting, data domain (diagnoses, drugs, or laboratory tests) and concept sets (specific or unspecified pertussis). Algorithm- and database-specific BorPer incidence rates (IRs) were estimated in children aged 0-14 years enrolled in 2012 and 2014 and followed up until the end of each calendar year and compared with IRs of confirmed pertussis from the ECDC surveillance system (TESSy). Novel formulas were used to approximate validity indices, based on a small set of assumptions. They were applied to approximately estimate positive predictive value (PPV) and sensitivity in SIDIAP., Results: The number of cases and the estimated BorPer IRs per 100,000 person-years in PC, using data representing 3,173,268 person-years, were 0 (IR = 0.0), 21 (IR = 4.3), 21 (IR = 5.1), 79 (IR = 5.7), and 2 (IR = 2.3) in BIFAP, SIDIAP, THIN, RCGP RSC and PEDIANET respectively. The IRs for combined specific/unspecified pertussis were higher than TESSy, suggesting that some false positives had been included. In SIDIAP the estimated IR was 45.0 when discharge diagnoses were included. The sensitivity and PPV of combined PC specific and unspecific diagnoses for BorPer cases in SIDIAP were approximately 85% and 72%, respectively., Conclusion: Retrieving BorPer cases using only specific concepts has low sensitivity in PC databases, while including cases retrieved by unspecified concepts introduces false positives, which were approximately estimated to be 28% in one database. The share of cases that cannot be retrieved from a PC database because they are only seen in hospital was approximately estimated to be 15% in one database. This study demonstrated that quantifying the impact of different event-finding algorithms across databases and benchmarking with disease surveillance data can provide approximate estimates of algorithm validity., Competing Interests: Declaration of Competing Interest Caitlin Dodd, Kaatje Bollaerts, Claudia Bartolini, Giuseppe Roberto, Consuelo Huerta-Alvarez, Elisa Martín-Merino, Talita Duarte-Salles, Gino Picelli, Lara Tramontan, Giorgia Danieli, Ana Correa, Chris McGee, Benedikt Becker, Charlotte Switzer, Jorgen Bauwens, Nicoline van der Maas, Gianfranco Spiteri, Emmanouela Sdona declared no conflicts of interest. Rosa Gini declared that her institution participates in studies funded by Novartis, Eli Lilly, Daiichi Sankyo, compliant with the ENCePP Code of Conduct. Sonja Gandhi-Banga declared that she works for Sanofi Pasteur and holds company shares. Daniel Weibel declared that he has received personal fees from GSK for work unrelated to the submitted work. Miriam Sturkenboom declared that she has received grants from Novartis, CDC and Bill & Melinda Gates Foundation for work unrelated to the submitted work., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private partnership aiming to develop and test a system for rapid benefit-risk (B/R) monitoring of vaccines using European electronic health record (eHR) databases. This proof-of-concept study aimed to test the feasibility of near real-time (NRT) monitoring of vaccination coverage, benefits and risks based on multiple European eHR databases, using acellular pertussis vaccination in children aged <6 years as test case., Methods: A qualitative feasibility assessment on NRT monitoring was carried out using a survey and face-to-face discussion with ADVANCE data partners. Subsequently, a dynamic cohort study was conducted containing two distinct observation periods: a first period to establish a baseline (Jan 2014 to Mar 2018) and a subsequent 3-month period to test the actual feasibility of weekly NRT monitoring, based on which data latencies were calculated. An interactive web-application was additionally developed to facilitate the visual monitoring of vaccination coverage, the vaccine preventable disease incidence rates (benefits) and the incidence rates of adverse events (risks)., Results: Nine databases from four countries (Denmark, Italy, Spain and UK) participated in the qualitative feasibility assessment. Of them, five databases took part in the dynamic cohort study, with 5 databases providing baseline data and 3 databases participating to the NRT monitoring, providing data extractions on an almost weekly basis. The median data latency (time between event date and data release date) was between 1 and 2 weeks except for the benefit and risk events in one of the databases (latency 16 weeks)., Conclusion: Three European eHR databases successfully demonstrated the feasibility of providing data for weekly NRT monitoring, with short data latencies of 1-2 weeks for most events., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tom de Smedt, Chris McGee, Hanne-Dorthe Emborg, Marco Villa, Talita Duarte-Salles, declared no potential conflicts of interest. Kaatje Bollaerts and Maria Alexandridou received consultancy fees from GSK for work unrelated to the submitted work. Rosa Gini declared that her institution is participating in studies funded by Novartis, Eli Lilly, and Daiichi outside the scope of this project. Claudia Bartolini declared she has received grants from PHARMO Institute for work outside the submitted work. Simon de Lusignan declared he has received funding through his University to conduct enhanced surveillance of influenza vaccine (GSK), and is a member Seqirus and Sanofi Pasteur advisory boards for which he received personal payment within the limits defined by his university. Myint TinTin Htar declared that she is employed by Pfizer and holds company shares. Miriam Sturkenboom declared that she has received grants from Novartis, CDC and Bill & Melinda Gates Foundation, for work unrelated to the submitted work. Lina Titievsky declared that she is employed by Pfizer and holds company stocks/shares. Vincent Bauchau declared that he is employed by GSK and holds company shares., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Kimchi is recognized worldwide as the flagship food of Korea. To date, most of the currently available microbiological studies on kimchi deal with Korean manufactures. Moreover, there is a lack of knowledge on the occurrence of eumycetes in kimchi. Given these premises, the present study was aimed at investigating the bacterial and fungal dynamics occurring during the natural fermentation of an artisan non-Korean kimchi manufacture. Lactic acid bacteria were dominant, while Enterobacteriaceae, Pseudomonadaceae, and yeasts progressively decreased during fermentation. Erwinia spp., Pseudomonas veronii , Pseudomonas viridiflava , Rahnella aquatilis, and Sphingomonas spp. were detected during the first 15 days of fermentation, whereas the last fermentation phase was dominated by Leuconostoc kimchi , together with Weissella soli . For the mycobiota at the beginning of the fermentation process, Rhizoplaca and Pichia orientalis were the dominant Operational Taxonomic Units (OTUs) in batch 1, whereas in batch 2 Protomyces inundatus prevailed. In the last stage of fermentation, Saccharomyces cerevisiae , Candida sake, Penicillium , and Malassezia were the most abundant taxa in both analyzed batches. The knowledge gained in the present study represents a step forward in the description of the microbial dynamics of kimchi produced outside the region of origin using local ingredients. It will also serve as a starting point for further isolation of kimchi-adapted microorganisms to be assayed as potential starters for the manufacturing of novel vegetable preserves with high quality and functional traits.

Purpose: To describe patterns of utilization, survival and infectious events in patients treated with rituximab at the University Hospital of Siena (UHS) to explore the feasibility of combining routinely collected administrative and hospital-pharmacy data for examining the real-world use of intravenous antineoplastic drugs., Methods: A retrospective, longitudinal cohort study was conducted using data from the Hospital Pharmacy of Siena (HPS) and the Regional Administrative Database of Tuscany (RAD). Patients aged ≥18 years with ≥1 rituximab administration recorded between January 2012 and June 2016 were identified in the HPS database. Anonymized patient-level data were linked to RAD. Rituximab utilization during the first year of treatment was described using HPS. Hospital diagnoses of adverse infectious events that occurred during the first year of follow-up and four-year survival were observed using RAD., Results: A total of 311 new users of rituximab were identified: 264 patients received rituximab for non-Hodgkin's lymphoma (NHL) and 47 were treated for chronic lymphocytic leukemia (CLL). Among new users with one complete year of follow-up (n = 203) over 95% received rituximab as the first-line treatment, and approximately 70% of them received 5-8 doses. No patient in the CLL group received >8 administrations. Four-year survival was approximately 70% in both CLL and NHL patients. Sepsis was the most frequent infectious event observed (5.1%)., Conclusion: HPS and RAD provided complementary information on rituximab utilization, demonstrating their potential for future pharmacoepidemiological studies on antineoplastic medications administered in the Italian hospital setting. Overall, this general description of the real-world utilization of rituximab in patients treated for NHL and CLL at UHS was in line with treatment guidelines and current knowledge on the rituximab safety profile., Competing Interests: The authors have declared that no competing interests exist.

Triple negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer (BC) for which limited therapeutic options are available. Recently, β-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.

Background: acute myocardial infarction (AMI), ischemic heart diseases (IHDs) and stroke are serious cardiovascular diseases (CVDs) which may lead to hospitalizations, require periodical medical monitoring and life-long drugs use, thus having a high impact on public health and Healthcare Service expenditure. In this contest, Italian Healthcare Administrative Databases (HADs), which routinely collect patientlevel information on healthcare services reimbursed by the National Healthcare service, are increasingly used for identification of these CVDs., Objectives: to identify and describe all AMI, IHDs and stroke case-identification algorithms by means of Italian HADs, through the review of papers published in the past 10 years., Methods: this study is part of a project that systematically reviewed case-identification algorithms for 18 acute and chronic conditions by means of HADs in Italy. PubMed was searched for original articles, published between 2007 and 2017, in Italian or English. The search string consisted of a combination of free text and MeSH terms with a common part that focused on HADs and a disease-specific part. All identified papers were screened by two independent reviewers. Pertinent papers were classified according to the objective for which the algorithm had been used, and only articles that used algorithms for primary objectives (I disease occurrence; II population/cohort selection; III outcome identification) were considered for algorithm extraction. The HADs used (hospital discharge records, drug prescriptions, etc.), ICD-9 and ICD-10 codes, ATC classification of drugs, follow-back periods, and age ranges applied by the algorithms have been reported. Further information on specific objective(s), accuracy measures, sensitivity analyses and the contribution of each HAD, have also been recorded., Results: the search strategy has led to the identification of 611 papers for AMI,801 for IHDs and 791 for stroke. Among these,45,12 and 31 papers for AMI, IHDs and stroke respectively, were considered pertinent for inclusion in the systematic review. The majority of the works was published during 2014-2017. The setting of the studies was mainly regional for AMI and stroke, while the majority of IHD's papers was based on a national multicenter context. By screening full texts, a total of 17,5 and 28 original algorithms for AMI, IHDs and stroke respectively, intended for the above-mentioned objectives, were found. Moreover, 3 original algorithms for STEMI, 3 for NSTEMI, 8 for ischemic stroke and 3 for hemorrhagic stroke were identified. The hospital discharge diagnosis database (HDD) was used in all algorithms. In only a few cases the co-payment exemption registry, drug prescription database, and mortality registry database were used as additional algorithm components. For the same event, there was always a difference of >=1 code. External validation was performed in only one case for AMI and stroke identification., Conclusion: a remarkable heterogeneity, in terms of both data sources and codes used, was observed for algorithms aimed to identify AMI, IHDs and stroke in HADs. This was likely due to the paucity of validation studies. Administrative data sources other than HDD remain underutilized.

Background: The incretin-based medicines GLP1 analogues (GLP1a) and dipeptidyl peptidase-4 inhibitors (DPP4i) are hypoglycaemic agents licensed for the treatment of type 2 diabetes mellitus (T2DM). Although these drugs possess comparable efficacy and low risk of hypoglycaemia, differences in terms of route of administration (subcutaneous versus oral), effect on body weight and gastrointestinal tolerabily can impact their actual use in clinical practice. This study aimed to describe the real-world utilization of incretin-based medicines in the Italian clinical practice., Methods: A multi-database, population-based, descriptive, cohort study was performed using administrative data collected between 2008 and 2014 from three Italian geographic areas. Subjects aged ≥18 were selected. New users were defined as those with ≥1 dispensing of GLP1a or DPP4i during the year of interest and none in the past. Trends of cumulative annual incidence of use in the general adult population were observed. New users of GLP1a or DPP4i were respectively described in terms of demographic characteristics and use of antidiabetic drugs during 1 year before and after the first incretin dispensing., Results: The overall study population included 4,943,952 subjects. A total of 7357 new users of GLP1a and 41,907 of DPP4i were identified during the study period. Incidence of use increased between 2008 (0.2‰ for both GLP1a and DPP4i) and 2011 (GLP1a = 0.6‰; DPP4i = 2.5‰) and slightly decreased thereafter. In 2014, 61% of new GLP1a users received once-daily liraglutide while 52% of new DPP4i users received metformin/DPP4i in fixed-dose. The percentage of new DPP4i users older than 65 years of age increased from 30.9 to 62.6% during the study period. Around 12% of new users had not received any antidiabetic before starting an incretin., Conclusions: During the study period, DPP4i rapidly became the most prescribed incretin-based medicine, particularly among older new user. The choice of the specific incretin-based medicine at first prescription appeared to be directed towards those with higher convenience of use (e.g. oral DPP4i rather than subcutaneous GLP1a, once-daily liraglutide rather than twice-daily exenatide). The non-negligibile use of incretin-based medicines as first-line pharmacotherapy for T2DM warrants further effectiveness and safety evaluations to better define their place in therapy.

Aims: Real-world data on treatment persistence, safety and effectiveness of non-Vitamin K antagonist oral anticoagulants (NOACs) play an important role in the assessment of risks and benefits of these drugs. Our aim was to evaluate persistence on treatment, incidence of major bleeding and incidence of a composite endpoint of major events, including all-cause death, myocardial infarction, stroke and systemic thromboembolism, during treatment with apixaban in a cohort of patients with nonvalvular atrial fibrillation (NVAF)., Methods: In this multicentre retrospective observational study, we retrieved data from medical records of five Italian hospitals on patients with a diagnosis of NVAF who initiated apixaban between 1 January 2014 and 31 March 2016 and had a first subsequent visit at the same hospital., Results: We studied 766 patients with mean age of 74.2 (standard deviation 11.1) years and median CHADS2 and CHA2DS2VASc scores of 2.0 and 4.0, respectively. Over a median follow-up period of 339 days, persistence on treatment was 83.5% [95% confidence interval (95% CI) 75.5-89.1%]. The rate of major bleeding (per 100 person-years) was 1.15 (95% CI 0.39-1.90 per 100 person-years), while the cumulative incidence was 4.4% (95% CI 1.6-12.0). The rate of major events was 1.97 (95% CI 1.08-2.86) per 100 patient-years, with a cumulative incidence over the entire follow-up period of 7.7% (95% CI 4.6-12.8)., Conclusion: In real-life conditions, NVAF patients treated with apixaban show rates of treatment discontinuation and major bleedings, which are comparable to those found in the ARISTOTLE pivotal study, thus supporting its external validity.

Objectives: To describe NSAID utilization for musculoskeletal conditions in a large cohort of Italian elderly with cerebro/cardiovascular disease, a population in which NSAIDs should be generally avoided due to the prothrombotic potential., Methods: Administrative data from five Italian geographic areas were analyzed. Patients aged ≥ 65 with a cerebro/cardiovascular event recorded between 2008 and 2011 (cohort entry) were selected. Prescription NSAIDs reimbursed for musculoskeletal conditions and dispensed during 1 year follow-up were retrieved to describe (i) prevalence of use, (ii) average amount of defined daily doses of NSAIDs claimed by users per day of follow-up, and (iii) distribution of the received daily dose (RDD) among patients with ≥ 2 dispensings. Among new users, i.e., patients without NSAID dispensings during 2 years before cohort entry, the first dispensed NSAID molecule was observed., Results: Overall, 511,989 patients were selected. Across the five geographic areas, prevalence of use ranged from 48 to 21% and average consumption ranged between 30 and 67 DDD/1000 users/day. Around 10% of patients in the overall cohort had a RDD > 1. Nimesulide (9.6%) and diclofenac (7.5%) had the highest prevalence of use. The most consumed NSAIDs were nimesulide and coxibs with 10.6 and 7.5 DDD/1000 users/day, respectively. Among new users recruited in 2011, 30% had diclofenac or a coxibs as the first prescription., Conclusions: NSAID use was common in the study cohort, particularly in central-southern areas. In contrast with current recommendations, coxibs and diclofenac were among the most prescribed active principles, even in new users. Interventions to promote appropriateness of use are warranted.

Background: The different geometric patterns of the left ventricle may or may not coexist with chamber dilatation. The prognostic impact of such a combination is unclear., Methods and Results: We studied a cohort of 2635 initially untreated patients with hypertension, mean age 50 years. At entry, 24-hour ambulatory blood pressure progressively increased across the patterns of normal geometry, concentric left ventricular (LV) remodeling, eccentric nondilated LV hypertrophy (LVH), eccentric dilated LVH, concentric nondilated LVH, and concentric dilated LVH. During a mean follow-up of 9.7 years, 360 patients developed a first major cardiovascular event at a rate (×100 patient-years) of 1.41. The event rate was 0.93 in the group with normal LV geometry, 1.10 in the group with LV concentric remodeling, 1.40 in the group with nondilated eccentric LVH, 2.10 in the group with eccentric dilated LVH, 2.34 in the group with nondilated concentric LVH, and 4.67 in the group with dilated concentric LVH (log-rank test: P <0.001). In a Cox model, after adjustment for several independent covariables (age, sex, diabetes mellitus, current smoking, total cholesterol, estimated glomerular filtration rate, and average 24-hour systolic blood pressure), concentric dilated LVH was associated with a 98% excess risk of cardiovascular events ( P =0.0037). However, LV geometric pattern lost statistical significance when LV mass was entered into the model., Conclusions: In initially untreated patients with hypertension, LV dilatation adds an adverse prognostic burden to the patterns of eccentric and concentric LVH. This phenomenon is explained by the greater LV mass associated with LV chamber dilatation., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

A total of 162 samples of bivalve molluscs (45 mussels and 117 clams) collected between December 2012 and 2014 from harvesting areas of the Central Adriatic were analysed by a culturing method for the presence of Arcobacter spp. Species identification was performed by PCR and sequencing analysis of a fragment of the rpoB gene. Overall, Arcobacter species were detected in 30% of samples, specifically 33% clams and 22% mussels. A. butzleri was the most common species (20% of the samples), followed by A. cryaerophilus (9%) and A. skirrowii (1%). A seasonal association of A. butzleri contamination was detected. A. butzleri was significantly more commonly recovered from samples collected during the winter-spring period (29%) than from those of the summer-autumn (8%). A. cryaerophilus was cultured from 6% to 11% of the samples collected in summer-autumn and winter-spring, respectively, but these differences were not statistically significant. A. skirrowii was recovered from a sample of mussels harvested in May 2014. To identify associations between the occurrence of Arcobacter spp. and E. coli levels, samples were divided into groups generating results with E. coli at >230MPN/100g and E. coli at ≤230MPN/100g, the latter corresponding to EU microbiological criteria allowed for live bivalve molluscs at retail level. A. butzleri was significantly more commonly detected in samples with higher E. coli levels (48%) than in those with lower levels of E. coli (10%), providing evidence for considering E. coli as an index organism for A. butzleri contamination in bivalve molluscs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The SPRINT study tested the hypothesis that hypertensive patients randomized to a more intensive treatment, aimed at lowering systolic blood pressure (BP) below 120 mmHg have a lower incidence of major cardiovascular events when compared to patients randomized to a less intensive treatment (systolic BP reduction below 140 mmHg). Overall, 9361 patients were randomized to the more intensive (n=4678) or less intensive (n=4683) antihypertensive treatment. The study was prematurely interrupted because of an excess benefit in the more intensive arm. Indeed, the group randomized to the more intensive arm showed, when compared to the group randomized to the less intensive arm, a 25% reduction in the primary endpoint (1.65 vs 2.19% per year; p<0.001), a 43% reduction in cardiovascular death (0.25 vs 0.43%; p=0.005), a 27% reduction in all-cause death (1.03% vs 1.40%; p=0.003) and a 38% reduction in hospitalizations for heart failure (0.41 vs 0.67%; p<0.002). Unexpectedly, there was no significant reduction in the risk of stroke (not significant 11% reduction). The SPRINT study unequivocally shows that, in hypertensive patients with systolic BP ≥130 mmHg and no history of diabetes, previous stroke and polycystic renal disease, we should try to lower systolic BP to levels below 120 mmHg with the objective to lower the incidence of heart failure in addition to all-cause and cardiovascular death. Future guidelines on the management of patients with hypertension should implement the results of the SPRINT study.

Several patients with non-valvular atrial fibrillation treated with warfarin or other vitamin-K antagonists (VKA) might benefit from switching to an oral non vitamin-K antagonist anticoagulant (NOAC). In the absence of randomised comparative trials of switching to NOACs versus maintaining VKA treatment, several considerations argue in favour of a switching strategy. First, there is conclusive evidence that haemorrhagic strokes and intracranial bleedings are much fewer in number with NOACs than with warfarin. The risk of intracranial bleeding is 52 % lower with NOACS than with warfarin, with extremes ranging from 33 to 70 %. Such benefit is applicable to different NOACs, and independent of the time-in-therapeutic range under warfarin. Patients at increased risk for intra-cranial bleeding (renal dysfunction, or prior stroke or intra-cranial bleeding) should benefit most from switching to NOACs. Patients with labile International Normalized Ratio are also considered good candidates for switching because of their increased risk of stroke, and the lack of interactions between the effects of NOACs versus warfarin and the time-in-therapeutic range. Furthermore, some NOACs proved to be superior to warfarin in reducing the risk of thromboembolic complications even in intention-to-treat analyses. As further advantage, NOACs show fewer drug-drug and drug-food interactions when compared with warfarin. Last, but not least, NOACs do not need frequent blood drawings except in patients with moderate renal dysfunction, in whom periodic controls of serum creatinine are generally advised. The higher cost remains a barrier to a wider use of NOACs, especially in low-income settings.

Hyperglycemia is a frequent condition in patients with acute coronary syndromes (ACS). Hyperglycemia during ACS is caused by an inflammatory and adrenergic response to ischemic stress, when catecholamines are released and glycogenolysis induced. Although the involved pathophysiological mechanisms have not yet been fully elucidated, it is believed that hyperglycemia is associated with an increase in free fat acids (which induce cardiac arrhythmias), insulin resistance, chemical inactivation of nitric oxide and the production of oxygen reactive species (with consequent microvascular and endothelial dysfunction), a prothrombotic state, and vascular inflammation. It is also related to myocardial metabolic disorders, leading to thrombosis, extension of the damaged area, reduced collateral circulation, and ischemic preconditioning. In the last few years, several observational studies demonstrated that hyperglycemia in ACS is a powerful predictor of survival, increasing the risk of immediate and long-term complications in patients both with and without previously known diabetes mellitus. Glucose management strategies in ACS may improve outcomes in patients with hyperglycemia, perhaps by reducing inflammatory and clotting mediators, by improving endothelial function and fibrinolysis and by reducing infarct size. Recent clinical trials of insulin in ACS have resulted in varying levels of benefit, but the clinical benefit of an aggressive treatment with insulin is yet unproved., (© The Author(s), 2015.)

Objective: Although regression of left ventricular hypertrophy (LVH) confers a marked prognostic benefit, it is unknown whether cardiovascular risk in these patients is comparable to those who never developed LVH., Methods: We analyzed the 'Massa Ventricolare sinistra nell'Ipertensione' (MAVI) study, a prospective study in which serial changes in left ventricular mass at echocardiography were associated with subsequent cardiovascular events. We also conducted a cumulative meta-analysis in order to investigate how evidence progressed in this field. We defined three phenotypes: persistently normal left ventricular mass; LVH regression; persistence/new development of LVH., Results: Left ventricular mass was measured at baseline and 2 years after the initial assessment in 374 patients (64% women). Clinical outcomes were ascertained after the 2-year echocardiographic evaluation (mean follow-up 3.2 years). Persistence or new development of LVH was associated with an increased risk of cardiovascular events (odds ratio 1.96, 95% confidence interval 1.07-3.57, P = 0.029). In a cumulative meta-analyses that included MAVI and six comparable studies for a total of 2954 patients and 339 cardiovascular events, when a persistently normal left ventricular mass was taken as reference, regression of LVH was associated with 56% higher risk of cardiovascular events (odds ratio 1.56, 95% confidence interval 1.04-2.36, absolute risk increase 3%, P = 0.033). Conversely, evidence accrued from previous studies that persistence or new development of LVH predicts an adverse outcome did not change after MAVI., Conclusions: Cardiovascular risk is higher in patients with LVH regression than in those with persistently normal left ventricular mass. Preventing development of LVH is thus an important target.

Obesity can be regarded as an energy balance disorder in which inappropriate expansion and dys-function of adipose tissue lead to unfavorable outcomes. Even in the absence of hypertension, adiposity induces structural and functional changes in the heart through hemodynamic and non hemodynamic factors. In the "obese" heart, besides the growth of cardiomyocytes, interstitial fat infiltration and triglyceride accumulation in the contractile elements importantly contribute to left-ventricular mass (LVM) accrual, hypertrophy (LVH) and geometric pattern. In harmony with this, the likelihood of LVH is greater in either obese normotensive or hypertensive individuals than in their non-obese counterparts. Interestingly, recent observations highlight the increasing prevalence of the "concentric" (ie, combined remodeling and hypertrophy), rather than "eccentric" pattern of LV geometry in obesity. Nonetheless, obesity is linked with lack of decrease, or even increase, of LVM over time, independently of blood pressure control and hypertensive treatment. Although obesity-related LV changes result in progressive systolic and diastolic heart failure, the assessment of LVM and LVH in obese individuals still remains a difficult task. In this scenario, it is tempting to speculate that therapeutic interventions for reversal of LVH in obesity should either overcome the "non-hemodynamic" factors or reduce the hemodynamic load. Indeed, weight loss, either achieved by lifestyle changes or bariatric procedures, decreases LVM and improves LV function regardless of blood pressure status. These and other mechanistic insights are discussed in this review, which focuses on "adipose dysfunction" as potential instigator of, and putative therapeutic target for, LVH regression in the setting of obesity.

Hyperglycemia recognized during hospitalization for acute coronary syndromes (ACS) is common. It is a powerful predictor of worse prognosis in patients both with and without previously known diabetes mellitus. Hyperglycemia during ACS is caused by an inflammatory and adrenergic response to ischemic stress, when catecholamines are released and glycogenolysis induced. The link between hyperglycemia and prognosis in ACS patients is multi-factorial. Hyperglycemia exerts detrimental effects on left ventricular and platelet function and it also activates other systemic pathological processes that contribute to cellular and tissue injury such as increasing oxidative stress and worsening endothelial function. Glucose management strategies in ACS may improve outcome in patients with hyperglycemia, by reducing inflammatory and clotting mediators, by improving endothelial function and fibrinolysis and by reducing infarct size. Most of available oral anti-diabetic drugs are contraindicated for the increased risk of hypoglycemia. Thus, insulin is the preferred agent for glycemic control in ACS and conversion from intravenous to subcutaneous therapy commonly occurs when the critical acute phase of ACS resolves. Pharmacodynamics of insulin allows it to be adaptable to the changing physiology of the ACS patient, is easily titrated and has no dosage threshold. Nevertheless, findings concerning the effect on ACS-related mortality of the control of glucose levels by intravenous infusion of insulin have been conflicting and intervention trials are needed to optimize the definition of hyperglycemia and to establish appropriate modalities and goals of glucose lowering treatment. In particular, the clinical benefit of an aggressive treatment with insulin is yet unproved.

Introduction: Choosing between different non-vitamin K antagonist oral anticoagulants (NOACs) in non-valvular atrial fibrillation (NVAF) is difficult due to the absence of head to head comparative studies. We performed a Bayesian meta-analysis to explore similarities and differences between different NOACs and to rank treatments overall for safety and efficacy outcomes., Areas Covered: Through a systematic literature search we identified randomized controlled Phase III trials of dabigatran, rivaroxaban, apixaban, and edoxaban versus adjusted-dose warfarin in patients with NVAF., Expert Opinion: Warfarin ranked worst for all-cause mortality and intracranial bleedings and had a nil probability of ranking first for any outcome. The risk of major bleeding versus warfarin was lower with apixaban, dabigatran 110 mg, and both doses of edoxaban. All agents reduced the risk of intracranial bleeding versus warfarin. Edoxaban 30 mg was the best among the treatments being compared for major and gastrointestinal bleeding. Dabigatran 150 mg was the best for stroke and systemic embolism. This study suggests that NOACs are generally preferable to warfarin in patients with NVAF. However, safety and efficacy differences do exist among NOACs, which might drive their use in specific subsets of AF patients, allowing prescribers to tailor treatment to distinct patient profiles.

In clinical practice, adherence to drugs and their safety may differ from randomised controlled trial settings. This study was undertaken to investigate the adherence to dabigatran, a direct thrombin inhibitor, and its safety in a real-world setting. We studied a prospective cohort of 114 elderly consecutive patients with non valvular atrial fibrillation (AF) who were treated with dabigatran 150 mg twice-daily (N=39) or 110 mg twice-daily (N=76). These patients were studied at baseline and after an average of 6 months. Mean age was 80 years and 53% were women. At entry, the average CHA2DS2VASc score was 4 and the HAS-BLED score was 2. AF was permanent in 49% of patients, persistent in 30%, paroxysmal in 12% and new-onset in 24%. In the follow-up clinical visit we ascertained vital status, adherence to treatment according to refill prescription orders, and side effects. Adherence was ≥80% in 76.5% of patients. Heartburn, the most frequent adverse effect, was reported by 25 patients (22%). Major and minor bleedings were experienced by 2 (1.8%) and 9 (7.9%) patients, respectively. Permanent discontinuation occurred in 18 patients (16%). The most frequent cause of permanent discontinuation was heartburn (10 patients). This real-life study suggests that safety of dabigatran and adherence to this drug in an elderly cohort of AF patients at high or very high risk of thromboembolism are generally good. Heartburn is the main cause of treatment discontinuation.

Aging leads to a multitude of changes in the cardiovascular system that include a rise in blood pressure. Age-related changes in blood pressure are mainly attributable to an increase in systolic blood pressure, generally associated with a slight decrease diastolic blood pressure. This leads to a widening in pulse pressure. Ambulatory blood pressure monitoring is a useful tool to understand these processes and to refine cardiovascular risk assessment. In the light of emerging data in this area, we reviewed the main features of ambulatory blood pressure in elderly and discussed the evidence showing that ambulatory blood pressure is superior to clinic blood pressure to reflect the true pattern of blood pressure over time. Furthermore, we discussed the role of weight control obtained by fitness programs to prevent an excessive rise in blood pressure with age. A thorough understanding of these concepts is of paramount importance and has therapeutic implications in the growing population of elderly subjects with increased blood pressure., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Accurate blood pressure (BP) measurement is essential for the diagnosis, monitoring and management of hypertension. However, conventional office-based BP readings have several limitations that include a low reproducibility, the white-coat effect and the existence of masked hypertension. These limitations can be addressed through the use of ambulatory BP monitoring. Because ambulatory monitoring provides measurements at specific time intervals throughout a 24-hour period, this technique represents a better picture of the normal fluctuations in BP levels associated with daily activities and sleep. In addition, end-organ damage associated with hypertension is more closely related to ambulatory BP than office BP measurements and ambulatory BP profile give better prediction of clinical outcome than conventional BP measurements.