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1. Impact of 2018 EU Risk Minimisation Measures and Revised Pregnancy Prevention Programme on Utilisation and Prescribing Trends of Medicinal Products Containing Valproate: An Interrupted Time Series Study

Author

Abtahi, Shahab, Pajouheshnia, Romin, Durán, Carlos E., Riera-Arnau, Judit, Gamba, Magdalena, Alsina, Ema, Hoxhaj, Vjola, Andersen, Morten, Bartolini, Claudia, Kristiansen, Sarah Brøgger, Brown, Jeremy, Hallgreen, Christine Erikstrup, Garcia-Poza, Patricia, Gardarsdottir, Helga, Gini, Rosa, Girardi, Anna, Holthuis, Emily, Huerta, Consuelo, Ibánez, Luisa, Limoncella, Giorgio, Martín-Pérez, Mar, Paoletti, Olga, Roberto, Giuseppe, Souverein, Patrick, Swart, Karin M. A., Wing, Kevin, Sturkenboom, Miriam, and Klungel, Olaf

Published
2023
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4. Describing diversity of real world data sources in pharmacoepidemiologic studies: The DIVERSE scoping review

Author

Gini, Rosa, primary, Pajouheshnia, Romin, additional, Gardarsdottir, Helga, additional, Bennett, Dimitri, additional, Li, Lin, additional, Gulea, Claudia, additional, Wientzek‐Fleischmann, Angelika, additional, Bazelier, Marloes T., additional, Burcu, Mehmet, additional, Dodd, Caitlin, additional, Durán, Carlos E., additional, Kaplan, Sigal, additional, Lanes, Stephan, additional, Marinier, Karine, additional, Roberto, Giuseppe, additional, Soman, Kanaka, additional, Zhou, Xiaofeng, additional, Platt, Robert, additional, Setoguchi, Soko, additional, and Hall, Gillian C., additional

Published
2024
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5. Describing diversity of real world data sources in pharmacoepidemiologic studies: The DIVERSE scoping review

Author

Gini, Rosa, Pajouheshnia, Romin, Gardarsdottir, Helga, Bennett, Dimitri, Li, Lin, Gulea, Claudia, Wientzek-Fleischmann, Angelika, Bazelier, Marloes T, Burcu, Mehmet, Dodd, Caitlin, Durán, Carlos E, Kaplan, Sigal, Lanes, Stephan, Marinier, Karine, Roberto, Giuseppe, Soman, Kanaka, Zhou, Xiaofeng, Platt, Robert, Setoguchi, Soko, Hall, Gillian C, Gini, Rosa, Pajouheshnia, Romin, Gardarsdottir, Helga, Bennett, Dimitri, Li, Lin, Gulea, Claudia, Wientzek-Fleischmann, Angelika, Bazelier, Marloes T, Burcu, Mehmet, Dodd, Caitlin, Durán, Carlos E, Kaplan, Sigal, Lanes, Stephan, Marinier, Karine, Roberto, Giuseppe, Soman, Kanaka, Zhou, Xiaofeng, Platt, Robert, Setoguchi, Soko, and Hall, Gillian C

Abstract

PURPOSE: Real-world evidence (RWE) is increasingly used for medical regulatory decisions, yet concerns persist regarding its reproducibility and hence validity. This study addresses reproducibility challenges associated with diversity across real-world data sources (RWDS) repurposed for secondary use in pharmacoepidemiologic studies. Our aims were to identify, describe and characterize practices, recommendations and tools for collecting and reporting diversity across RWDSs, and explore how leveraging diversity could improve the quality of evidence.METHODS: In a preliminary phase, keywords for a literature search and selection tool were designed using a set of documents considered to be key by the coauthors. Next, a systematic search was conducted up to December 2021. The resulting documents were screened based on titles and abstracts, then based on full texts using the selection tool. Selected documents were reviewed to extract information on topics related to collecting and reporting RWDS diversity. A content analysis of the topics identified explicit and latent themes.RESULTS: Across the 91 selected documents, 12 topics were identified: 9 dimensions used to describe RWDS (organization accessing the data source, data originator, prompt, inclusion of population, content, data dictionary, time span, healthcare system and culture, and data quality), tools to summarize such dimensions, challenges, and opportunities arising from diversity. Thirty-six themes were identified within the dimensions. Opportunities arising from data diversity included multiple imputation and standardization.CONCLUSIONS: The dimensions identified across a large number of publications lay the foundation for formal guidance on reporting diversity of data sources to facilitate interpretation and enhance replicability and validity of RWE.

Published
2024

6. Metadata for Data dIscoverability aNd Study rEplicability in obseRVAtional Studies (MINERVA): Development and Pilot of a Metadata List and Catalogue in Europe

Author

Infection & Immunity, Child Health, Data Science & Biostatistiek, Pajouheshnia, Romin, Gini, Rosa, Gutierrez, Lia, Swertz, Morris A, Hyde, Eleanor, Sturkenboom, Miriam, Arana, Alejandro, Franzoni, Carla, Ehrenstein, Vera, Roberto, Giuseppe, Gil, Miguel, Maciá, Miguel Angel, Schäfer, Wiebke, Haug, Ulrike, Thurin, Nicolas H, Lassalle, Régis, Droz-Perroteau, Cécile, Zaccagnino, Silvia, Busto, Maria Paula, Middelkoop, Bas, Gembert, Karin, Sanchez-Saez, Francisco, Rodriguez-Bernal, Clara, Sanfélix-Gimeno, Gabriel, Hurtado, Isabel, Acosta, Manuel Barreiro de, Poblador-Plou, Beatriz, Carmona-Pírez, Jonás, Gimeno-Miguel, Antonio, Prados-Torres, Alexandra, Schultze, Anna, Jansen, Ella, Herings, Ron, Kuiper, Josine, Locatelli, Igor, Jazbar, Janja, Žerovnik, Špela, Kos, Mitja, Smit, Steven, Lind, Sirje, Metspalu, Andres, Simou, Stefania, Hedenmalm, Karin, Cochino, Ana, Alcini, Paolo, Kurz, Xavier, Perez-Gutthann, Susana, Infection & Immunity, Child Health, Data Science & Biostatistiek, Pajouheshnia, Romin, Gini, Rosa, Gutierrez, Lia, Swertz, Morris A, Hyde, Eleanor, Sturkenboom, Miriam, Arana, Alejandro, Franzoni, Carla, Ehrenstein, Vera, Roberto, Giuseppe, Gil, Miguel, Maciá, Miguel Angel, Schäfer, Wiebke, Haug, Ulrike, Thurin, Nicolas H, Lassalle, Régis, Droz-Perroteau, Cécile, Zaccagnino, Silvia, Busto, Maria Paula, Middelkoop, Bas, Gembert, Karin, Sanchez-Saez, Francisco, Rodriguez-Bernal, Clara, Sanfélix-Gimeno, Gabriel, Hurtado, Isabel, Acosta, Manuel Barreiro de, Poblador-Plou, Beatriz, Carmona-Pírez, Jonás, Gimeno-Miguel, Antonio, Prados-Torres, Alexandra, Schultze, Anna, Jansen, Ella, Herings, Ron, Kuiper, Josine, Locatelli, Igor, Jazbar, Janja, Žerovnik, Špela, Kos, Mitja, Smit, Steven, Lind, Sirje, Metspalu, Andres, Simou, Stefania, Hedenmalm, Karin, Cochino, Ana, Alcini, Paolo, Kurz, Xavier, and Perez-Gutthann, Susana

Published
2024

7. Metadata for Data dIscoverability aNd Study rEplicability in obseRVAtional Studies (MINERVA): Lessons Learnt From the MINERVA Project in Europe

Author

Data Science & Biostatistiek, Child Health, Infection & Immunity, Gini, Rosa, Pajouheshnia, Romin, Gutierrez, Lia, Swertz, Morris A, Hyde, Eleanor, Sturkenboom, Miriam, Arana, Alejandro, Franzoni, Carla, Ehrenstein, Vera, Roberto, Giuseppe, Gil, Miguel, Maciá, Miguel Angel, Schäfer, Wiebke, Haug, Ulrike, Thurin, Nicolas H, Lassalle, Régis, Droz-Perroteau, Cécile, Zaccagnino, Silvia, Busto, Maria Paula, Middelkoop, Bas, Gembert, Karin, Sanchez-Saez, Francisco, Rodriguez-Bernal, Clara, Sanfélix-Gimeno, Gabriel, Hurtado, Isabel, Acosta, Manuel Barreiro de, Poblador-Plou, Beatriz, Carmona-Pírez, Jonás, Gimeno-Miguel, Antonio, Prados-Torres, Alexandra, Schultze, Anna, Jansen, Ella, Herings, Ron, Kuiper, Josine, Locatelli, Igor, Jazbar, Janja, Žerovnik, Špela, Kos, Mitja, Smit, Steven, Lind, Sirje, Metspalu, Andres, Simou, Stefania, Hedenmalm, Karin, Cochino, Ana, Alcini, Paolo, Kurz, Xavier, Perez-Gutthann, Susana, Data Science & Biostatistiek, Child Health, Infection & Immunity, Gini, Rosa, Pajouheshnia, Romin, Gutierrez, Lia, Swertz, Morris A, Hyde, Eleanor, Sturkenboom, Miriam, Arana, Alejandro, Franzoni, Carla, Ehrenstein, Vera, Roberto, Giuseppe, Gil, Miguel, Maciá, Miguel Angel, Schäfer, Wiebke, Haug, Ulrike, Thurin, Nicolas H, Lassalle, Régis, Droz-Perroteau, Cécile, Zaccagnino, Silvia, Busto, Maria Paula, Middelkoop, Bas, Gembert, Karin, Sanchez-Saez, Francisco, Rodriguez-Bernal, Clara, Sanfélix-Gimeno, Gabriel, Hurtado, Isabel, Acosta, Manuel Barreiro de, Poblador-Plou, Beatriz, Carmona-Pírez, Jonás, Gimeno-Miguel, Antonio, Prados-Torres, Alexandra, Schultze, Anna, Jansen, Ella, Herings, Ron, Kuiper, Josine, Locatelli, Igor, Jazbar, Janja, Žerovnik, Špela, Kos, Mitja, Smit, Steven, Lind, Sirje, Metspalu, Andres, Simou, Stefania, Hedenmalm, Karin, Cochino, Ana, Alcini, Paolo, Kurz, Xavier, and Perez-Gutthann, Susana

Published
2024

8. Describing diversity of real world data sources in pharmacoepidemiologic studies: The DIVERSE scoping review

Author

Apotheek O&O&O, Child Health, Infection & Immunity, Regenerative Medicine and Stem Cells, RWE/Causal inference, Gini, Rosa, Pajouheshnia, Romin, Gardarsdottir, Helga, Bennett, Dimitri, Li, Lin, Gulea, Claudia, Wientzek-Fleischmann, Angelika, Bazelier, Marloes T., Burcu, Mehmet, Dodd, Caitlin, Durán, Carlos E., Kaplan, Sigal, Lanes, Stephan, Marinier, Karine, Roberto, Giuseppe, Soman, Kanaka, Zhou, Xiaofeng, Platt, Robert, Setoguchi, Soko, Hall, Gillian C., Apotheek O&O&O, Child Health, Infection & Immunity, Regenerative Medicine and Stem Cells, RWE/Causal inference, Gini, Rosa, Pajouheshnia, Romin, Gardarsdottir, Helga, Bennett, Dimitri, Li, Lin, Gulea, Claudia, Wientzek-Fleischmann, Angelika, Bazelier, Marloes T., Burcu, Mehmet, Dodd, Caitlin, Durán, Carlos E., Kaplan, Sigal, Lanes, Stephan, Marinier, Karine, Roberto, Giuseppe, Soman, Kanaka, Zhou, Xiaofeng, Platt, Robert, Setoguchi, Soko, and Hall, Gillian C.

Published
2024

9. Gastric neuroendocrine tumors: 20‐Year experience in a reference center

Author

Ravizza, D, Giunta, M, Sala, I, Bagnardi, V, Tamayo, D, de Roberto, G, Trovato, C, Bravi, I, Soru, P, Maregatti, M, Pisa, E, Bertani, E, Bonomo, G, Spada, F, Nicola, F, Ravizza, Davide, Giunta, Mariangela, Sala, Isabella, Bagnardi, Vincenzo, Tamayo, Darina, de Roberto, Giuseppe, Trovato, Cristina, Bravi, Ivana, Soru, Pietro, Maregatti, Margherita, Pisa, Eleonora, Bertani, Emilio, Bonomo, Guido, Spada, Francesca, Nicola, Fazio, Ravizza, D, Giunta, M, Sala, I, Bagnardi, V, Tamayo, D, de Roberto, G, Trovato, C, Bravi, I, Soru, P, Maregatti, M, Pisa, E, Bertani, E, Bonomo, G, Spada, F, Nicola, F, Ravizza, Davide, Giunta, Mariangela, Sala, Isabella, Bagnardi, Vincenzo, Tamayo, Darina, de Roberto, Giuseppe, Trovato, Cristina, Bravi, Ivana, Soru, Pietro, Maregatti, Margherita, Pisa, Eleonora, Bertani, Emilio, Bonomo, Guido, Spada, Francesca, and Nicola, Fazio

Abstract

Few studies have been published on the long-term outcomes of patients with gastric neuroendocrine tumors (gNETs). We analyzed their management over a two-decade period, focusing on endoscopic and clinical outcomes. Clinical, laboratory, endoscopic, surgical, and histopathological data from Types 1 and 3 gNETs histologically diagnosed between March 2000 and December 2021 at the European Institute of Oncology (IEO, Milan) were retrospectively collected. Sixty-nine patients were included (60 Type 1, 9 Type 3): 53 (77%) were treated endoscopically, 6 (9%) surgically, and 10 (14%) did not receive any treatment. Overall, 293 lesions were removed endoscopically: 74% by forceps, 20% by endoscopic mucosal resection (EMR), and 5% by endoscopic submucosal dissection (ESD). No differences were observed between EMR and ESD in terms of complete resection rate (p value = .50) and complications rate (p value = .084). The median follow-up period was 5.8 years (range: 0.3-20.5), during which no gNET-related deaths were observed. Metachronous gNETs developed in 60% of patients with Type 1 gNET. Six patients with lymph node metastases (LNM) were younger (p value = .006) and had larger lesions (p value <.001) than patients without LNM. Most Type 1 gNETs were successfully excised using forceps, with EMR and ESD being equally effective. The presence of incomplete resection was not associated with a worse prognosis, which remains excellent in this highly recurrent disease. Younger age and a size ≥10 mm were associated with an increased risk of LNM. CLINICAL TRIAL REGISTRATION: Project code UID 2854.

Published
2024

10. Describing diversity of real world data sources in pharmacoepidemiologic studies: The DIVERSE scoping review

Author

Afd Pharmacoepi & Clinical Pharmacology, PECP - Centre for Pharmacoepidemiology, Pharmacoepidemiology and Clinical Pharmacology, Gini, Rosa, Pajouheshnia, Romin, Gardarsdottir, Helga, Bennett, Dimitri, Li, Lin, Gulea, Claudia, Wientzek-Fleischmann, Angelika, Bazelier, Marloes T, Burcu, Mehmet, Dodd, Caitlin, Durán, Carlos E, Kaplan, Sigal, Lanes, Stephan, Marinier, Karine, Roberto, Giuseppe, Soman, Kanaka, Zhou, Xiaofeng, Platt, Robert, Setoguchi, Soko, Hall, Gillian C, Afd Pharmacoepi & Clinical Pharmacology, PECP - Centre for Pharmacoepidemiology, Pharmacoepidemiology and Clinical Pharmacology, Gini, Rosa, Pajouheshnia, Romin, Gardarsdottir, Helga, Bennett, Dimitri, Li, Lin, Gulea, Claudia, Wientzek-Fleischmann, Angelika, Bazelier, Marloes T, Burcu, Mehmet, Dodd, Caitlin, Durán, Carlos E, Kaplan, Sigal, Lanes, Stephan, Marinier, Karine, Roberto, Giuseppe, Soman, Kanaka, Zhou, Xiaofeng, Platt, Robert, Setoguchi, Soko, and Hall, Gillian C

Published
2024

12. Metadata for Data dIscoverability aNd Study rEplicability in obseRVAtional Studies (MINERVA): Lessons Learnt From the MINERVA Project in Europe.

Author

Gini, Rosa, Pajouheshnia, Romin, Gutierrez, Lia, Swertz, Morris A., Hyde, Eleanor, Sturkenboom, Miriam, Arana, Alejandro, Franzoni, Carla, Ehrenstein, Vera, Roberto, Giuseppe, Gil, Miguel, Maciá, Miguel Angel, Schäfer, Wiebke, Haug, Ulrike, Thurin, Nicolas H., Lassalle, Régis, Droz‐Perroteau, Cécile, Zaccagnino, Silvia, Busto, Maria Paula, and Middelkoop, Bas

Published
2024
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13. Metadata for Data dIscoverability aNd Study rEplicability in obseRVAtional Studies (MINERVA): Development and Pilot of a Metadata List and Catalogue in Europe.

Author

Pajouheshnia, Romin, Gini, Rosa, Gutierrez, Lia, Swertz, Morris A., Hyde, Eleanor, Sturkenboom, Miriam, Arana, Alejandro, Franzoni, Carla, Ehrenstein, Vera, Roberto, Giuseppe, Gil, Miguel, Maciá, Miguel Angel, Schäfer, Wiebke, Haug, Ulrike, Thurin, Nicolas H., Lassalle, Régis, Droz‐Perroteau, Cécile, Zaccagnino, Silvia, Busto, Maria Paula, and Middelkoop, Bas

Abstract

Purpose: Metadata for data dIscoverability aNd study rEplicability in obseRVAtional studies (MINERVA), a European Medicines Agency–funded project (EUPAS39322), defined a set of metadata to describe real‐world data sources (RWDSs) and piloted metadata collection in a prototype catalogue to assist investigators from data source discoverability through study conduct. Methods: A list of metadata was created from a review of existing metadata catalogues and recommendations, structured interviews, a stakeholder survey, and a technical workshop. The prototype was designed to comply with the FAIR principles (findable, accessible, interoperable, reusable), using MOLGENIS software. Metadata collection was piloted by 15 data access partners (DAPs) from across Europe. Results: A total of 442 metadata variables were defined in six domains: institutions (organizations connected to a data source); data banks (data collections sustained by an organization); data sources (collections of linkable data banks covering a common underlying population); studies; networks (of institutions); and common data models (CDMs). A total of 26 institutions were recorded in the prototype. Each DAP populated the metadata of one data source and its selected data banks. The number of data banks varied by data source; the most common data banks were hospital administrative records and pharmacy dispensation records (10 data sources each). Quantitative metadata were successfully extracted from three data sources conforming to different CDMs and entered into the prototype. Conclusions: A metadata list was finalized, a prototype was successfully populated, and a good practice guide was developed. Setting up and maintaining a metadata catalogue on RWDSs will require substantial effort to support discoverability of data sources and reproducibility of studies in Europe. [ABSTRACT FROM AUTHOR]

Published
2024
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14. Circulating tumor DNA in patients with locally advanced rectal cancer treated with multimodal treatment.

Author

Gervaso, Lorenzo, Ciardiello, Davide, Gregato, Giuliana, Guidi, Lorenzo, Valenza, Carmine, Ascione, Liliana, Boldrini, Laura, Frassoni, Samuele, Cella, Chiara Alessandra, Spada, Francesca, Funicelli, Luigi, De Roberto, Giuseppe, Petz, Wanda, Borin, Simona, Gerardi, Marianna Alessandra, Bottiglieri, Luca, Tamayo, Darina, Bertani, Emilio, Fumagalli Romario, Uberto, and Bagnardi, Vincenzo

Abstract

Background: The management of locally advanced rectal cancer (LARC) relies on a multimodal approach. Neither instrumental work-up nor molecular biomarkers are currently available to identify a risk-adapted strategy. Objectives: We aim to investigate the role of circulating tumor DNA (ctDNA) and its clearance at different timepoints during chemo-radiotherapy (CRT) and correlate them with clinical outcomes. Design: Between November 2014 and November 2019, we conducted a monocentric prospective observational study enrolling consecutive patients with LARC managed with neoadjuvant standard CRT (capecitabine and concomitant pelvic long-course radiotherapy), followed by consolidation capecitabine in selected cases and surgery. Methods: Blood samples for ctDNA were obtained at pre-planned timepoints. We evaluated the correlation of baseline variant allele frequency (VAF) with pathologic complete response (pCR) down-staging, node regression (pN0), event-free survival (EFS), and overall survival (OS). Results: Among 112 screened patients, 61 were enrolled. In all, 38 (62%) had a positive ctDNA at baseline with VAF > 0 and 23 had negative ctDNA (VAF = 0). Among patients with negative ctDNA, 30% had a complete response, while only 13% of positive ctDNA patients had pCR [odds ratio (OR) 0.35 (95% confidence interval (CI): 0.10–1.26), p = 0.11]. Similarly, 96% and 74% of pN0 were observed among negative and positive ctDNA patients, respectively [OR 0.13 (95% CI: 0.02–1.07), p = 0.058]. The presence of a baseline VAF > 0 was associated with a trend toward a lower EFS compared with VAF = 0 patients [hazard ratio (HR) = 2.30, 95% CI: 0.63–8.36, p = 0.21]. Within the limitations of small sample size, no difference in OS was observed according to the baseline ctDNA status (HR = 1.18, 95% CI: 0.35–4.06, p = 0.79). Conclusion: Within the limitations of a reduced number of patients, patients with baseline negative ctDNA seem to show a higher probability of pN0 status and a trend toward improved EFS. Prospective translational studies are required to define the role of ctDNA analysis in the multimodal treatment of LARC. [ABSTRACT FROM AUTHOR]

Published
2024
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15. End-of-life care in cancer patients: how much drug therapy and how much palliative care? Record linkage study in Northern Italy

Author

Giulio Formoso, Massimiliano Marino, Monica Guberti, and Roberto Giuseppe Grilli

Subjects
Medicine
Abstract

Objectives Investigating end-of-life use of anticancer drugs and of palliative care services.Design Population based cohort linked to mortality registry and administrative databases.Setting Emilia-Romagna Region (Northern Italy).Participants 55 625 residents who died of cancer between 2017 and 2020.Primary and secondary outcome measures Multivariate analyses were carried out to assess the relationship between cancer drug therapy and palliative care services, and their association with factors related to tumour severity.Results In the last month of life, 15.3% of study population received anticancer drugs (from 12.5% to 16.9% across the eight Local Health Authorities—LHA) and 40.2% received palliative care services (from 36.2% to 43.7%). Drug therapy was inversely associated with receiving palliative care services within the last 30 days (OR 0.92, 95% CI 0.87 to 0.97), surgery within the last 6 months (OR 0.59, 95% CI 0.52 to 0.67), aggressive tumours (OR 0.88, 95% CI 0.84 to 0.93) and increasing age (OR 0.95, 95% CI 0.95 to 0.95). Drug therapy was more likely among those with haematologic tumours (OR 2.15, 95% CI 2.00 to 2.30) and in case of hospital admissions within the last 6 months (OR 1.63, 95% CI 1.55 to 1.72). Palliative care was less likely among those with haematologic compared with other tumours (OR 0.52, 95% CI 0.49 to 0.56), in case of surgery (OR 0.44, 95% CI 0.39 to 0.49) or hospital admissions (OR 0.70, 95% CI 0.67 to 0.72) within the last 6 months, if receiving anticancer drugs during the last 30 days (OR 0.90, 95% CI 0.85 to 0.94) and for each year of increasing age (OR 0.99, 95% CI 0.99 to 0.99). Palliative care was more likely in the presence of aggressive tumours (OR 1.12, 95% CI 1.08 to 1.16).Conclusion Use of anticancer drugs and palliative care in the last month of life were inversely associated, showing variability across different LHAs. While administrative data have limits, our findings are in line with conclusions of other studies.

Published
2022
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16. Biosensor-based isolation of amino acid-producing Vibrio natriegens strains

Author

Roberto Giuseppe Stella, Philipp Baumann, Sophia Lorke, Felix Münstermann, Astrid Wirtz, Johanna Wiechert, Jan Marienhagen, and Julia Frunzke

Subjects
Transcription factor-based biosensors, Metabolic engineering, Amino acid production, High-throughput screening, Biotechnology, TP248.13-248.65, Biology (General), QH301-705.5
Abstract

The marine bacterium Vibrio natriegens has recently been demonstrated to be a promising new host for molecular biology and next generation bioprocesses. V. natriegens is a Gram-negative, non-pathogenic slight-halophilic bacterium, with a high nutrient versatility and a reported doubling time of under 10 min. However, V. natriegens is not an established model organism yet, and further research is required to promote its transformation into a microbial workhorse.In this work, the potential of V. natriegens as an amino acid producer was investigated. First, the transcription factor-based biosensor LysG, from Corynebacterium glutamicum, was adapted for expression in V. natriegens to facilitate the detection of positively charged amino acids. A set of different biosensor variants were constructed and characterized, using the expression of a fluorescent protein as sensor output. After random mutagenesis, one of the LysG-based sensors was used to screen for amino acid producer strains. Here, fluorescence-activated cell sorting enabled the selective sorting of highly fluorescent cells, i.e. potential producer cells. Using this approach, individual L-lysine, L-arginine and L-histidine producers could be obtained producing up to 1 mM of the effector amino acid, extracellularly. Genome sequencing of the producer strains provided insight into the amino acid production metabolism of V. natriegens.This work demonstrates the successful expression and application of transcription factor-based biosensors in V. natriegens and provides insight into the underlying physiology, forming a solid basis for further development of this promising microbe.

Published
2021
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17. PCSK9 Inhibitors’ New Users: Analysis of Prescription Patterns and Patients’ Characteristics from an Italian Real-world Study

Author

Piccinni, Carlo, Antonazzo, Ippazio Cosimo, Maggioni, Aldo P., Pedrini, Antonella, Calabria, Silvia, Ronconi, Giulia, Dondi, Letizia, Martini, Nello, Roberto, Giuseppe, Sampietro, Tiziana, Sbrana, Francesco, Pino, Beatrice Dal, Bigazzi, Federico, Surdo, Giuseppa Lo, Volpi, Elisabetta, Biagini, Stefania, and Gini, Rosa

Published
2020
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18. Complications and early mortality in percutaneous endoscopic gastrostomy placement in lombardy: A multicenter prospective cohort study

Author

Anderloni, Andrea, Di Leo, Milena, Barzaghi, Franco, Semeraro, Rossella, Meucci, Gianmichele, Marino, Roberta, Amato, Loretta, Frigerio, Mauro, Saladino, Valeria, Toldi, Anna, Manfredi, Guido, Redaelli, Alessandro, Feliziani, Marcella, De Roberto, Giuseppe, Boni, Francesca, Scacchi, Gianlorenzo, Mosca, Davide, Devani, Massimo, Arena, Monica, Massidda, Marco, Zanoni, Paolo, Ciscato, Camilla, Casini, Valentina, Beretta, Paolo, Forti, Edoardo, Salerno, Raffaele, Caramia, Vitantonio, Bianchetti, Mario, Tomba, Carolina, Evangelista, Andrea, Repici, Alessandro, Soncini, Marco, Maconi, Giovanni, Manes, Gianpiero, and Gullotta, Renzo

Published
2019
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20. Skull Bone Defects Reconstruction with Custom-Made Titanium Graft shaped with Electron Beam Melting Technology: Preliminary Experience in a Series of Ten Patients

Author

Francaviglia, Natale, Maugeri, Rosario, Odierna Contino, Antonino, Meli, Francesco, Fiorenza, Vito, Costantino, Gabriele, Giammalva, Roberto Giuseppe, Iacopino, Domenico Gerardo, Steiger, H.-J., Series editor, Visocchi, Massimiliano, editor, Mehdorn, H. Maximilian, editor, Katayama, Yoichi, editor, and von Wild, Klaus R. H., editor

Published
2017
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22. Adherence of Elderly Patients with Cardiovascular Disease to Statins and the Risk of Exacerbation of Chronic Obstructive Pulmonary Disease: Evidence from an Italian Real-World Investigation

Author

Rea, Federico, Calusi, Giulia, Franchi, Matteo, Vetrano, Davide Liborio, Roberto, Giuseppe, Bonassi, Stefano, Kirchmayer, Ursula, Chinellato, Alessandro, Bettiol, Alessandra, Sultana, Janet, Mugelli, Alessandro, Corrao, Giovanni, and the I-GrADE Investigators

Published
2018
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23. Impact of the 2018 revised Pregnancy Prevention Programme by the European Medicines Agency on the use of oral retinoids in females of childbearing age in Denmark, Italy, Netherlands, and Spain: an interrupted time series analysis

Author

Durán, Carlos E., primary, Riera-Arnau, Judit, additional, Abtahi, Shahab, additional, Pajouheshnia, Romin, additional, Hoxhaj, Vjola, additional, Gamba, Magdalena, additional, Alsina, Ema, additional, Martin-Perez, Mar, additional, Garcia-Poza, Patricia, additional, Llorente-Garcia, Ana, additional, Gonzalez-Bermejo, Diana, additional, Ibánez, Luisa, additional, Sabaté, Mònica, additional, Vidal, Xavier, additional, Ballarín, Elena, additional, Sanfélix-Gimeno, Gabriel, additional, Rodríguez-Bernal, Clara, additional, Peiró, Salvador, additional, García-Sempere, Aníbal, additional, Sanchez-Saez, Francisco, additional, Ientile, Valentina, additional, Ingrasciotta, Ylenia, additional, Guarneri, Claudio, additional, Tanaglia, Matilde, additional, Tari, Michele, additional, Herings, Ron, additional, Houben, Eline, additional, Swart-Polinder, Karin, additional, Holthuis, Emily, additional, Huerta, Consuelo, additional, Gini, Rosa, additional, Roberto, Giuseppe, additional, Bartolini, Claudia, additional, Paoletti, Olga, additional, Limoncella, Giorgio, additional, Girardi, Anna, additional, Hyeraci, Giulia, additional, Andersen, Morten, additional, Kristiansen, Sarah Brøgger, additional, Hallgreen, Christine Erikstrup, additional, Klungel, Olaf, additional, and Sturkenboom, Miriam, additional

Published
2023
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24. Evaluation of Clensia®, a new low-volume PEG bowel preparation in colonoscopy: Multicentre randomized controlled trial versus 4L PEG

Author

Spada, Cristiano, Cesaro, Paola, Bazzoli, Franco, Saracco, Giorgio Maria, Cipolletta, Livio, Buri, Luigi, Crosta, Cristiano, Petruzziello, Lucio, Ceroni, Liza, Fuccio, Lorenzo, Giordanino, Chiara, Elia, Chiara, Rotondano, Gianluca, Bianco, Maria A., Simeth, Catrin, Consalvo, Danilo, De Roberto, Giuseppe, Fiori, Giancarla, Campanale, Mariachiara, and Costamagna, Guido

Published
2017
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26. Bleeding events attributable to concurrent use of warfarin and other medications in high-risk elderly: meta-analysis and Italian population-based investigation

Author

Comoretto, Rosanna Irene, Rea, Federico, Lucenteforte, Ersilia, Mugelli, Alessandro, Trifirò, Gianluca, Cascini, Silvia, Roberto, Giuseppe, Chinellato, Alessandro, Filippelli, Amelia, Corrao, Giovanni, and on behalf of the Italian Group for Appropriate Drug prescription in the Elderly (I-GrADE)

Published
2018
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27. NSAIDs utilization for musculoskeletal indications in elderly patients with cerebro/cardiovascular disease

Author

Roberto, Giuseppe, Bartolini, Claudia, Rea, Federico, Onder, Graziano, Vitale, Cristiana, Trifirò, Gianluca, Kirchmayer, Ursula, Chinellato, Alessandro, Lucenteforte, Ersilia, Corrao, Giovanni, Mugelli, Alessandro, Lapi, Francesco, Gini, Rosa, and on behalf of the Italian Group for Appropriate Drug prescription in the Elderly (I-GrADE)

Published
2018
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28. Validity of Italian administrative healthcare data in describing the real-world utilization of infusive antineoplastic drugs: the study case of rituximab use in patients treated at the University Hospital of Siena for onco-haematological indications

Author

Bartolini, Claudia, primary, Roberto, Giuseppe, additional, Girardi, Anna, additional, Moscatelli, Valentino, additional, Spini, Andrea, additional, Barchielli, Alessandro, additional, Bocchia, Monica, additional, Fabbri, Alberto, additional, Donnini, Sandra, additional, Ziche, Marina, additional, Monti, Maria Cristina, additional, and Gini, Rosa, additional

Published
2023
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29. Guided Zygomatic Implantology for Oral Cancer Rehabilitation: A Case Report

Author

Grecchi, Francesco, primary, D’Ambrogio, Roberto Giuseppe, additional, Stefanelli, Luigi Vito, additional, Grivetto, Fabrizio, additional, Goker, Funda, additional, Del Fabbro, Massimo, additional, Schreiber, Alberto, additional, Piazza, Cesare, additional, Salgarello, Stefano, additional, Dosio, Camilla, additional, and Grecchi, Emma, additional

Published
2023
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30. The impact of palivizumab reimbursement criteria on neonatal RSV hospitalizations and drug prescriptions: an area-based cohort study from the Tuscany Region, Italy

Author

Lastrucci, Vieri, primary, Alderotti, Giorgia, additional, Pacifici, Martina, additional, Stacchini, Lorenzo, additional, Puglia, Monia, additional, Berti, Elettra, additional, Hyeraci, Giulia, additional, Roberto, Giuseppe, additional, Gini, Rosa, additional, and Voller, Fabio, additional

Published
2023
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31. Resurgence of the respiratory syncytial virus epidemic in infants after the easing of the COVID-19 containment measures: a retrospective cohort study from Tuscany Region, Italy

Author

Lastrucci, Vieri, primary, Pacifici, Martina, additional, Alderotti, Giorgia, additional, Stacchini, Lorenzo, additional, Berti, Elettra, additional, Puglia, Monia, additional, Hyeraci, Giulia, additional, Roberto, Giuseppe, additional, Gini, Rosa, additional, and Voller, Fabio, additional

Published
2023
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32. Data from A Randomized, Placebo-Controlled, Preoperative Trial of Allopurinol in Subjects with Colorectal Adenoma

Author

Puntoni, Matteo, primary, Branchi, Daniela, primary, Argusti, Alessandra, primary, Zanardi, Silvia, primary, Crosta, Cristiano, primary, Meroni, Emanuele, primary, Munizzi, Francesco, primary, Michetti, Paolo, primary, Coccia, Gianni, primary, De Roberto, Giuseppe, primary, Bandelloni, Roberto, primary, Turbino, Laura, primary, Minetti, Egle, primary, Mori, Marco, primary, Salvi, Sandra, primary, Boccardo, Simona, primary, Gatteschi, Beatrice, primary, Benelli, Roberto, primary, Sonzogni, Angelica, primary, and DeCensi, Andrea, primary

Published
2023
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33. Commentary on This Article from A Randomized, Placebo-Controlled, Preoperative Trial of Allopurinol in Subjects with Colorectal Adenoma

Author

Puntoni, Matteo, primary, Branchi, Daniela, primary, Argusti, Alessandra, primary, Zanardi, Silvia, primary, Crosta, Cristiano, primary, Meroni, Emanuele, primary, Munizzi, Francesco, primary, Michetti, Paolo, primary, Coccia, Gianni, primary, De Roberto, Giuseppe, primary, Bandelloni, Roberto, primary, Turbino, Laura, primary, Minetti, Egle, primary, Mori, Marco, primary, Salvi, Sandra, primary, Boccardo, Simona, primary, Gatteschi, Beatrice, primary, Benelli, Roberto, primary, Sonzogni, Angelica, primary, and DeCensi, Andrea, primary

Published
2023
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36. Impact of the 2018 revised Pregnancy Prevention Programme by the European Medicines Agency on the use of oral retinoids in females of childbearing age in Denmark, Italy, Netherlands, and Spain: an interrupted time series analysis

Author

Durán, Carlos E, Riera-Arnau, Judit, Abtahi, Shahab, Pajouheshnia, Romin, Hoxhaj, Vjola, Gamba, Magdalena, Alsina, Ema, Martin-Perez, Mar, Garcia-Poza, Patricia, Llorente-Garcia, Ana, Gonzalez-Bermejo, Diana, Ibánez, Luisa, Sabaté, Mònica, Vidal, Xavier, Ballarín, Elena, Sanfélix-Gimeno, Gabriel, Rodríguez-Bernal, Clara, Peiró, Salvador, García-Sempere, Aníbal, Sanchez-Saez, Francisco, Ientile, Valentina, Ingrasciotta, Ylenia, Guarneri, Claudio, Tanaglia, Matilde, Tari, Michele, Herings, Ron, Houben, Eline, Swart-Polinder, Karin, Holthuis, Emily, Huerta, Consuelo, Gini, Rosa, Roberto, Giuseppe, Bartolini, Claudia, Paoletti, Olga, Limoncella, Giorgio, Girardi, Anna, Hyeraci, Giulia, Andersen, Morten, Kristiansen, Sarah Brøgger, Hallgreen, Christine Erikstrup, Klungel, Olaf, Sturkenboom, Miriam, Durán, Carlos E, Riera-Arnau, Judit, Abtahi, Shahab, Pajouheshnia, Romin, Hoxhaj, Vjola, Gamba, Magdalena, Alsina, Ema, Martin-Perez, Mar, Garcia-Poza, Patricia, Llorente-Garcia, Ana, Gonzalez-Bermejo, Diana, Ibánez, Luisa, Sabaté, Mònica, Vidal, Xavier, Ballarín, Elena, Sanfélix-Gimeno, Gabriel, Rodríguez-Bernal, Clara, Peiró, Salvador, García-Sempere, Aníbal, Sanchez-Saez, Francisco, Ientile, Valentina, Ingrasciotta, Ylenia, Guarneri, Claudio, Tanaglia, Matilde, Tari, Michele, Herings, Ron, Houben, Eline, Swart-Polinder, Karin, Holthuis, Emily, Huerta, Consuelo, Gini, Rosa, Roberto, Giuseppe, Bartolini, Claudia, Paoletti, Olga, Limoncella, Giorgio, Girardi, Anna, Hyeraci, Giulia, Andersen, Morten, Kristiansen, Sarah Brøgger, Hallgreen, Christine Erikstrup, Klungel, Olaf, and Sturkenboom, Miriam

Abstract

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

Published
2023

37. Impact of the 2018 revised Pregnancy Prevention Programme by the European Medicines Agency on the use of oral retinoids in females of childbearing age in Denmark, Italy, Netherlands, and Spain: an interrupted time series analysis

Author

Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, PECP - Centre for Pharmacoepidemiology, Durán, Carlos E, Riera-Arnau, Judit, Abtahi, Shahab, Pajouheshnia, Romin, Hoxhaj, Vjola, Gamba, Magdalena, Alsina, Ema, Martin-Perez, Mar, Garcia-Poza, Patricia, Llorente-Garcia, Ana, Gonzalez-Bermejo, Diana, Ibánez, Luisa, Sabaté, Mònica, Vidal, Xavier, Ballarín, Elena, Sanfélix-Gimeno, Gabriel, Rodríguez-Bernal, Clara, Peiró, Salvador, García-Sempere, Aníbal, Sanchez-Saez, Francisco, Ientile, Valentina, Ingrasciotta, Ylenia, Guarneri, Claudio, Tanaglia, Matilde, Tari, Michele, Herings, Ron, Houben, Eline, Swart-Polinder, Karin, Holthuis, Emily, Huerta, Consuelo, Gini, Rosa, Roberto, Giuseppe, Bartolini, Claudia, Paoletti, Olga, Limoncella, Giorgio, Girardi, Anna, Hyeraci, Giulia, Andersen, Morten, Kristiansen, Sarah Brøgger, Hallgreen, Christine Erikstrup, Klungel, Olaf, Sturkenboom, Miriam, Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, PECP - Centre for Pharmacoepidemiology, Durán, Carlos E, Riera-Arnau, Judit, Abtahi, Shahab, Pajouheshnia, Romin, Hoxhaj, Vjola, Gamba, Magdalena, Alsina, Ema, Martin-Perez, Mar, Garcia-Poza, Patricia, Llorente-Garcia, Ana, Gonzalez-Bermejo, Diana, Ibánez, Luisa, Sabaté, Mònica, Vidal, Xavier, Ballarín, Elena, Sanfélix-Gimeno, Gabriel, Rodríguez-Bernal, Clara, Peiró, Salvador, García-Sempere, Aníbal, Sanchez-Saez, Francisco, Ientile, Valentina, Ingrasciotta, Ylenia, Guarneri, Claudio, Tanaglia, Matilde, Tari, Michele, Herings, Ron, Houben, Eline, Swart-Polinder, Karin, Holthuis, Emily, Huerta, Consuelo, Gini, Rosa, Roberto, Giuseppe, Bartolini, Claudia, Paoletti, Olga, Limoncella, Giorgio, Girardi, Anna, Hyeraci, Giulia, Andersen, Morten, Kristiansen, Sarah Brøgger, Hallgreen, Christine Erikstrup, Klungel, Olaf, and Sturkenboom, Miriam

Published
2023

38. Impact of the 2018 revised Pregnancy Prevention Programme by the European Medicines Agency on the use of oral retinoids in females of childbearing age in Denmark, Italy, Netherlands, and Spain:an interrupted time series analysis

Author

Durán, Carlos E., Riera-Arnau, Judit, Abtahi, Shahab, Pajouheshnia, Romin, Hoxhaj, Vjola, Gamba, Magdalena, Alsina, Ema, Martin-Perez, Mar, Garcia-Poza, Patricia, Llorente-Garcia, Ana, Gonzalez-Bermejo, Diana, Ibánez, Luisa, Sabaté, Mònica, Vidal, Xavier, Ballarín, Elena, Sanfélix-Gimeno, Gabriel, Rodríguez-Bernal, Clara, Peiró, Salvador, García-Sempere, Aníbal, Sanchez-Saez, Francisco, Ientile, Valentina, Ingrasciotta, Ylenia, Guarneri, Claudio, Tanaglia, Matilde, Tari, Michele, Herings, Ron, Houben, Eline, Swart-Polinder, Karin, Holthuis, Emily, Huerta, Consuelo, Gini, Rosa, Roberto, Giuseppe, Bartolini, Claudia, Paoletti, Olga, Limoncella, Giorgio, Girardi, Anna, Hyeraci, Giulia, Andersen, Morten, Kristiansen, Sarah Brøgger, Hallgreen, Christine Erikstrup, Klungel, Olaf, Sturkenboom, Miriam, Durán, Carlos E., Riera-Arnau, Judit, Abtahi, Shahab, Pajouheshnia, Romin, Hoxhaj, Vjola, Gamba, Magdalena, Alsina, Ema, Martin-Perez, Mar, Garcia-Poza, Patricia, Llorente-Garcia, Ana, Gonzalez-Bermejo, Diana, Ibánez, Luisa, Sabaté, Mònica, Vidal, Xavier, Ballarín, Elena, Sanfélix-Gimeno, Gabriel, Rodríguez-Bernal, Clara, Peiró, Salvador, García-Sempere, Aníbal, Sanchez-Saez, Francisco, Ientile, Valentina, Ingrasciotta, Ylenia, Guarneri, Claudio, Tanaglia, Matilde, Tari, Michele, Herings, Ron, Houben, Eline, Swart-Polinder, Karin, Holthuis, Emily, Huerta, Consuelo, Gini, Rosa, Roberto, Giuseppe, Bartolini, Claudia, Paoletti, Olga, Limoncella, Giorgio, Girardi, Anna, Hyeraci, Giulia, Andersen, Morten, Kristiansen, Sarah Brøgger, Hallgreen, Christine Erikstrup, Klungel, Olaf, and Sturkenboom, Miriam

Abstract

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

Published
2023

39. Impact of 2018 EU Risk Minimisation Measures and Revised Pregnancy Prevention Programme on Utilisation and Prescribing Trends of Medicinal Products Containing Valproate:An Interrupted Time Series Study

Author

Abtahi, Shahab, Pajouheshnia, Romin, Durán, Carlos E., Riera-Arnau, Judit, Gamba, Magdalena, Alsina, Ema, Hoxhaj, Vjola, Andersen, Morten, Bartolini, Claudia, Kristiansen, Sarah Brøgger, Brown, Jeremy, Hallgreen, Christine Erikstrup, Garcia-Poza, Patricia, Gardarsdottir, Helga, Gini, Rosa, Girardi, Anna, Holthuis, Emily, Huerta, Consuelo, Ibánez, Luisa, Limoncella, Giorgio, Martín-Pérez, Mar, Paoletti, Olga, Roberto, Giuseppe, Souverein, Patrick, Swart, Karin M.A., Wing, Kevin, Sturkenboom, Miriam, Klungel, Olaf, Abtahi, Shahab, Pajouheshnia, Romin, Durán, Carlos E., Riera-Arnau, Judit, Gamba, Magdalena, Alsina, Ema, Hoxhaj, Vjola, Andersen, Morten, Bartolini, Claudia, Kristiansen, Sarah Brøgger, Brown, Jeremy, Hallgreen, Christine Erikstrup, Garcia-Poza, Patricia, Gardarsdottir, Helga, Gini, Rosa, Girardi, Anna, Holthuis, Emily, Huerta, Consuelo, Ibánez, Luisa, Limoncella, Giorgio, Martín-Pérez, Mar, Paoletti, Olga, Roberto, Giuseppe, Souverein, Patrick, Swart, Karin M.A., Wing, Kevin, Sturkenboom, Miriam, and Klungel, Olaf

Abstract

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 pregnanci

Published
2023

40. Impact of 2018 EU Risk Minimisation Measures and Revised Pregnancy Prevention Programme on Utilisation and Prescribing Trends of Medicinal Products Containing Valproate: An Interrupted Time Series Study

Author

Pharmacoepidemiology and Clinical Pharmacology, Afd Pharmacoepi & Clinical Pharmacology, PECP - Centre for Pharmacoepidemiology, Abtahi, Shahab, Pajouheshnia, Romin, Durán, Carlos E, Riera-Arnau, Judit, Gamba, Magdalena, Alsina, Ema, Hoxhaj, Vjola, Andersen, Morten, Bartolini, Claudia, Kristiansen, Sarah Brøgger, Brown, Jeremy, Hallgreen, Christine Erikstrup, Garcia-Poza, Patricia, Gardarsdottir, Helga, Gini, Rosa, Girardi, Anna, Holthuis, Emily, Huerta, Consuelo, Ibánez, Luisa, Limoncella, Giorgio, Martín-Pérez, Mar, Paoletti, Olga, Roberto, Giuseppe, Souverein, Patrick, Swart, Karin M A, Wing, Kevin, Sturkenboom, Miriam, Klungel, Olaf, Pharmacoepidemiology and Clinical Pharmacology, Afd Pharmacoepi & Clinical Pharmacology, PECP - Centre for Pharmacoepidemiology, Abtahi, Shahab, Pajouheshnia, Romin, Durán, Carlos E, Riera-Arnau, Judit, Gamba, Magdalena, Alsina, Ema, Hoxhaj, Vjola, Andersen, Morten, Bartolini, Claudia, Kristiansen, Sarah Brøgger, Brown, Jeremy, Hallgreen, Christine Erikstrup, Garcia-Poza, Patricia, Gardarsdottir, Helga, Gini, Rosa, Girardi, Anna, Holthuis, Emily, Huerta, Consuelo, Ibánez, Luisa, Limoncella, Giorgio, Martín-Pérez, Mar, Paoletti, Olga, Roberto, Giuseppe, Souverein, Patrick, Swart, Karin M A, Wing, Kevin, Sturkenboom, Miriam, and Klungel, Olaf

Published
2023

41. Impact of the 2018 revised Pregnancy Prevention Programme by the European Medicines Agency on the use of oral retinoids in females of childbearing age in Denmark, Italy, Netherlands, and Spain: an interrupted time series analysis

Author

RWE/Causal inference, Epi Infectieziekten Team 2, Data Science & Biostatistiek, Child Health, Durán, Carlos E, Riera-Arnau, Judit, Abtahi, Shahab, Pajouheshnia, Romin, Hoxhaj, Vjola, Gamba, Magdalena, Alsina, Ema, Martin-Perez, Mar, Garcia-Poza, Patricia, Llorente-Garcia, Ana, Gonzalez-Bermejo, Diana, Ibánez, Luisa, Sabaté, Mònica, Vidal, Xavier, Ballarín, Elena, Sanfélix-Gimeno, Gabriel, Rodríguez-Bernal, Clara, Peiró, Salvador, García-Sempere, Aníbal, Sanchez-Saez, Francisco, Ientile, Valentina, Ingrasciotta, Ylenia, Guarneri, Claudio, Tanaglia, Matilde, Tari, Michele, Herings, Ron, Houben, Eline, Swart-Polinder, Karin, Holthuis, Emily, Huerta, Consuelo, Gini, Rosa, Roberto, Giuseppe, Bartolini, Claudia, Paoletti, Olga, Limoncella, Giorgio, Girardi, Anna, Hyeraci, Giulia, Andersen, Morten, Kristiansen, Sarah Brøgger, Hallgreen, Christine Erikstrup, Klungel, Olaf, Sturkenboom, Miriam, RWE/Causal inference, Epi Infectieziekten Team 2, Data Science & Biostatistiek, Child Health, Durán, Carlos E, Riera-Arnau, Judit, Abtahi, Shahab, Pajouheshnia, Romin, Hoxhaj, Vjola, Gamba, Magdalena, Alsina, Ema, Martin-Perez, Mar, Garcia-Poza, Patricia, Llorente-Garcia, Ana, Gonzalez-Bermejo, Diana, Ibánez, Luisa, Sabaté, Mònica, Vidal, Xavier, Ballarín, Elena, Sanfélix-Gimeno, Gabriel, Rodríguez-Bernal, Clara, Peiró, Salvador, García-Sempere, Aníbal, Sanchez-Saez, Francisco, Ientile, Valentina, Ingrasciotta, Ylenia, Guarneri, Claudio, Tanaglia, Matilde, Tari, Michele, Herings, Ron, Houben, Eline, Swart-Polinder, Karin, Holthuis, Emily, Huerta, Consuelo, Gini, Rosa, Roberto, Giuseppe, Bartolini, Claudia, Paoletti, Olga, Limoncella, Giorgio, Girardi, Anna, Hyeraci, Giulia, Andersen, Morten, Kristiansen, Sarah Brøgger, Hallgreen, Christine Erikstrup, Klungel, Olaf, and Sturkenboom, Miriam

Published
2023

42. Impact of 2018 EU Risk Minimisation Measures and Revised Pregnancy Prevention Programme on Utilisation and Prescribing Trends of Medicinal Products Containing Valproate: An Interrupted Time Series Study

Author

RWE/Causal inference, Epi Infectieziekten Team 2, Apotheek O&O&O, Child Health, Infection & Immunity, Regenerative Medicine and Stem Cells, Data Science & Biostatistiek, Abtahi, Shahab, Pajouheshnia, Romin, Durán, Carlos E, Riera-Arnau, Judit, Gamba, Magdalena, Alsina, Ema, Hoxhaj, Vjola, Andersen, Morten, Bartolini, Claudia, Kristiansen, Sarah Brøgger, Brown, Jeremy, Hallgreen, Christine Erikstrup, Garcia-Poza, Patricia, Gardarsdottir, Helga, Gini, Rosa, Girardi, Anna, Holthuis, Emily, Huerta, Consuelo, Ibánez, Luisa, Limoncella, Giorgio, Martín-Pérez, Mar, Paoletti, Olga, Roberto, Giuseppe, Souverein, Patrick, Swart, Karin M A, Wing, Kevin, Sturkenboom, Miriam, Klungel, Olaf, RWE/Causal inference, Epi Infectieziekten Team 2, Apotheek O&O&O, Child Health, Infection & Immunity, Regenerative Medicine and Stem Cells, Data Science & Biostatistiek, Abtahi, Shahab, Pajouheshnia, Romin, Durán, Carlos E, Riera-Arnau, Judit, Gamba, Magdalena, Alsina, Ema, Hoxhaj, Vjola, Andersen, Morten, Bartolini, Claudia, Kristiansen, Sarah Brøgger, Brown, Jeremy, Hallgreen, Christine Erikstrup, Garcia-Poza, Patricia, Gardarsdottir, Helga, Gini, Rosa, Girardi, Anna, Holthuis, Emily, Huerta, Consuelo, Ibánez, Luisa, Limoncella, Giorgio, Martín-Pérez, Mar, Paoletti, Olga, Roberto, Giuseppe, Souverein, Patrick, Swart, Karin M A, Wing, Kevin, Sturkenboom, Miriam, and Klungel, Olaf

Published
2023

46. Multidimensional characterization of early-stage gastric cancer: Preliminary results of MIMETIC trial.

Author

Catanese, Silvia, primary, Catozzi, Carlotta, additional, Macandog, Angeli Dominique, additional, Fazio, Nicola, additional, Fumagalli, Uberto, additional, De Roberto, Giuseppe, additional, De Pascale, Stefano, additional, Funicelli, Luigi, additional, Sabbatini, Annarita, additional, Gnagnarella, Patrizia, additional, Nezi, Luigi, additional, Gervaso, Lorenzo, additional, and Cella, Chiara Alessandra, additional

Published
2023
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47. Utilization patterns, cardiovascular risk, and concomitant serotoninergic medications among triptan users between 2008 and 2018: A gender analysis in one Italian region, Tuscany

Author

Hyeraci, Giulia, primary, Gini, Rosa, additional, Bezin, Julien, additional, Iannone, Luigi Francesco, additional, Benemei, Silvia, additional, Lupi, Chiara, additional, De Cesaris, Francesco, additional, Geppetti, Pierangelo, additional, and Roberto, Giuseppe, additional

Published
2023
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48. Impact of EU label changes and revised pregnancy prevention programme for medicinal products containing valproate: utilisation and prescribing trends

Author

Klungel, Olaf, Sturkenboom, Miriam, Abtahi, Shahab, Pajouheshnia, Romin, Durán Salinas, Carlos, Riera Arnau, Judit, Dodd, Caitlin, Gardarsdottir, Helga, Souverein, Patrick, Hoxhaj, Vjola, Siiskonen, Satu Johanna, Gamba, Magdalena, Alsina, Ema, Huerta, Consuelo, Bermejo, Diana Gonzalez, Corominas, Dolores Montero, Martín-Pérez, Mar, Garcia-Poza, Patricia, García, Ana Llorente, Ibanez, Luisa, Douglas, Ian, Wing, Kevin, Brown, Jeremy, Herings, Ron, Houben, Eline, Penning-van Beest, Fernie, Swart, Karin, Holthuis, Emily, Gini, Rosa, Roberto, Giuseppe, Bartolini, Claudia, Paoletti, Olga, Limoncella, Giorgio, Girardi, Anna, Hyeraci, Giulia, Andersen, Morten, Kristiansen. Sarah Brøgger, Hallgreen, Christine Erikstrup, Kant, Agnes, van Puijenbroek, Eugene, and Lely, Titia

Subjects
Sodium valproate, congenital abnormalities, contraceptive agents, pregnancy, risk minimisation measures (RMMs), bipolar disorder, epilepsy, migraine prophylaxis
Abstract

Rationale and background In March 2018, the European risk minimisation measures (RMMs) with a Pregnancy Prevention Program (PPP) for valproate-containing medicines was updated. A pharmacoepidemiological study was conducted using longitudinal data collected in five electronic health care databases from four EU countries and the UK to investigate the use of valproates authorised in the EU before and after implementation of the 2018 revised measures for pregnancy prevention in clinical practice, and effectiveness of the 2018 intervention. Objectives Objective 1: To determine drug utilisation and prescription patterns of valproate-containing medicinal products in females of childbearing potential, and to investigate whether significant changes in prescribing patterns occurred (pre-/post-intervention). Objective 2: To determine prescribers’ compliance with the recommendations in the Summary of Products Characteristics (SmPC) for valproate-containing medicinal products, by indication, age group, duration of use, and database. Objective 3: To determine patients’ use of effective contraception in compliance with recommendations in the SmPC for valproate-containing medicinal products, by indication, age group, method of contraception, and database. Objective 4: To determine drug utilisation and prescription patterns over time for alternative medicines prescribed in women who became pregnant, where valproate-containing medicinal products had previously been prescribed or discontinued, by indication, by age group and by database. Objective 5: Based on the results of the above, to estimate the effectiveness of the 2018 RMMs for valproates. Methods We performed an observational times series study including all female subjects of childbearing age (aged 12 to 55 years) from the corresponding databases in Denmark (Danish National Registers, DNR), Italy (ARS Tuscany), the Netherlands (PHARMO Database Network), Spain (Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria, BIFAP), and UK (Clinical Practice Research Datalink, CPRD) between 01 January 2010 to 31 December 2020. In Objective 1, the incident use, prevalent use and rate of discontinuation thereof was estimated per month in each data source, in addition to the change in level and trend in use after the implementation of the 2018 EU RMMs, using an interrupted time series (ITS) analysis design. In Objective 2, first, we separately estimated the proportion of valproate users with a record of a pregnancy test within the 90 days i) before and ii) after the date of valproate prescribing or dispensing per month. We estimated the change in level and trend in these proportions after the implementation of the 2018 EU RMMs. Second, we estimated the proportion of valproate users with a record of contraceptive (prescribed or dispensed with a prescription, or identified through medical events or procedures records) in 90-days before the prescription, or prescribed/dispensed during a contraceptive episode. We then estimated the change in level and trend in this proportion after the implementation of the 2018 EU intervention, using an ITS analysis design. In Objective 3, we estimated the incidence of new pregnancies during a period of valproate use per month and the change in level and trend in this rate after the implementation of the 2018 EU intervention, using an ITS analysis design. In Objective 4, we estimated the rates of alternative medication prescriptions/dispensings for the indications epilepsy, bipolar disorder, and migraine among valproate users and the rate of switching from valproate to an alternative medicine per month. Then, the change in trend of switches from valproate to alternative medications before and after the implementation of the 2018 EU intervention was estimated, using an ITS analysis design. In Objective 5, evidence generated from Objectives 1-4, weighed by the strengths and limitations of the analyses, was used to draw conclusions on the effectiveness of the RMMs, per country and across European countries included in the study. Results Objective 1: There were 69,533 valproate users out of a total of 9,699,371 female subjects of childbearing age from the five participating centres during the study period. The median follow-up time of the study population ranged between 3.5-10.0 years and the mean age at the start of follow-up was always ≥30 years in different centres. The monthly incidence rate of valproate use ranged between 0.01-0.47 per 1000 persons months across databases and the prevalence rate ranged between 1.2-7.7 per 1000 female subjects. While the observed rates were similar for DNR, PHARMO, BIFAP and CPRD, the rates of prevalent use were much higher in ARS Tuscany. We observed a statistically significant declining trend in prevalent use of valproates in all countries/regions, for which an ITS analysis could be performed, but no significant decreasing trend in incidence rates after the 2018 RMMs compared to the period before. The monthly rate of valproate discontinuers ranged between 1-8% across all databases, and in no database we observed a significant increase in trend or level of valproate discontinuation after the 2018 intervention compared to time prior. Objective 2: We included 69,533 female valproate users from the five participating centres during the study period, with a median follow-up time between 4.4-11.0 years and the mean age at the start of follow-up ≥34 years. Due to the limited data on pregnancy tests from all databases, modelling of any trend change in proportion of valproate prescriptions or dispensings with an adherent pregnancy test before versus after 2018 RMMs was not possible. The rate of recorded contraceptive coverage at the start of valproate treatment was low across all centres, as only 0.5-23% of valproate prescriptions/dispensings each month were accompanied by a contraceptive prescription in 90-days before, and only between 0.5-25% of new valproate treatment episode had started during contraceptive use. There was no increasing trend in compliant valproate prescriptions/ dispensings with a contraceptive coverage after the 2018 RMMs across the studied databases, and the only increase in level was observed in PHARMO. Objective 3: We included 69,533 female valproate users from the five participating centres during study period, with a median follow-up time between 4.4-11.0 years and the mean age at the start of follow-up ≥34 years. In general, we observed a substantial number of concurrent new valproate prescriptions/dispensings during a pregnancy time window in ARS Tuscany (386 pre- and 40 post 2018 intervention), BIFAP (330 pre and 20 post) and CPRD (204 pre and 56 post), while there were fewer concurrent events in PHARMO (27 pre and 0 post). However, the rates of concurrent events declined for most databases after the 2018 intervention. There was no data on pregnancy counts available from DNR. Objective 4: We included 69,533 female valproate users from the five participating centres during study period, with a median follow-up time between 4.4-11.0 years and the mean age at the start of follow-up ≥34 years. We found an increasing trend in rates of alternative medicine use for epilepsy and bipolar diseases indications of valproates across the study period in most databases (i.e., DNR, ARS Tuscany, PHARMO and CPRD), while the rates for migraine were mostly steady. The monthly rate of switch from a valproate to an alternative medication was similar across all DAPs and ranged between 1-8%. Running an ITS analysis was not possible for most of the included databases due to the low frequency of switching, but there was a significant increase in trend in switching rates from valproates to alternative medicine after the 2018 RMMs in ARS Tuscany. Objective 5: We found a generally declining trend in prevalence rate of valproate use after the 2018 RMMs in almost all databases (Objective 1), but also no increasing trend in compliant valproate prescriptions/dispensings with a contraceptive coverage (Objective 2). There was a substantial number of occurrences of pregnancy events (as the final endpoint) concurrently with valproate exposure across most included databases, but the rates declined after 2018 (Objective 3). Furthermore, we observed a significant increase in switching rates from valproates to alternative medications only in few regions (such as ARS Tuscany) (Objective 4). Noteworthy, these findings should be interpreted in context of the limitations that we faced, such as an inability to investigate some objectives due to limited data availability on pregnancy test or over-the-counter use of some contraceptives, and the occurrence of COVID-19 pandemic, which has shortened and impacted our post-intervention period and limited our ability to run ITS analyses for some objectives and some databases. Conclusions Objective 1: We observed declining trends in prevalent use of valproates after the 2018 RMMs across all databases. However, there were no declining trends in incidence rate of valproates in none of databases. The rate of discontinuation of valproates was not affected by the 2018 RMMs. Objective 2: We found in general low rates of recorded adherent contraceptive coverage with valproate use across all studied regions/countries, and there was no increased trend in compliant valproate prescriptions/dispensings with a contraceptive coverage after the 2018 RMMs compared to time prior. Due to limited data availability, rates of adherent pregnancy tests and the trend change after the intervention could not be studied. Objective 3: Despite the declining rates after the 2018 intervention, high counts and rates of concurrent pregnancy events with a valproate prescription/dispensing were observed across most studied countries/regions. Objective 4: Although the trend in alternative medication use for most indications of valproates (epilepsy and bipolar disorder) was increasing during the study period, the only significant increase in trend in switching rates from valproates to alternative medications after the 2018 RMMs was observed in ARS Tuscany. Objective 5: Based on the findings on various objectives in this study, we can conclude that there was a small impact of the 2018 RMMs on valproate use and prescribing in the studied European countries/regions. Considering the limitations of this study (such as not studying all PPP elements, the included databases had important limitations, and the study period after 2018 intervention was rather short), the results of other currently ongoing studies are needed to have a clearer picture of the appropriate implementation of 2018 RMMs on valproate use in Europe., The research leading to these results was conducted as part of the activities of the EU PE&PV (Pharmacoepidemiology and Pharmacovigilance) Research Network which is a public academic partnership coordinated by the Utrecht University, the Netherlands. The project has received support from the European Medicines Agency under the Framework service contract nr EMA/2018/28/PE. The content of this paper expresses the opinion of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties.

Published
2022
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