Drug Safety最新文献

{"title":"Emergency Department Use of Heart Failure-Exacerbating Medications in Patients with Chronic Heart Failure","authors":"Martin F. Casey, Joy Hallmark, Patricia P. Chang, Jo E. Rodgers, Aakash Mehta, Srihari V. Chari, Preston Skersick, Thomas Bohrmann, Parag Goyal, Michelle L. Meyer","doi":"10.1007/s40264-024-01479-5","DOIUrl":"https://doi.org/10.1007/s40264-024-01479-5","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Use of heart failure-exacerbating medications (HFEMs) may lead to preventable episodes of acute decompensated heart failure (HF). HFEMs use is common in patients with HF, and there may be opportunities to reduce their use from the emergency department (ED).</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We performed an observational study on patients with HF presenting to EDs within a healthcare system between 1 January 2016 and 31 December 2020. Patients with chronic HF were identified using diagnostic codes within the electronic health record. The cohort was restricted to ambulatory (i.e., discharged to home) ED encounters. Medications, either ordered in the ED or prescribed at ED discharge, were extracted from the medication administration record and identified as potential HFEMs based on the 2016 American Heart Association Scientific Statement. Descriptive statistics were used to summarize the prevalence of HFEM use during ambulatory ED encounters. Exploratory analyses to identify correlates of HFEM use were performed.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>The study cohort included 23,907 ED encounters. ED administration or prescription of HFEMs occurred during 20% of ambulatory ED encounters. HFEM administration in the ED (17%) was more common than HFEM prescription at ED discharge (6%). The most common HFEMs administered in the ED included nonsteroidal anti-inflammatory drugs (11%) and albuterol (7%).</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>HFEM use is common in patients with HF seeking ED care, occurring in roughly one-fifth of ambulatory ED encounters. There may be opportunities to optimize medication use among patients with HF in the ED.</p>","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":"1 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142200716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Use of Sotrovimab in Pregnancy: Experiences from the COVID-19 International Drug Pregnancy Registry.","authors":"Diego F Wyszynski, Lydia Demetriou, Cheryl Renz, Shirin Aliabadi, Dragutin Rafailovic, Lee P Shulman, Myriam Drysdale, Keele E Wurst","doi":"10.1007/s40264-024-01439-z","DOIUrl":"10.1007/s40264-024-01439-z","url":null,"abstract":"<p><strong>Introduction: </strong>Available data regarding the safety and efficacy of sotrovimab in pregnant patients remain limited due to their exclusion from clinical trials.</p><p><strong>Methods: </strong>The COVID-19 International Drug Pregnancy Registry (COVID-PR) was established to gather comprehensive safety data from pregnant women who have received monoclonal antibody (mAb) or antiviral treatments for mild, moderate, or severe coronavirus disease 2019 (COVID-19) during pregnancy. Participants actively contributed self-reported data concerning their COVID-19 symptoms, in addition to sociodemographic and health-related characteristics. Obstetric, neonatal, and infant outcomes were also documented, with follow-up extending up to 12 months after childbirth.</p><p><strong>Results: </strong>As of 30 November 2023, sotrovimab was administered to 39 participants enrolled in the COVID-PR. At the time of this report, 26 participants had given birth, with nine deliveries performed via cesarean section. The infants' birthweight ranged from 2381 g to 4762 g, with a mean of 3439.91 g. Twenty-five infants were born at ≥37 weeks. A total of 31 adverse events (AEs) were reported by 12 participants. The most frequently reported AE was gestational hypertension, observed in three participants. COVID-19 re-infection, fatigue, gestational diabetes, headache, and morning sickness were each reported by two participants. Of the reported AEs, eight (in five participants) were classified as serious, including four AEs (prolonged labor, pre-eclampsia, polyhydramnios, premature labor) that affected pregnancy. Seven of these eight serious AEs (SAEs) were found to be unrelated to sotrovimab, with one event (urinary retention) not assessable. A total of 44 AEs were reported in 19 delivered infants or in utero fetuses. The most common were COVID-19 (n = 6 events), ear infection (n = 5 events), neonatal dyspnea (n = 3 events), and respiratory syncytial virus infection (n = 3 events). Sixteen AEs (in 11 infants/fetuses) were classified as serious, including one report each of fetal cardiac disorder, congenital ankyloglossia, persistent right umbilical vein, and congenital hydronephrosis; the latter was considered a major congenital malformation. For all assessable SAEs, causality of sotrovimab treatment was ruled out based on lack of a temporal relationship alone or in combination with absence of a plausible mechanism.</p><p><strong>Conclusion: </strong>A sizable proportion of sotrovimab-treated participants in the COVID-PR had underlying medical conditions associated with an increased risk of severe COVID-19. None of the assessable SAEs were considered to be related to sotrovimab treatment.</p>","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":"843-851"},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11324716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140896100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting CCL24 in Inflammatory and Fibrotic Diseases: Rationale and Results from Three CM-101 Phase 1 Studies.","authors":"Adi Mor, Scott Friedman, Sharon Hashmueli, Amnon Peled, Massimo Pinzani, Matthew Frankel, Rifaat Safadi","doi":"10.1007/s40264-024-01436-2","DOIUrl":"10.1007/s40264-024-01436-2","url":null,"abstract":"<p><strong>Background: </strong>Overexpression of C-C motif chemokine ligand 24 (CCL24) is associated with inflammatory and fibrotic diseases, including primary sclerosing cholangitis (PSC), systemic sclerosis, metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). CM-101 is a humanized monoclonal antibody that neutralizes CCL24 to attenuate inflammation and fibrosis in preclinical models. Here we report the results from two Phase 1a studies investigating the safety and tolerability of intravenous (IV) and subcutaneous (SC) CM-101 in healthy participants, and in one Phase 1b study of IV and SC CM-101 in patients with MASLD without evidence of MASH.</p><p><strong>Methods: </strong>In each dose group (0.75 mg/kg, 2.5 mg/kg, 5.0 mg/kg, and 10.0 mg/kg) of the single-center, double-blind, placebo-controlled Phase 1a IV study, healthy volunteers were randomized 3:1 to receive a single IV infusion of CM-101 or placebo. In another Phase 1a, single-center, double-blind placebo-controlled study, healthy volunteers were randomized 3:1 to receive a single SC injection of CM-101 5.0 mg/kg or placebo. In the multicenter, double-blind, placebo-controlled Phase 1b MASLD study, patients with MASLD without evidence of MASH were randomized 3:1 to receive the following: cohort 1, IV CM-101 2.5 mg/kg or placebo, and cohort 2, SC CM-101 5.0 mg/kg or placebo every three weeks for 12 weeks. The primary endpoints (for all these studies) were safety, tolerability, and serum pharmacokinetic parameters of CM-101.</p><p><strong>Results: </strong>In each study, adverse events were rare and mild to moderate. The CM-101 pharmacokinetics profile was typical of a monoclonal antibody, with a terminal half-life of approximately 19 days when given IV and approximately 17 days when given as SC injection. In patients with MASLD without evidence of MASH, CM-101 was associated with decreased serum levels of inflammatory, fibrotic, and collagen turnover biomarkers.</p><p><strong>Conclusions: </strong>In healthy volunteers and patients with MASLD without evidence of MASH, IV and SC CM-101 was well tolerated at doses ranging from 0.75 mg/kg to10.0 mg/kg and engaged its target (i.e., CCL24), indicating therapeutic potential in treating inflammatory and fibrotic diseases.</p><p><strong>Clinical trial retrospectively registration: </strong>NCT06025851, NCT06037577, and NCT06044467. Date of registration: September 2023.</p>","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":"869-881"},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11324678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141185543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Can We Ask ChatGPT About Drug Safety? Appropriateness of ChatGPT Responses to Questions About Drug Use and Adverse Reactions Received by Pharmacovigilance Centers.","authors":"Antoine Pariente, Francesco Salvo, Virginie Bres, Jean-Luc Faillie","doi":"10.1007/s40264-024-01437-1","DOIUrl":"10.1007/s40264-024-01437-1","url":null,"abstract":"","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":"921-923"},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140876141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Post-Conceptional Exposure to Clomiphene Citrate and Congenital Malformations: A Cohort Study.","authors":"Rebeccah Nehard, Catherine Vauzelle, Delphine Beghin, Mathilde Latour, Elisabeth Elefant, Bénédicte Coulm, Benoît Marin","doi":"10.1007/s40264-024-01438-0","DOIUrl":"10.1007/s40264-024-01438-0","url":null,"abstract":"<p><strong>Background: </strong>Clomiphene citrate is an ovulation inductor for which inadvertent post-conceptional exposures may occur in early pregnancy. In preclinical studies, post-conceptional exposures showed a teratogenic effect in different species. In humans, to date, little is known about the outcomes of inadvertently post-conceptionally exposed pregnancies.</p><p><strong>Objectives: </strong>The objectives of our study were to assess the association between post-conceptional exposures to clomiphene citrate and major and minor congenital malformations in the offspring.</p><p><strong>Methods: </strong>A retrospective cohort study of prospectively ascertained cases was undertaken, based on clinical data from the Centre de Référence sur les Agents Tératogènes (CRAT), Paris, France. Women with post-conceptional exposure to clomiphene citrate (n = 309), and unexposed pregnant women (n = 1236, 1:4 ratio) with prospectively collected data, known pregnancy outcome and delivery date prior to 01/02/2022, were matched by calendar year. An adjudication committee classified major and minor congenital malformations according to the EUROCAT (European Registration of Congenital Anomalies and Twins) classification.</p><p><strong>Results: </strong>Among post-conceptional exposed women, no increased risk of major malformation was found (crude relative risk = 0.64, 95% confidence interval 0.19-2.15) as compared to unexposed women. Three major and ten minor congenital malformations were reported in the exposed group. An increased risk of minor malformations was found (crude relative risk = 4.05, 95% confidence interval 1.70-9.64) although there was no specific clinical pattern.</p><p><strong>Conclusions: </strong>Post-conceptional exposure to clomiphene citrate was not associated with an increased risk of major congenital malformations. Given potential confounding and information biases, the results about minor malformations should be interpreted with caution as no specific clinical pattern was identified.</p>","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":"883-894"},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140911082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Key Opinion Leaders' Interviews to Inform the Future of Benefit-Risk Planning in the Medical Total Product Life Cycle of Global Pharmaceutical and Medical Device Organizations.","authors":"Arianna Simonetti, Susan Colilla, Brian Edwards, Jürgen Kübler, Leila Lackey, Lisa Rodriguez, Susan Talbot, Hong Yang, William Wang, Danae Williams, James Matthew Higginson","doi":"10.1007/s40264-024-01442-4","DOIUrl":"10.1007/s40264-024-01442-4","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objectives: &lt;/strong&gt;Key opinion leader (KOL) interviews were conducted by the Benefit-Risk Assessment Planning (BRAP) Taskforce to seek expert opinion mainly from industry and regulatory bodies, about the current status and future direction of benefit-risk assessment (BRA) planning in the lifecycle of medical product development. The findings from these interviews are intended to help communication concerning planning for BRA between industry and regulators and shape future guidance.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Key opinion leader interviews consisted of 5 questions related to BRA planning, which were administered to volunteers (mainly clinicians and statisticians) within a pool of experienced pharmaceutical and medical device professionals representing academia, industry, regulatory agencies and a patient group. The interviewees' responses to the 5 questions were summarized. To analyze the qualitative data, a Coding System was developed to label themes arising from the interviews. The key findings from the interviews were summarized into a Master Template. A quantitative analysis based on descriptive statistics was also conducted.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Of the 27 interviewees, there were 11 professionals from regulatory agencies, 11 from industry, 4 from academia and 1 from a patient advocacy group. Key findings based on the comments provided by 48% of the interviewees indicated the need of incorporating BRA into other (e.g., existing) processes with the importance of alignment between processes being stressed in the comments provided by 59% of the interviewees. Commencing BRA early in the product lifecycle was emphasized in comments provided by 44% of the interviewees. Among other needs identified were an appropriate contextualization of benefits and risks (based on comments provided by 41% of interviewees) through adoption of an integrated approach with structured support by regulatory agencies and a need for understanding the audience with better communication of benefit-risk (BR) among all stakeholders (based on comments provided by 44% of the interviewees). Almost all comments provided by interviewees (96%) highlighted the importance of utilizing patient experience/preference to guide new product development and BRA. Comments provided by 74% of the interviewees expressed the need to understand patient tolerance for risk and trade-offs, with a majority (78%) of interviewees highlighting how to gather information, and 59% stressing the need for the selection and development of appropriate methodologies as important considerations for enhancing the quality and relevance of the data collected from patients.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Interviewees indicated that BRA should commence early in the medical product development and inform decision-making throughout the product lifecycle. Better planning and integration of BRA into existing processes within industry would be valuable. The importance of in","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":"853-868"},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11324710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141185624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proceedings of the Canadian Medication Appropriateness and Deprescribing Network's 2023 National Meeting.","authors":"Tiphaine Pierson, Verna Arcand, Barbara Farrell, Camille L Gagnon, Larry Leung, Lisa M McCarthy, Andrea L Murphy, Nav Persaud, Lalitha Raman-Wilms, James L Silvius, Michael A Steinman, Cara Tannenbaum, Wade Thompson, Johanna Trimble, Cheryl A Sadowski, Emily G McDonald","doi":"10.1007/s40264-024-01444-2","DOIUrl":"10.1007/s40264-024-01444-2","url":null,"abstract":"","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":"829-839"},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11324714/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141330594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bridging the Evidence Gap: Sotrovimab Use in Pregnancy and the Need for Comprehensive Drug Safety Data.","authors":"Ursula Winterfeld","doi":"10.1007/s40264-024-01457-x","DOIUrl":"10.1007/s40264-024-01457-x","url":null,"abstract":"","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":"841-842"},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141320735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trends in Use and Evidence of Adherence to Risk Evaluation and Mitigation Strategy Pregnancy Testing Requirements for Thalidomide, Lenalidomide, and Pomalidomide in the USA, 2000-2020.","authors":"Mufaddal Mahesri, Ameet Sarpatwari, Krista F Huybrechts, Joyce Lii, Su Been Lee, Gita A Toyserkani, Cynthia LaCivita, Esther H Zhou, Gerald J Dal Pan, Aaron S Kesselheim, Katsiaryna Bykov","doi":"10.1007/s40264-024-01443-3","DOIUrl":"10.1007/s40264-024-01443-3","url":null,"abstract":"<p><strong>Introduction: </strong>Lenalidomide, pomalidomide, and thalidomide are effective treatments for multiple myeloma but are teratogenic. To mitigate this risk, the US Food and Drug Administration (FDA) required risk evaluation and mitigation strategy (REMS) programs for these drugs, which include pregnancy testing among women of childbearing potential-twice before initiation, weekly in the first month on treatment, and every 2-4 weeks thereafter.</p><p><strong>Objective: </strong>We evaluated dispensing trends of lenalidomide, pomalidomide, and thalidomide and assessed adherence to REMS pregnancy testing requirements among at-risk patients taking these drugs.</p><p><strong>Methods: </strong>Using three US health insurance claims databases (Optum Clinformatics® [2004-2020], Merative Marketscan [2003-2019], and Medicaid [2000-2018]), we assessed monthly use of the drugs, patient characteristics and treatment persistence among drug initiators, and claims-based evidence for adherence to pregnancy testing requirements among initiators with child-bearing potential.</p><p><strong>Results: </strong>Lenalidomide was the most prescribed agent following its approval in 2006 and through the end of the study period. A total of 48,311 lenalidomide (mean age = 59 years [standard deviation (SD) = 16]), 17,550 thalidomide (mean age = 65 years [SD = 12]), and 6560 pomalidomide initiators (mean age = 65 years [SD = 11]) were identified; 45% of initiators of each drug were women. Among initiators under follow-up on day 90, 70% were still on therapy. Initiators of childbearing potential comprised 3% (N = 1,920) of all initiators; among this cohort, 12% had evidence in claims data of two pregnancy tests before initiation, and 9% with at least 33 days of follow-up of four tests during the first month of treatment. By contrast, 52% who received a refill had claims-based evidence of a pregnancy test within 7 days of dispensing.</p><p><strong>Conclusion: </strong>Although most patients who initiated lenalidomide, pomalidomide, and thalidomide were not of child-bearing potential, further investigation into actual non-adherence to pregnancy testing is needed.</p>","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":"909-919"},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11324373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140956699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author's Reply to Avó-Baião et al.'s Comment on \"Maternal and Early-Life Exposure to Antibiotics and the Risk of Autism and Attention-Deficit Hyperactivity Disorder in Childhood: A Swedish Population-Based Cohort Study\".","authors":"Nele Brusselaers","doi":"10.1007/s40264-024-01463-z","DOIUrl":"10.1007/s40264-024-01463-z","url":null,"abstract":"","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":"823-825"},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}