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In daily practice, we believe symptoms of arthralgia must be tracked with systematic in-depth patient interview in dupilumab-treated patients. Women were over-represented in arthralgia, joint stiffness and joint swelling, with a sex ratio ranging from 0-32 to 0-62, and men were slightly more represented in enthesopathy, with a sex ratio of 1-25, but the difference was not statistically significant. Arthralgia and enthesopathy reports were defined with the preferred terms of the Medical Dictionary for Regulatory Activities, version 22.1: "arthralgia", "enthesopathy", "joint stiffness" and "joint swelling". [Extracted from the article]

What is known and objective A randomized phase III study was designed to assess the efficacy and safety of second-line platinum-based chemotherapy with or without erlotinib in non-small cell lung cancer ( NSCLC) with EGFR-activating mutation after secondary resistance to EGFR- TKIs (epidermal growth factor receptor tyrosine kinase inhibitors). Case summary We report herein two of the first three patients who presented with major gastrointestinal toxicities in the experimental arm of the trial. What is new and conclusion Pending further data, it would seem safer to administer EGFR- TKIs and chemotherapy sequentially rather than concomitantly. [ABSTRACT FROM AUTHOR]

In daily practice, we believe symptoms of arthralgia must be tracked with systematic in-depth patient interview in dupilumab-treated patients. Women were over-represented in arthralgia, joint stiffness and joint swelling, with a sex ratio ranging from 0-32 to 0-62, and men were slightly more represented in enthesopathy, with a sex ratio of 1-25, but the difference was not statistically significant. Arthralgia and enthesopathy reports were defined with the preferred terms of the Medical Dictionary for Regulatory Activities, version 22.1: "arthralgia", "enthesopathy", "joint stiffness" and "joint swelling". [Extracted from the article]

Purpose: While statins and antiplatelet therapies are largely prescribed together worldwide, limited information is available on the safety of their association regarding rhabdomyolysis occurrence. We aimed to assess the reporting of rhabdomyolysis in patients treated with a combination of statin and antiplatelet therapy, compared to statin alone., Methods: We used the World Health Organization pharmacovigilance database (VigiBase®) to compare the rhabdomyolysis reporting between statin (atorvastatin, fluvastatin, pravastatin, rosuvastatin, and simvastatin) plus antiplatelet therapy (acetylsalicylic acid, clopidogrel, prasugrel and ticagrelor) groups versus statin alone groups, for each statin and antiplatelet therapy. Study setting was restricted to patients aged 45 or older, including reports up until 1 st September, 2021. We computed reporting Odds-Ratio (ROR) and their 95% confidence interval (CI) to quantify the disproportionality between groups, adjusted on age and sex., Results: Among the 11,431,708 reports of adverse reactions, we extracted 9,489 cases of rhabdomyolysis in patients treated with statins, of whom 2,464 (26%) were also treated with antiplatelet therapy. The reporting of rhabdomyolysis was increased when ticagrelor was associated with atorvastatin (ROR 1.30 [1.02-1.65]) or rosuvastatin (ROR 1.90 [1.42-2.54]) compared to the respective statin alone but did not change when aspirin, clopidogrel or prasugrel were considered., Conclusion: Rhabdomyolysis reporting was increased when ticagrelor -but not other antiplatelet agents- was notified with the most prescribed statins in practice. This finding needs to be considered by physicians especially in high-risk patients., Competing Interests: Declarations. Competing Interests: Dr Roule has received research grants from Medtronic; speaker fees from Bristol-Myers Squibb, AstraZeneca. Dr Beygui reports receiving consulting and lecture from Astrazeneca, Bristol-myers Squibb, medtronic, biosensors, Boston scientific Institutionnal research grants: Medtronic, Biosensors, Acist, Boston scientific. Other authors have nothing to report., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Fall is one of the five main causes of drug-related hospital admissions (DRA) in France. A standardized chart review method, to identify DRA adapted to elderly patients, has recently been developed by Thevelin et al. Our first aim was to assess the reliability of this method for detecting DRA for falls in elderly subjects. Our second aim was to assess the feasibility of this method and to evaluate its reliability for assessing causality, the contribution of DRA to hospitalization, and the avoidability of DRAs in elderly patients hospitalized for a medication-related fall. A retrospective observational study was conducted on 16 patient cases admitted to the hospital for falls in May 2022, in the geriatric department of a French university hospital. Six healthcare professionals (pharmacists, pharmacologists, and geriatricians) assessed a method for detecting DRA individually and then in multidisciplinary pairs of raters. Inter-rater agreement (individually and in pairs) was assessed for DRA detection, causality, avoidability, and contribution of the DRA to hospitalization. A κ > 0,4 was considered a satisfactory threshold for agreement. The mean age was 86 years. When the assessment was done individually, detection of DRA-related hospitalizations (κ = 0,46; p < ,001), and DRA contribution to hospitalization (κ = 0,50; p < ,001) were moderately concordant. The causality assessment (κ = 0,09; p = 0,24) did not agree, and the avoidability assessment (κ = 0,63; p < ,001) agreed substantially. When the evaluation was done in pairs, detection of DRA-related hospitalizations (κ = 0,47; p < ,001) was moderately concordant between pairs. Avoidability assessment (κ = 0,79; p < ,001) concurred substantially. The assessment of causality (κ = 0,29; p = 0,01) and DRA contribution to hospitalization (κ = 0,38; p < .001) agreed fairly well. This study validated, individually and in pairs, the reliability of the method to identify DRA in the context of falls. This method will be of great use in research and epidemiological studies.

Introduction: Clozapine is primarily reserved for treatment-resistant schizophrenia due to safety concerns associated with its use. Infections have been reported with clozapine, which may lead to elevated serum levels of the drug. However, the existing literature on this topic is limited. Therefore, we conducted a study using VigiBase ® to investigate the potential over-reporting of infections associated with clozapine, to explore the presence of dose-dependency, and to investigate the underlying mechanism. Methods: Disproportionality analyses were performed using VigiBase to assess the association between clozapine and all types of infections, the association between clozapine-associated infections and neutropenia, the association between clozapine-associated infections and agranulocytosis, the dose-effect relationship between clozapine and infections, and the interaction between clozapine and the main strong CYP450 inhibitors using reports carried out until 11 April 2023. Results: A statistically significant signal of infections was observed with clozapine, as indicated by an information component of 0.43 [95% CI: (0.41-0.45)]. The most commonly reported infections were respiratory and gastrointestinal in nature. Neutropenia showed weaker association with clozapine-associated reports of infections compared to other clozapine-associated reports [X2 (1, N = 204,073) = 454; p < 0.005], while agranulocytosis demonstrated a stronger association with clozapine-associated reports of infections [X2 (1, N = 204,073) = 56; p < 0.005]. No evidence of dose-dependency was observed. Among the 17 tested CYP inhibitors, significant drug-drug interactions were found with clarithromycin, metronidazole, valproic acid, lansoprazole, omeprazole, amiodarone, and esomeprazole. Discussion: Our study revealed a significant safety signal between clozapine use and infections, predominantly respiratory and gastrointestinal infections. The co-administration of clozapine with valproic acid or proton pump inhibitors may potentially contribute to an increased risk of infection. Further vigilance is warranted in clinical practice, and consideration of therapeutic drug monitoring of clozapine in cases involving concomitant use of these drugs or in the presence of infections may be beneficial., 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 Chrétien, Brazo, Da Silva, Sassier, Dolladille, Lelong-Boulouard, Alexandre and Fedrizzi.)

Background: Hypertension (HTN) is a well-established and a major risk factor for cardiovascular disease. Lifestyle behaviours for its prevention and control are recommended within worldwide guidelines. Their relationship with HTN need more investigations., Aim: We aimed to investigate the associations between lifestyle, anthropometric and biological measurements and BP in the Gubbio residential study., Methods: Cross-sectional analyses were performed using data from Gubbio study. Information concerning lifestyle factors were collected using self-reported questionnaire and were further completed with a baseline clinical examination and blood exams. Three BP measurements were performed following a standard protocol. Age-adjusted and multivariable logistic regressions were used to examine the relationships between lifestyle parameters and HTN separately for each sex. We used heterogeneity test to observe sex differences., Results: There were 3,183 persons included (48% men, 43 ± 17 years old). Mean systolic BP (SBP) was 119 ± 16 mmHg and 10.6% were hypertensives. Age [OR: 129.70 (95%CI: 18.57-905.79) in women and OR: 8.37 (95%CI: 4.01-17.48) ( p  < 0.0001) in men] and BMI [OR: 2.14 (95%CI: 1.32-3.46) ( p  = 0.006) in women and OR: 1.81 (95%CI: 1.05-3.12), p  = 0.03 in men], were positively associated with SBP in both sexes. Serum uric acid [OR: 3.86 (95%CI: 2.03-7.26), p  = 0.04] was positively associated with HTN in women while fasting blood glucose [OR: 3.04 (95%CI: 1.55-5.97), p  < 0.001] were associated to HTN only in men., Discussion: In addition to age, BMI is associated with HTN in both sexes while sex differences were observed in the associations between serum uric acid, fasting blood glucose and HTN.

Background: The prescription of antidepressant drugs during pregnancy has been steadily increasing for several decades. Meta-analyses (MAs), which increase the statistical power and precision of results, have gained interest for assessing the safety of antidepressant drugs during pregnancy., Objective: We aimed to provide a meta-review of MAs assessing the benefits and risks of antidepressant drug use during pregnancy., Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a literature search on PubMed and Web of Science databases was conducted on 25 October, 2021, on MAs assessing the association between antidepressant drug use during pregnancy and health outcomes for the pregnant women, embryo, fetus, newborn, and developing child. Study selection and data extraction were carried out independently and in duplicate by two authors. The methodological quality of included studies was evaluated with the AMSTAR-2 tool. Overlap among MAs was assessed by calculating the corrected covered area. Data were presented in a narrative synthesis, using four levels of evidence., Results: Fifty-one MAs were included, all but one assessing risks. These provided evidence for a significant increase in the risks for major congenital malformations (selective serotonin reuptake inhibitors, paroxetine, fluoxetine, no evidence for sertraline; eight MAs), congenital heart defects (paroxetine, fluoxetine, sertraline; 11 MAs), preterm birth (eight MAs), neonatal adaptation symptoms (eight MAs), and persistent pulmonary hypertension of the newborn (three MAs). There was limited evidence (only one MA for each outcome) for a significant increase in the risks for postpartum hemorrhage, and with a high risk of bias, for stillbirth, impaired motor development, and intellectual disability. There was inconclusive evidence, i.e., discrepant results, for an increase in the risks for spontaneous abortion, small for gestational age and low birthweight, respiratory distress, convulsions, feeding problems, and for a subsequent risk for autism with an early antidepressant drug exposure. Finally, MAs provided no evidence for an increase in the risks for gestational hypertension, preeclampsia, and for a subsequent risk for attention-deficit/hyperactivity disorder. Only one MA assessed benefits, providing limited evidence for preventing relapse in severe or recurrent depression. Effect sizes were small, except for neonatal symptoms (small to large). Results were based on MAs in which overall methodological quality was low (AMSTAR-2 score = 54.8% ± 12.9%, [19-81%]), with a high risk of bias, notably indication bias. The corrected covered area was 3.27%, which corresponds to a slight overlap., Conclusions: This meta-review has implications for clinical practice and future research. First, these results suggest that antidepressant drugs should be used as a second-line treatment during pregnancy (after first-line psychotherapy, according to the guidelines). The risk of major congenital malformations could be prevented by observing guidelines that discourage the use of paroxetine and fluoxetine. Second, to decrease heterogeneity and bias, future MAs should adjust for maternal psychiatric disorders and antidepressant drug dosage, and perform analyses by timing of exposure., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

To investigate whether marital status is associated to long-term major fatal and non-fatal cardiovascular events in men and women from the Gubbio Population Study. The incidence of cardiovascular disease (CVD), including stroke and coronary heart disease (CHD) and CVD death together with all-cause mortality were analyzed. The analysis included 2832 persons (44% men, 54 ± 11 years old). Marital status was defined at entry as married (married or living conjugally) versus unmarried subjects (widowed, separated, divorced or single). Married and unmarried subjects did not differ concerning socio-demographic, anthropometric and biological variables at baseline. Over 191 months median follow-up, the incidence of CHD was lower among married versus unmarried women [HR: 0.63 (95% CI 0.41-0.96)] only; the same was true for CHD mortality [HR: 0.43 (95% CI 0.22-0.84)] and all-cause mortality [HR: 0.75 (95% CI 0.59-0.96)] independently of traditional risk factors (age, SBP, total and HDL cholesterol, cigarette smoke and BMI). In men, marital status was not associated to any of the investigated outcomes. In primary care, marital status should be investigated as it can be associated with long-term CHD and all-cause incidence and mortality risks among women., (© 2023. The Author(s).)

Aims: Due to their central mechanism of action, antiseizure medications (ASMs) could lead to adverse effects likely to impair driving skills. Their extended use to neuropsychiatric disorders makes it a class of drugs to monitor for their road traffic accidental (RTA) potential. We aimed to assess the reporting association between ASMs and RTAs using the World Health Organization pharmacovigilance database (VigiBase)., Methods: We performed a disproportionality analysis to compute adjusted reporting odds ratios to evaluate the strength of reporting association between ASMs and RTAs. A univariate analysis using the reporting odds-ratio was used to assess drug-drug interactions between ASMs and RTAs., Results: There were 1 341 509 reports associated with at least 1 ASM in VigiBase of whom 2.91‰ were RTAs reports. Eight ASMs were associated with higher reporting of RTAs compared to others (ranging from 1.35 [95% confidence interval 1.11-1.64] for lamotrigine to 4.36 [95% confidence interval 3.56-5.32] for cannabis). Eight significant drug-drug interactions were found between ASMs and the onset of RTA, mainly involving CYP450 induction., Conclusion: A significant safety signal between RTAs and some ASMs was identified. Association of several ASMs might further increase the occurrence of RTA. ASMs prescription in patients with identified risk factors of RTA should be considered with caution. Study number: ClinicalTrials.gov, NCT04480996., (© 2022 British Pharmacological Society.)

Background: Transverse myelitis (TM) has recently been associated by health authorities with Ad26.COV2.S (Janssen/Johnson & Johnson), one of the 5 US Food and Drug Administration (FDA) or European Medicines Agency (EMA) labeled severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines. It is unknown whether a similar association exists for the other FDA or EMA labeled SARS-CoV-2 vaccines (BNT162b2 [Pfizer/BioNTech], mRNA-1273 [Moderna], ChAdOx1nCov-19 [Oxford-AstraZeneca], and NVX-CoV2373 [Novavax]). This study aimed to evaluate the association between SARS-CoV-2 vaccine class and TM., Methods: This observational, cross-sectional, pharmacovigilance cohort study examined individual case safety reports from VigiBase, the World Health Organization's pharmacovigilance database. We first conducted a disproportionality analysis with the information component (IC) using the reports of TM that occurred within 28 days following exposure to the FDA or EMA labeled SARS-CoV-2 vaccines, from December 1, 2020 (first adverse event related to a SARS-CoV-2 vaccine) to March 27, 2022. Second, we analyzed the clinical features of SARS-CoV-2 vaccine-associated TM cases reported in VigiBase., Results: TM was significantly associated both with the messenger ribonucleic acid (mRNA)-based (n = 364; IC 025  = 0.62) and vector-based (n = 136; IC 025  = 0.52) SARS-CoV-2 vaccines that are authorized by the FDA or the EMA., Conclusions: Findings from this observational, cross-sectional pharmacovigilance study showed that mRNA-based and vector-based FDA/EMA labeled SARS-CoV-2 vaccines can be associated with TM. However, because TM remains a rare event, with a previously reported rate of 0.28 cases per 1 million vaccine doses, the risk-benefit ratio in favor of vaccination against SARS-CoV-2 virus remains unchallenged. Rather, this study suggests that clinicians should consider the diagnosis of TM in patients presenting with early signs of spinal cord dysfunction after SARS-CoV-2 vaccination. ANN NEUROL 2022;92:1080-1089., (© 2022 American Neurological Association.)

The association between COVID-19 vaccines and vasovagal malaise (VVM) has recently been reported in the literature. Our study aimed to describe COVID-19 vaccines associated VVM cases and to identify risk factors of COVID-19 vaccines associated VVM. To this end, we performed a descriptive study of VVM reports associated with COVID-19 vaccines from two French mass COVID-19 vaccination centers. We also extracted reports of VVM associated with all-COVID-19 vaccines in VigiBase®, the World Health Organization (WHO) pharmacovigilance database to analyze demographic data. In the two French mass vaccination center database, 408 entries reported VVM after the standard administration of tozinameran - Pfizer® (1.63/1,000 vaccinated persons). Of these cases, 213 (52.2%) occurred in women, and 193 (47.3%) occurred in the 18-29 year-old (yo) age group. In 232 cases (56.8%), patients had a history of anxiety related to needles or medical visits, 213 (52.2%) reported a fear of COVID-19 vaccination in particular, and 233 (57.1%) had a history of VVM. In VigiBase®, 336,291 notifications of COVID-19 vaccines associated with VVM were identified in the adult population during the period of analysis. The most reported age class was 18-44 years (52.4%), and women represented 71.7% of the reports. Reporting widely differed depending on the country. This study, performed in real-life conditions, highlights that VVM is associated with all-COVID-19 vaccines. Young age and history of anxiety related in young adults could be a triggering factor of vaccines-associated VVM. Further studies are needed to confirm our results.

Associations between fetal exposure to antidepressants and neonatal hypotonia were studied using VigiBase and the French PharmacoVigilance Database. We identified significant associations between neonatal hypotonia and clomipramine, venlafaxine, and imipramine. Reports from the French database implicated prolonged fetal exposure. Neonatal hypotonia may be associated with in utero exposure to antidepressants., (Copyright © 2022 Elsevier Inc. All rights reserved.)