Dr Basile Chrétien

Clindamycin is a common β-lactam substitute for surgical prophylaxis. Whether peri-operative disturbances in consciousness are disproportionately reported with clindamycin in global pharmacovigilance data remains unclear. Using WHO VigiBase (up to January 27, 2025), we performed a de-duplicated case/non-case disproportionality analysis of Individual Case Safety Reports (ICSRs) co-reporting ≥ 1 anesthetic or sedative. Cases were defined by the MedDRA HLT "Disturbances in consciousness NEC." We estimated RORs and aRORs for clindamycin versus cefazolin and other peri-operative comparators (metronidazole, vancomycin, ampicillin), adjusting for age group, sex, and co-reported medications. K-modes clustering characterized co-reporting patterns among clindamycin reports. Sensitivity analyses excluded sepsis-related terms/vasopressors and applied a narrower outcome definition excluding syncope/presyncope. Of 3623 clindamycin ICSRs, 159 (4.4%) included a consciousness-disturbance term. Versus cefazolin, clindamycin generated a disproportionality signal (ROR 2.59, 95% CI 2.07-3.24; aROR 2.23, 95% CI 1.70-2.91), with similar estimates after excluding sepsis/vasopressors (aROR 2.21, 95% CI 1.64-2.98) and syncope/presyncope (aROR 2.11, 95% CI 1.60-2.79). Clustering suggested co-reporting patterns consistent with lidocaine-enriched older-age reports, sedative/anesthetic-enriched younger-age reports, and opioid-enriched reports with high-acuity markers. In VigiBase, disproportionality analyses identified a reporting signal for disturbances in consciousness with clindamycin relative to cefazolin in surgical settings. Because spontaneous reports lack exposure denominators and are susceptible to residual confounding, these findings are hypothesis-generating and do not estimate incidence or comparative risk. Evaluation in data sources with denominators and prospective clinical characterization is warranted.

Peptide receptor radionuclide therapy with [177Lu]Lu-DOTATATE is an effective treatment for metastatic or inoperable neuroendocrine tumors. While clinical trials have demonstrated its efficacy and safety in a limited number of selected patients, real-world data on [¹⁷⁷Lu]Lu-DOTATATE remain scarce. This study aims to investigate the safety profile of [¹⁷⁷Lu]Lu-DOTATATE in a real-world setting using VigiBase, the World Health Organization’s global pharmacovigilance database. A retrospective disproportionality analysis was conducted on individual case safety reports from VigiBase using a deduplicated dataset. Signal detection was performed using the information component (IC) with a 95% credibility interval (IC₀₂₅) to assess the association between each adverse drug reaction (ADR) and [¹⁷⁷Lu]Lu-DOTATATE. A total of 3,984 reports were analyzed. Associations were identified for hematologic malignancies, hematological disorders, hepatic disorders, renal toxicity, and infections (IC₀₂₅ = 2.48, 2.15, 1.43, 1.16, and 0.91, respectively). Notably, certain gastrointestinal disorders initially significant saw their IC₀₂₅ values turn negative over time, while other ADR categories remained consistently positive. Key overlaps between ADR categories were observed, supported by coherent time-to-onset data and positive [¹⁷⁷Lu]Lu-DOTATATE dechallenge. This VigiBase analysis reveals essential information on ADR associated with [177Lu]Lu-DOTATATE providing a complete safety profile with real-life data enabling better patient management.

OBJECTIVES: Growing evidence exists about the pivotal role of immune mechanisms in the physiopathology of atrial fibrillation (AF). Drugs that modulate the immune system (immunomodulators) may contribute to the development of AF. We aimed to identify immunomodulators that are associated with AF to better define their safety profile, and elucidating their mechanisms of action could yield novel insights into AF's immune physiopathology. DESIGN: A descriptive and disproportionality analysis of claims data. SETTINGS: World pharmacovigilance database VigiBase until 1 March 2025. PRIMARY AND SECONDARY OUCTOMES: First, we ascertained the association of immunomodulators with AF over-reporting with a disproportionality analysis evaluating the multivariable-adjusted reporting odds ratio (aROR) for AF reporting performed for 141 immunomodulators in VigiBase. Then, a literature review was done to explore the underlying mechanisms of AF through immunomodulator mechanisms. RESULTS: A total of 6 148 556 reports encompassing at least one of the 141 immunomodulators were identified in Vigibase. Our primary analysis revealed 20 immunomodulators associated with AF over-reporting. The three immunomodulators with the greatest signal were: recombinant interleukin-11 with an aROR=20.91 (99.96% CI 12.08 to 36.17), efgartigimod alfa with an aROR=6.75 (99.96% CI 3.96 to 11.52) and recombinant interleukin-2 with an aROR=6.15 (99.96% CI 3.62 to 10.45). A derivative literature review posited a hypothetical immune 'vicious circle' promoting AF, involving T helper cells, macrophages and natural killer cells which could lead to electrophysiologic and histologic atrial remodelling. CONCLUSIONS: Twenty Food and Drug Administration (FDA)-labelled immunomodulators are associated with AF overreporting in Vigibase with a substantial signal on recombinant IL-11. These data contribute substantively to the prevailing understanding of the safety profile of these immunomodulators. Moreover, these findings support a multidirectional interaction between the immune system and AF development and might lead to considering future therapeutic targets. TRIAL REGISTRATION NUMBER: NCT06095791.

BACKGROUND: Pharmacology education faces challenges due to evolving student learning behaviors. This study examined the feasibility of identifying which student-level characteristics, academic background and learning activities were associated with performance at the pharmacology exam using routinely-collected data. METHODS: In a prospective cohort study of second-year medical students at Caen Normandie University (2024-2025), we analyzed in-person lecture, online resource, and peer tutoring mock exam attendance, as well as use of student-written lecture support, and pharmacology exam outcomes. The primary outcome was final pharmacology exam score (over 20points), according to pedagogical methods, estimated through multivariate linear regression. RESULTS: year medical students, with two thirds of women, high prior academic achievement, and a median age of 19. In the univariate analysis, higher in-person lecture attendance was significantly associated with a higher score at the pharmacology exam (+ 0.41points for each additional 10h of attendance, 95%Confidence Interval (CI): + 0.05 to + 0.77). Similarly, the number of online resources downloaded showed a positive association in univariate analysis (+ 0.53points for each additional 10downloads, 95%CI: + 0.09 to + 0.97). In-person lecture attendance remained significant in the multivariate model (+ 0.46points, 95%CI:0.03-0.88). Peer tutoring exam attendance and student-written lecture support use were not associated with a significant change in exam score. In-person lecture attendance exhibited a U-shaped relationship with exam performance: initial declines (up to 10h) preceded gradual improvement, plateauing at 25-30 h (spline regression, p < 0.05). Prior academic achievement (baccalaureate distinction, rapid first-year completion) and curriculum (first-year major being health-science) were significantly associated with higher exam score. CONCLUSIONS: This pilot study demonstrates the feasibility and value of quantitatively evaluating pharmacology education among French medical students. Academic background and pedagogical methods seem to influence pharmacology exam success. Broader replication, and long-term follow-up are needed to confirm these insights and identify determinants of student success more robustly.

IMPORTANCE: Sirolimus is increasingly used for complex vascular and lymphatic anomalies in neonates and infants. While dyslipidemia is a known adverse effect in adults, the incidence, timing, and severity in this population remain poorly characterized. OBJECTIVE: The aim of this study was to evaluate the reporting odds and characteristics of sirolimus-associated dyslipidemia in neonates and infants compared with older populations. DESIGN, SETTING, AND PARTICIPANTS: This study combined a single-center retrospective cohort study and global pharmacovigilance analysis. The clinical cohort included neonates and infants treated with sirolimus at Nagoya University Hospital (October 2018-September 2025). The pharmacovigilance analysis utilized VigiBase (up to September 1, 2025) to perform age-stratified disproportionality analyses. MAIN OUTCOMES AND MEASURES: In the clinical cohort, lipid profiles (total cholesterol, LDL-C, triglycerides) were assessed pre- and post-treatment. In VigiBase, adjusted reporting odds ratios (aRORs) for dyslipidemia and time-to-onset (TTO) were estimated across age groups, adjusting for sex, region, and concomitant medications. RESULTS: The cohort included 10 patients (median age, 44.5 days). Post-initiation, 100% developed hypertriglyceridemia and 90% developed hypercholesterolemia. In VigiBase (17,802 sirolimus-related reports), the dyslipidemia reporting signal was highest in infants (28 days-23 months), with an aROR of 147.08 (95% CI 79.67-271.54), substantially exceeding that in adults aged 18-45 years (aROR 2.31; 95% CI 1.75-3.06). Among infant reports with available TTO data, median TTO was 11.0 days (IQR 5.5-15.8), compared with 29.5 days in adults. CONCLUSIONS AND RELEVANCE: Neonates and infants showed a markedly stronger dyslipidemia reporting signal than older age groups, and lipid abnormalities were common in the clinical cohort. These findings support baseline lipid assessment and early monitoring after sirolimus initiation in very young patients, including within the first two weeks of therapy. The pharmacovigilance findings should be interpreted as hypothesis generating.

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating condition, with cerebral vasospasm and subsequent delayed cerebral ischemia being key contributors to poor neurological outcomes. In Japan, fasudil is the standard prophylactic agent used to mitigate vasospasm, though its efficacy in improving long-term functional outcomes remains uncertain. Clazosentan, a selective endothelin-A receptor antagonist, has demonstrated potential in reducing vasospasm-related morbidity in phase 3 trials. However, no randomized controlled trial directly comparing the effects of fasudil and clazosentan on functional independence exists in Japan. The primary objective of this study is to determine the superiority of clazosentan over fasudil in enhancing functional outcomes among patients with aSAH. The Subarachnoid Hemorrhage: Clazosentan vs. Fasudil for Vasospasm Prevention (SAVIOR) study is a multicenter, randomized, open-label, parallel-group superiority trial conducted across 21 high-volume stroke centers. Patients with aSAH secured within 48 h of onset will be randomized in a 1:1 ratio to receive either intravenous clazosentan or fasudil. The primary outcome is the proportion of patients achieving a favorable functional outcome (modified Rankin Scale 0-2 at 90 days post-onset). Secondary outcomes include modified Rankin Scale (mRS) score at discharge, incidence of cerebral vasospasm and vasospasm-related delayed cerebral ischemia, and safety profiles, with particular attention to fluid retention-related complications. This trial is the first to directly compare the efficacy and safety of clazosentan vs. fasudil. By selecting the local standard of care as the comparator, the study is designed to generate pragmatic, high-impact evidence that can inform clinical decision-making and potentially reshape treatment guidelines for aSAH management in Japan. It will provide the first high-quality data from a direct comparison of clazosentan and fasudil, in a nimodipine-free population-a clinical question not addressed by previous international trials.

BACKGROUND: Clazosentan reduces angiographic vasospasm after aneurysmal subarachnoid hemorrhage (aSAH), but functional benefit may vary across patients. We used causal machine learning to explore heterogeneity and derive an interpretable rule. METHODS: In a secondary analysis of the RECOVER dataset [multicenter retrospective cohort of aSAH treated by clipping or coiling within 48 h (N = 506)], we compared clazosentan-containing management (with or without fasudil) with fasudil-only prophylaxis. After applying inverse probability of treatment weighting for prespecified confounders [age, World Federation of Neurosurgical Societies (WFNS) grade, Fisher grade, and body mass index (BMI)], we used a causal forest to estimate conditional average treatment effects (CATEs) on favorable discharge outcome (modified Rankin Scale 0-2 at discharge). A policy tree summarized CATEs, and external validation was performed in an independent cohort (N = 181). RESULTS: ): patients with BMI ≤ 20.03 and WFNS ≤ 2 showed no clear estimated benefit (mean CATE - 0.058), whereas those with BMI > 20.03 or WFNS > 2 showed higher estimated benefit (CATE 0.24-0.25). In external validation, the same rule identified a subgroup with higher odds of favorable recovery with clazosentan; estimates in the low-benefit subgroup were imprecise (n = 27). CONCLUSIONS: In observational cohorts with limited overlap in treatment assignment, causal machine learning suggested heterogeneity in the estimated association of a clazosentan-containing strategy with discharge outcomes and produced a simple BMI/WFNS policy tree. These findings are hypothesis-generating and require prospective validation including safety endpoints and longer-term functional outcomes.

Depressive symptomatology is prevalent among oncology patients and may influence the perception of adverse drug reactions (ADRs) to anticancer drugs. Understanding this relationship is crucial for optimizing treatment strategies and improving ADR management. This pharmacovigilance study analyzed VigiBase® data from 1968 (year of its establishment) to 2024. Focusing on reports involving antineoplastic or immunomodulating agents, a case/non-case disproportionality analysis was conducted to assess the reporting and seriousness of ADRs in patients receiving antidepressants. Multivariable analyses were performed for all ADRs and the most frequently reported ADRs. Reporting Odds Ratios (RORs) were considered significant if the 95% credible interval lower bound exceeded 1. Among 8,804,863 reports, 428,102 involved patients receiving antidepressants. Antidepressant use was associated with a higher likelihood of serious ADRs reporting(58%vs45%; adjusted-ROR:1.78, 95%CI:1.76–1.79). Increased reporting was observed for most tested ADRs, including fatigue(ROR:2.19, 95%CI:2.13–2.25), pain(ROR:2.79, 95%CI:2.69–2.89), and headache(ROR:2.56, 95%CI:2.46–2.62). The timing of antidepressant initiation did not significantly impact ADR reporting. Antidepressant use in oncology patients is associated with increased ADR reporting and seriousness, emphasizing the need for heightened clinical vigilance. Effective management of depressive symptomatology may improve ADR perception, treatment adherence, and patient well-being. Prospective studies are required to confirm these findings and inform targeted interventions.

OBJECTIVES: The objective is to investigate the association between antidepressant drugs intake and falls reporting, as well as the potential mediators in-between, in older adults. METHODS: In VigiBase®, the World Health Organization's pharmacovigilance database, we performed a disproportionality analysis to probe the putative associations between each antidepressant drugs class (non-selective monoamine reuptake inhibitors [NSMRIs], selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], alpha-2-adrenergic receptor antagonists, and "other antidepressants") and reports of falls in people aged 65 and over (NCT05628467). The reporting odds ratios and their 95% confidence interval were derived from logistic regression models with adjustment for confounders. We studied the falls-inducing mechanisms (delirium, hyponatremia, hypotension) by using causal mediation analyses and by using a disproportionality analysis for the co-occurrence of falls and these events. RESULTS: Our main analysis included 86,200 cases of falls reporting in older adults (of which 57% were 75 and over). A significant association was found between falls and every antidepressant drugs class, except for NSMRIs. According to causal mediation analysis, a direct effect on the falls reports was shown for alpha-2-adrenergic receptor antagonists and for "other antidepressants". According to the co-reports analyses, all antidepressant drugs classes except SNRIs were associated with the co-event fall-delirium; SSRIs, alpha-2-adrenergic receptor antagonists, and "other antidepressants" with fall-hypotension; all antidepressant drugs classes except NSMRIs with fall-hyponatremia. CONCLUSIONS: In multivariate disproportionality analyses, all antidepressant drugs classes were associated with signals of disproportionate reporting of falls in older adults, except for NSMRIs. In mediation analyses, a direct effect on the falls reports was only found for alpha-2-adrenergic receptor antagonists. Single-mediators based models seem insufficient to explain the diversity of clinical settings resulting in falls. These findings underline the necessity of a comprehensive analysis of all clinical and pharmacological features in older falling adults treated with antidepressant drugs.

IMPORTANCE: The safety profile of a rechallenge with BRAF inhibitors (BRAFi) or a combination of BRAF and MEK inhibitors (MEKi) following an adverse drug reaction (ADR) remains largely unexplored. OBJECTIVE: To identify the reported recurrence rate of the same ADR after a BRAFi±MEKi targeted therapy (TT) rechallenge in patients with cancer and to identify factors associated with recurrence. DESIGN, SETTING, AND PARTICIPANTS: In this observational, pharmacovigilance study, ADR reports were sourced from VigiBase, the World Health Organization database. The inclusion criteria encompassed all BRAFi cases (with or without MEKi) through September 01, 2023, irrespective of the primary cancer diagnosis. MAIN OUTCOMES AND MEASURES: The primary outcome was the reported recurrence rate of the same initial ADR following TT rechallenge. Secondary outcomes measures included were identification of variables associated with recurrence among informative rechallenges, defined as those with known recurrence status. RESULTS: Out of 21,339 ADR cases linked to TT, 4771 (22.4%) reported a rechallenge, with 563 yielding informative data (11.8%). Recurrence of the initial ADR was reported in 223 cases, resulting in a reported recurrence rate of 39.6% (95% CI: 35.7-43.7). The highest recurrence rates in a rechallenge were observed for pyrexia (47%, 95% CI: 39-55), renal failure (46%, 95% CI: 32-60), and musculoskeletal disorders (44%, 95%CI: 33-56). There was no significant influence of factors such as TT regimen (either BRAFi monotherapy or any TT combination), age, sex, or the type of cancer on reported recurrence rate. CONCLUSIONS AND RELEVANCE: In real-world settings, approximately two-fifths of cases with notified TT rechallenges led to a reporting of recurrence of the same initial ADR. The primary determinant of reported recurrence seems to be the nature of the initial ADR rather than the TT regimen, or any other baseline patient characteristic.

BACKGROUND: Data regarding the diagnostic efficacy of radial endobronchial ultrasound (R-EBUS) findings obtained via transbronchial needle aspiration (TBNA)/biopsy (TBB) with endobronchial ultrasonography with a guide sheath (EBUS-GS) for peripheral pulmonary lesions (PPLs) are lacking. We evaluated whether intraoperative probe repositioning improves R-EBUS imaging and affects diagnostic yield and safety of EBUS-guided sampling for PPLs. METHODS: We retrospectively studied 363 patients with PPLs who underwent TBNA/TBB (83 lesions) or TBB (280 lesions) using EBUS-GS. Based on the R-EBUS findings before and after these procedures, patients were categorized into three groups: the improved R-EBUS image (n = 52), unimproved R-EBUS image (n = 69), and initial within-lesion groups (n = 242). The impact of improved R-EBUS findings on diagnostic yield and complications was assessed using multivariable logistic regression, adjusting for lesion size, lesion location, and the presence of a bronchus leading to the lesion on CT. A separate exploratory random-forest model with SHAP analysis was used to explore factors associated with successful repositioning in lesions not initially "within." RESULTS: The diagnostic yield in the improved R-EBUS group was significantly higher than that in the unimproved R-EBUS group (76.9% vs. 46.4%, p = 0.001). The regression model revealed that the improvement in intraoperative R-EBUS findings was associated with a high diagnostic yield (odds ratio: 3.55, 95% confidence interval, 1.57-8.06, p = 0.002). Machine learning analysis indicated that inner lesion location and radiographic visibility were the most influential predictors of successful repositioning. The complication rates were similar across all groups (total complications: 5.8% vs. 4.3% vs. 6.2%, p = 0.943). CONCLUSIONS: Improved R-EBUS findings during TBNA/TBB or TBB with EBUS-GS were associated with a high diagnostic yield without an increase in complications, even when the initial R-EBUS findings were inadequate. This suggests that repeated intraoperative probe repositioning can safely boost outcomes.

This article relates to Comment on: Is clozapine use a risk of hematological malignancies? Insights from a meta-analysis "Clozapine and Malignancy Risk".

Headache is a significant public health issue due to its high prevalence, associated disability, and socioeconomic burden. In Japan, awareness of migraine prevention and the risks of medication overuse remains limited. This study examined whether increasing knowledge about headaches through an online educational campaign could lead to behavioral changes, such as more frequent visits to headache clinics and reduced misuse of headache medications. An online educational program on headaches was conducted for 1,829 hospital staff members, who first completed a questionnaire before watching an educational video. Six months later, they completed a second questionnaire to assess behavioral changes. The initial survey revealed that although headaches interfered with work and daily life for approximately 50% of participants, only 20% regularly sought medical care. The most common reason for not visiting a medical facility was reliance on over-the-counter medications. In the follow-up survey, 20% of participants had independently gathered information about headaches, 6% had visited a medical institution for a new headache, and 40% had reduced their use of painkillers after becoming aware of medication overuse headache (MOH). A decision tree model, using the reduction in painkiller use as the outcome, indicated that correct knowledge about migraine, including preventive treatments, and active information-seeking behavior were key factors in promoting behavioral change. These findings suggest that providing online headache education to hospital staff may contribute to improved headache management by increasing awareness of migraine prevention and MOH while reducing excessive painkiller use.

Nagashima-type palmoplantar keratoderma (NPPK) is the most common form of palmoplantar keratoderma in Asian populations and is primarily caused by biallelic variants in SERPINB7. As SERPINA12 variants were reported in Chinese patients with NPPK, we analysed SERPINA12 variants in 18 Japanese patients with NPPK lacking biallelic SERPINB7 variants and found significantly higher frequencies of SERPINA12 variants c.635-7A&gt;G and c.656A&gt;G compared with the general population. This suggests a potential digenic effect involving SERPINB7 and SERPINA12, highlighting the need for considering digenic inheritance in NPPK diagnosis and genetic counselling.

The use of immune checkpoint inhibitors (ICIs) for treating melanoma has dramatically improved patient prognosis. The genomic profiles of patients receiving ICI therapy would provide valuable information for disease management and treatment. We investigated the genomic profiles of patients with melanoma who had received ICI therapy and explored associations with clinical features and outcomes via a large-scale nationwide database in Japan (the C-CAT database). We identified 339 patients eligible for this study. The most frequent genetic mutations were found in the BRAF (27%), TERT (24%), and NRAS (19%) genes, and the most common copy number variations (CNVs) were in the CDKN2A (36%), CDKN2B (26%), and MTAP (19%) genes. Associations with high tumor mutational burden (TMB-high) status were significant for TERT (p < 0.001), NF1 (p < 0.001), ROS1 (p = 0.015), POLE (p = 0.045), and POLD1 (p = 0.008) mutations, along with older age (≥65 years, p = 0.036). Patients with multiple metastases (two or more) were more likely to have NOTCH3 mutations (p = 0.017) and be younger than 65 years (p = 0.024). In particular, as well as younger age, patients with brain metastases were more likely to harbor BRAF mutations (p < 0.001), while those with liver metastases were more likely to harbor NOTCH3 mutations (p < 0.001) but not CDKN2B CNVs (p = 0.041). Patients with NRAS mutations were less likely to respond to ICI therapy (p = 0.014) and exhibited shorter overall survival (p = 0.006). In this population, the frequency of BRAF mutations was lower than that in fair-skinned populations, but the associations between genomic profiles, clinical features, and outcomes were similar to those previously reported in fair-skinned populations.

Guillain-Barré syndrome (GBS) is a life-threatening condition that has been associated with exposure to immune checkpoint inhibitors (ICIs); however, available data remain limited. We conducted a retrospective, worldwide, observational analysis of individual case safety reports in VigiBase, the World Health Organization’s pharmacovigilance database. To minimize competition bias, we excluded reports of vaccines and infectious associated with a known or potential risk of GBS. Subsequently, we searched for reports of GBS linked to ICI regimens, whether as monotherapy or dual immunotherapy, from the Food and Drug Administration (FDA) approval date of each agent until 12 February 2024. The primary endpoint of this study was to assess the association between GBS reporting and exposure to ICI regimens (either monotherapy or dual immunotherapy) using disproportionality analysis. This analysis was performed utilizing the Information Component (IC) and its 95% credibility interval lower boundary (IC 025 ). A total of 412 cases of GBS associated with ICIs were reported in VigiBase. The disproportionality analysis revealed a significant reporting signal between GBS and the anti-CTLA-4 and anti-PD-1 combination therapy (n = 102, IC 025 = 4.6), specifically with nivolumab and ipilimumab (n = 100, IC 025 = 4.6); anti-CTLA-4 monotherapy (n = 39, IC 025 = 3.6) with ipilimumab monotherapy (n = 39, IC 025 = 3.6); anti-PD-1 monotherapy (n = 217, IC 025 = 3.4), including pembrolizumab (n = 124, IC 025 = 3.5), nivolumab (n = 88, IC 025 = 3), and cemiplimab (n = 5, IC 025 = 1.2); and anti-PD-L1 monotherapy (n = 53, IC 025 = 3) with atezolizumab (n = 36, IC 025 = 3), durvalumab (n = 11, IC 025 = 1.8), and avelumab (n = 6, IC 025 = 1.1) in monotherapy. Among cases with available data (n = 123), the median time to onset was 68 days (interquartile range [IQR]: 24.5–119.5), with a shorter delay observed in patients receiving dual immunotherapy compared to those treated with monotherapy. Among the cases for which data was available (n = 242), data recovery or partial recovery was reported in 58.3% (n = 141/242), while a fatal outcome was reported in 9% (n = 21). A significant reporting signal of GBS exists with the majority of ICI regimens employed in both monotherapy and dual immunotherapy.

BACKGROUND: The diagnostic yield of virtual bronchoscopy with radial endobronchial ultrasound (r-EBUS) for peripheral pulmonary lesions (PPLs) remains unsatisfactory because of limited lesion access by biopsy instruments. r-EBUS-guided transbronchial needle aspiration (TBNA) followed by transbronchial biopsy (TBB) (TBNA/TBB) with a guide sheath (GS) potentially increases the PPL diagnostic yield as the needle penetrates the bronchial wall, enabling subsequent forceps biopsy closer to the lesion. However, regarding the application of r-EBUS-guided TBNA/TBB for PPL diagnosis, data on the diagnostic yield of TBNA/TBB with a GS are limited compared with those on TBNA/TBB without a GS. METHODS: We conducted a retrospective analysis of consecutive patients who underwent r-EBUS-guided TBNA/TBB for PPLs with or without a GS at 3 institutions. The objective was to evaluate the effect of GS usage on diagnostic yield of PPLs, focusing on lesion location from the hilum on computed tomography. To estimate the probability of successful diagnosis based on GS status, we applied an adjusted logistic regression model with inverse probability of treatment weighting to account for potential confounding. RESULTS: The interaction between GS usage and lesion location was significant (odds ratio=14.19; 95% CI: 1.48-135.75). The rates of successful diagnosis were 83% and 75% for lesions within the middle third ellipse during no and GS use, respectively, and 44% and 87% for lesions within the outer third ellipse during no and GS use, respectively. CONCLUSION: This study demonstrated that GS use in r-EBUS-guided TBNA/TBB improves diagnostic success for lesions within the outer third ellipse.

INTRODUCTION: Recent literature has reported instances of drug associated with hypertension with serotonin reuptake inhibitors (SRIs). Nonetheless, the association between SRIs and hypertension development is the subject of ongoing debate. It remains uncertain whether this is indicative of a class effect, and if dose-effect exist. To investigate the potential class effect associating SRIs with hypertension reporting, we utilized real-world data from VigiBase®, the World Health Organization (WHO) pharmacovigilance database. METHODS: We conducted an updated disproportionality analysis within VigiBase® to identify a signal of hypertension reporting with individual SRIs by calculating adjusted reporting odds ratios (aRORs) within a multivariate case/non-case study design. Additionally, we explored the presence of a dose-effect relationship. RESULTS: The database contained 13,682 reports of SRI associated with hypertension (2.2%), predominantly in women (70.0%). Hypertension was most reported in the 45-64 years old age group (44.8%). A total of 3,879 cases were associated with sertraline, 2,862 with fluoxetine, 2,516 with citalopram, 2,586 with escitalopram, 2,441 with paroxetine, 201 with fluvoxamine and 8 with zimeldine. A significant ROR was observed for all SRIs in both univariate (RORs ranging from 1.39 to 1.54) and multivariable analyses (aRORs ranging from 1.16 to 1.40) after adjustments for age group, sex, concurrent antihypertensive medication and drugs knowns to induce hypertension, except for fluvoxamine and zimeldine. No dose-response relationship was identified. CONCLUSION: This investigation, conducted under real life conditions, unveils a notable pharmacovigilance safety signal associating SRI usage with hypertension reporting. No dose-response effect was detectable. Further longitudinal studies are warranted.

AIMS: Cardiovascular toxicities associated with anticancer drugs constitute a significant concern for pediatric patients undergoing cancer treatment. Comprehensive data on the burden of cancer therapy-related cardiac dysfunction (CTRCD) are lacking, particularly for this high-risk population susceptible to develop myocardial toxicity. By analyzing VigiBase, the World Health Organization's individual case safety report database, we sought to determine anticancer drugs associated with CTRCD in pediatric patients. METHODS AND RESULTS: To evaluate the association between 249 anticancer drugs labeled by the FDA or EMA and CTRCD reporting, we performed a disproportionality analysis, calculating multivariable adjusted reporting odds ratios (aROR) with their 95% confidence intervals (CI) across four pediatric age classes (0-27 days, 28 days to 23 months, 2-11 years, 12-17 years); ClinicalTrial registration number: NCT05602103. We identified 796 cases of CTRCD associated with at least one anticancer drug in VigiBase. Multivariate analysis across the pediatric age spectrum revealed 16 anticancer drugs significantly associated with CTRCD, of which 10 (63%) are primarily used for hematologic malignancies. Two drugs, a topoisomerase 1 inhibitor (topotecan) and cytotoxic antibiotics (dactinomycin), represented novel associations with CTRCD not previously documented in the literature. CONCLUSION: Within VigiBase, we pinpointed 16 anticancer drugs significantly associated with CTRCD reporting in pediatrics. Our research validated several associations already thoroughly reported in children (such as with anthracyclines), and unveiled novel signals for systemic exposure to topotecan and dactinomycin. The relevance of these findings, especially considering the frequency of co-administration of agents and the lack of information regarding radiation exposure and chemotherapy dosage, would need to be evaluated in the context of clinical trials that use or have used these agents.

BACKGROUND: Controlling delayed cerebral ischemia (DCI) is crucial for improving the prognosis in patients with aneurysmal subarachnoid hemorrhage (aSAH). This study aimed to identify prognostic factors in patients with aSAH in Japan. METHODS: A multicenter, retrospective, observational cohort study was conducted from April 2021 to March 2024. Patients underwent surgical repair of ruptured aneurysms within 48 h of onset, followed by postoperative treatment with multiple drugs, including clazosentan and fasudil, to prevent cerebral vasospasm. The primary outcome was the proportion of patients with a good outcome, defined as a modified Rankin Scale score of 0 to 2 at discharge. Multivariate logistic regression and stepwise model selection were applied to identify prognostic factors. SHapley Additive exPlanations (SHAP) analysis was used to visualize the relative importance of predictors and their impact on outcomes. RESULTS: Among 506 patients (mean age 63.5 years, 66.6% female), 53.0% achieved a favorable outcome. In multivariate analysis, treatment with clazosentan was associated with 1.84 times higher odds of a favorable outcome (p = 0.021), increasing to 1.97 when clazosentan was administered without fluid retention complications (p = 0.010). SHAP analysis further highlighted the impact of each factor on prognosis, identifying a lower WFNS grade, lower Fisher grade, younger age, clazosentan, cilostazol, and statin use as significant predictors of favorable outcomes. CONCLUSION: Clinical status at aSAH onset and age are uncontrollable factors; therefore, improving prognosis requires targeted prevention of DCI and effective management of brain edema. The administration of therapies such as clazosentan, cilostazol, and statins may contribute to favorable outcomes. CLINICAL TRIAL NUMBER: Not applicable.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are crucial in managing type 2 diabetes mellitus (T2DM) and obesity. Agents like dulaglutide, semaglutide, and liraglutide mimic endogenous GLP-1, enhancing insulin secretion and promoting satiety. Beyond glycemic control, they offer cardioprotective and neuroprotective benefits. However, concerns about psychiatric adverse effects have emerged, necessitating a systematic assessment of their safety profile. MATERIAL & METHODS: This multinational pharmacovigilance study utilized VigiBase® data up to December 1, 2024, focusing on adverse drug reaction (ADR) reports for GLP-1 RAs. Psychiatric ADRs were classified using MedDRA terminology. Disproportionality analyses were conducted via logistic regression to calculate reporting adjusted Reporting Odds Ratios (aRORs) within reports involving antidiabetic or anti-obesity medications. A causal forest model assessed the individual treatment effect (ITE) of semaglutide on depression and suicidality reporting. RESULTS: Among 2,061,901 reports, 21,414 involved psychiatric ADRs for GLP-1 RAs. Significant signals were observed for anxiety (aROR: 1.26, 95%CI: 1.18-1.35), depressed mood disorders (aROR: 1.70, 95%CI: 1.57-1.84) and suicidality (aROR 1.45, 95%CI: 1.29-1.63) with semaglutide, and eating disorders with all three GLP-1 RAs (aRORs between 4.17 and 6.80). The causal forest model estimated an average treatment effect of 0.0046 for semaglutide on depression and suicidality reporting, with significant heterogeneity across regions and demographic groups. DISCUSSION: The study found no significant increase in overall psychiatric ADR reporting for GLP-1 RAs, except for eating disorders and depression/suicidality in semaglutide-treated patients. Sensitivity analyses before June 4, 2021, found no signals, aligning with RCT data. Post-marketing reports linked semaglutide to depression and suicidal ideation, prompting regulatory investigations. The causal forest model revealed significant heterogeneity in the psychiatric safety profile of semaglutide, with regional factors influencing ADR reporting. CONCLUSION: While GLP-1 RAs do not show a significant increase in overall psychiatric ADR reporting, findings suggest that clinicians should remain vigilant for potential depressive symptoms and suicidality, particularly in individuals with obesity treated with semaglutide since its approval for weight management.

The Joint PhD Degree Program (JDP) between Nagoya University (NU) and the University of Adelaide (UoA), launched in 2015, was the first such initiative of its type in Japan. Evolving from a student exchange, it required the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT) accreditation and alignment of differing PhD admission criteria. Challenges included degree naming and eligibility requirements, which NU and UoA addressed through mutual recognition agreements. Since inception, the JDP has maintained steady enrolment, with doctoral degree students engaging in joint research and publishing over 30 peer-reviewed articles. Future developments include postdoctoral pathways and industry internships, reinforcing the Program's role in fostering and enhancing global medical research collaboration.

BACKGROUND: An association between total hydrocortisone (HC) dosage in infants with extremely low birth weight (ELBW) and subsequent neurodevelopmental outcomes up to school age remains unclear. METHOD: We conducted a retrospective longitudinal cohort study across eight centers in Japan, including ELBW infants born between 2015 and 2017. We investigated the association between total HC dosage administered up to 36 weeks postmenstrual age and neurodevelopmental outcomes to school age. RESULTS: Linear mixed model analysis showed a significant association between higher HC dosage and lower developmental and intelligence quotient (DQ/IQ) scores. This trend persisted at 6 years of age, suggesting a sustained effect of HC on cognitive outcomes. For every 10 mg increase in HC dosage, IQ scores decreased by 2.82 points (95% CI: -3.89 to -1.06, p = 0.001). The interaction term between HC dosage and time was not statistically significant (0.10, 95% CI: -0.18 to 0.37, p = 0.481), suggesting the association of HC dosage on DQ/IQ did not vary substantially throughout the study period. CONCLUSIONS: We found a relationship between total neonatal HC dosage in ELBW infants and DQ/IQ scores over time that persisted at school age. Clinicians should be aware of this potential dose-dependent effect on neurodevelopmental outcomes. IMPACT: As neonatal dexamethasone administration is known to affect neurodevelopment outcomes, hydrocortisone (HC) is considered an alternative to dexamethasone as a glucocorticoid treatment. In infants with extremely low birth weight (ELBW), a relationship has been noted between total HC dosage and neurodevelopment in early childhood. We confirmed the association between total HC dosage in infants with ELBW and poor developmental and intelligence quotients to school age. Although HC is commonly used in the management of ELBW infants, clinicians should be aware of its potential dose-dependent effects on neurodevelopmental outcomes.

BACKGROUND: Psychoactive drugs frequently cause delirium adverse events in older adults. However, few data on the relationship between antidepressants and delirium are available. Here, we investigated the association between antidepressant prescription and pharmacovigilance reports of delirium in older adults. METHODS: Using the World Health Organization's VigiBase® global pharmacovigilance database from 1967 to 2022, we performed a disproportionality analysis in order to probe the putative associations between each antidepressant class (non-selective monoamine reuptake inhibitors (NSMRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), alpha-2-adrenergic receptor antagonists, and other antidepressants) and reports of delirium in people aged 65 or over. We calculated the reporting odds ratios (r-OR) and their 95% confidence interval ([95%CI]) with logistic regression models before and after adjustment for confounding factors. Secondary analyses were performed for each drug and within each class by age group (65-74, and 75 and over). We also studied the reports of concomitant delirium and hyponatremia. RESULTS: Our main analysis included 87,524 cases of delirium. After adjustment for confounders, a significant association was found between delirium and all antidepressant classes other than SNRIs. Intraclass disparities were found for the association between the most frequently prescribed antidepressants and reports of delirium. An elevated risk of reports of concomitant delirium and hyponatremia was found for SSRIs (4.46 [4.01-4.96]), SNRIs (1.25 [1.07-1.46]), MAOIs (1.72 [1.41-2.09]), and the "other antidepressants" class (1.47 [1.30-1.65]). CONCLUSIONS: There was a significant association between reports of delirium and antidepressant classes (other than SNRIs). However, this association varied from one drug to another within a given antidepressant class. Moreover, this association could not always be explained by antidepressant-induced hyponatremia.

OBJECTIVES: Proton pump inhibitor (PPI) exposure can lead to hyponatraemia, which is a common cause of delirium. An association between PPI exposure and delirium without hyponatraemia has been suggested in the literature. We aimed to describe the association between reports of delirium and PPI exposure and to assess the association between PPI and delirium with and without hyponatraemia. DESIGN: A descriptive and disproportionality analysis of claims data. SETTING: World pharmacovigilance database VigiBase between 1 January 1991 and 9 February 2022. PRIMARY AND SECONDARY OUTCOME MEASURES: In the first part, we described reports of delirium for which involvement of a PPI or interactions of PPIs with other drugs were suspected. In the second part, delirium cases and non-cases were used to assess the disproportionality signal using the reporting OR (ROR) for the associations of PPI exposure with delirium or delirium/hyponatraemia co-events. RESULTS: We identified 2395 reports of delirium in which involvement of PPI exposure was suspected. Omeprazole, esomeprazole and pantoprazole were the most frequently reported PPIs. Hyponatraemia was present in 11% of the reports. The disproportionality analysis included 1 264 798 reports of adverse drug reactions in patients using PPIs, including 19 081 reports of delirium. We did not find a disproportionality signal for the association between PPI use and delirium (ROR 0.89, 95% CI 0.87 to 0.91). We detected an association of PPI use with delirium/hyponatraemia co-events (ROR 1.53, 95% CI 1.41 to 1.65). CONCLUSIONS: Most reports of delirium in which the involvement of PPIs was suspected did not include concomitant hyponatraemia. However, no significant signal of disproportionate reporting of delirium was observed for PPIs compared with other drugs, except in cases of delirium associated with hyponatraemia. Hyponatraemia may be the main mechanism linking PPI exposure with delirium, and this possibility should be further explored in prospective studies. TRIAL REGISTRATION NUMBER: NCT05815550.

Spontaneous reporting of adverse drug reactions (ADRs) is the cornerstone of pharmacovigilance. However, major underreporting exists. The main objective of this study was to assess the use of a pharmacovigilance simplified reporting tool (PSRT) by general practitioners (GPs) and, secondarily, to describe the quality of ADR reports during this period. The PSRT was proposed on June 1st, 2015, for the 1290 GPs in the Western Normandy Region. The number and quality of ADRs reported monthly by GPs were prospectively collected from June 1st, 2015, to May 31st, 2020 (Period 2), and compared to those reported during a control period (June 1st, 2010, to May 31st, 2015, Period 1). During all the periods, 920 reports were made by 307 GPs (198 reports in Period 1 and 722 reports in Period 2), with 477 reports (51.8%) using the PSRT. During Period 2, the monthly number of reports was multiplied by 3.5 (p < 0.0001), and the number of GPs was 1.4 compared to that in Period 1 (p = 0.01). Our PSRT showed effectiveness in quantitative and qualitative terms. It must now go further and be integrated into GP software to facilitate ADR reporting nationwide.

Whether ibrutinib-related atrial fibrillation (IRAF) is a dose-dependent adverse drug reaction (ADR) and whether ibrutinib should be discontinued or dose-reduced in case of IRAF occurrence remains unknown. Using the World Health Organization individual case safety report pharmacovigilance database, VigiBase®, we aimed to determine the association between ibrutinib dosing regimens and IRAF reporting. Ibrutinib daily dose was extracted from IRAF cases from VigiBase® and was divided into 5 ibrutinib dosing regimen (140-280-420-560 and >560 mg/day). Disproportionality analysis was used to evaluate the association between IRAF reporting and ibrutinib daily dose, through logistic regression. Single term deletions produced the ibrutinib daily dose global p-value. Then, a multivariable adjusted reporting odds-ratio with its 95% confidence interval was calculated for each ibrutinib dosing regimen, against the lowest dosing regimen (140 mg/day) as reference. A total of 1162 IRAF cases were identified in VigiBase® (n = 62 for ibrutinib 140 mg/day, 114 for ibrutinib 280 mg/day, 811 for ibrutinib 420 mg/day, 164 for ibrutinib 560 mg/day and 11 for ibrutinib >560 mg/day). After adjustment on several variables of interest, IRAF reporting was not significantly associated with ibrutinib dosing regimen (p = 0.09). Our results from Vigibase® do not support IRAF as a dose-dependent ADR (ClinicalTrial registration number: NCT06224452).

Acute arterial hypertension within the critical care context may necessitate the administration of intravenous antihypertensive agents. Nicardipine and urapidil are notable for their application in intensive care units. Nonetheless, dihydropyridine calcium channel inhibitors (DCCIs) such as nicardipine are implicated in the impairment of hypoxic pulmonary vasoconstriction, potentially disrupting oxygenation. This study aimed to assess the differences in patient oxygenation when these antihypertensive agents are administered intravenously. This bicentric, prospective, observational investigation spanning five intensive care units evaluated patients requiring intravenous nicardipine or urapidil. Oxygenation data were recorded from the start of therapy until the 12th hour. Comparative analysis was performed between patient groups based on the antihypertensive agent administered, along with subgroup investigations to identify populations with an elevated risk of hypoxemia. From November 2021 to November 2023, 197 patients were included: 98 (50%) were treated with nicardipine, and 99 (50%) were treated with urapidil. Hypoxemia occurred in 97 (49%) patients and was more prevalent in the nicardipine cohort, affecting 65 (66%) patients, as opposed to 32 (32%) patients in the urapidil cohort (RR 2.05, 95% CI [1.48-2.82], P < 0.001). Subgroup analysis revealed a significant association between patients with pulmonary atelectasis (RR 2.30, 95% CI [1.4-3.7], P < 0.001) and obesity (RR 2.7, 95% CI [1.5-4.6], P < 0.001). Considering these findings, cautious consideration of the patient's respiratory status should be exercised when initiating intravenous DCCI treatment. However, given the limitations of this study, a controlled trial on hypertension management in the ICU is needed.

INTRODUCTION: In order to reduce the under-reporting of adverse drug reactions (ADR) in general practice, the Caen Normandie regional pharmacovigilance center (CRPV) has implemented a training program for the French health insurance representatives (DAM) of the Manche department in order to raise awareness among general practitioners (GPs) to ADR reporting. PURPOSE OF RESEARCH: During quarterly visits of DAM to GPs, the mode of operation and the value of pharmacovigilance reporting was presented. This pilot study presents the impact of these DAM visits to GPs in term of ADRs reporting quantification. RESULTS: Assessment of this first year showed a doubling of ADR reporting by GPs of the Manche department in 2019 compared to 2017 and 2018. This phenomenon was not found in the two control departments (departments of Calvados and Orne) where the information had not been issued. These ADRs first concerned drugs of the renin-angiotensin system, then psychotropic drugs and anti-infectives. These were cutaneous, then neurological and gastrointestinal ADRs, preferentially affecting women. CONCLUSIONS: This experimentation should continue on a larger scale. The longer-term evaluation of this tool also requires evaluating its relevance.

Due to their negative effects on hypoxic pulmonary vasoconstriction, dihydropyridine calcium channel inhibitors (DCCIs) can lead to hypoxia in patients with a pulmonary shunt. To date, only preclinical studies and case reports have focused on this potential adverse drug reaction. We aimed to assess the reporting association between DCCIs and hypoxia using the World Health Organization pharmacovigilance database (VigiBase). We performed a disproportionality analysis to evaluate the strength of the reporting association between i.v. clevidipine and nicardipine, thought to be a surrogate of patients in the intensive care unit, and hypoxia. The information component and the lower end of its 95% credibility interval were used to evaluate disproportionality. A description of the cases was made. Secondary outcomes included the association between all DCCIs and hypoxia compared with other treatments with similar indications, urapidil and labetalol, regardless of the route of administration. Association between oral nicardipine and hypoxia was also searched. A statistically significant signal of hypoxia was found for intravenous clevidipine and nicardipine. The time to onset was reported with a median of 2 days (interquartile range 1.5-4.5). Four dechallenges were performed with intravenous nicardipine, leading to the resolution of the symptoms. Regardless of the route of administration, a signal of hypoxia was also found for nimodipine but not for other drugs, including comparators. For nicardipine no signal of hypoxia was found with the oral route of administration. Our pharmacovigilance database analysis showed a significant association between the use of intravenous DCCIs and hypoxia.

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 &lt; 0.005], while agranulocytosis demonstrated a stronger association with clozapine-associated reports of infections [X2 (1, N = 204,073) = 56; p &lt; 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.

Importance: Endocrine therapies (ETs) and inhibitors of cyclin-dependent kinases-4/6 (iCDK4/6s) are a standard treatment in breast cancer. However, data on potential neurocognitive impacts remain inconsistent for ET and are scarce for iCDK4/6s. Objective: To evaluate whether ET and iCDK4/6s are associated with neurocognitive impairment (NCI). Methods: We used observational, real-world cases of NCI from the World Health Organization’s database VigiBase ® to perform disproportionality analysis. Cases were defined as any symptom of NCI in females treated with ETs or iCDK4/6s. The study period was from the date of the first adverse event reported in VigiBase ® with iCDK4/6s (1 January 2014) until the date of data extraction (16 March 2022). In our primary analysis, we calculated the reporting odds ratio (ROR) adjusted for age to identify a potential association between NCI and individual ETs in isolation or in combination with iCDK4/6s. We also performed subgroup analyses by the NCI class. Results: We identified 2.582 and 1.943 reports of NCI associated with ETs and iCDK4/6s, respectively. NCI was significantly associated with each ET [anastrozole: n = 405, aROR = 1.52 (95% CI: 1.37–1.67); letrozole: n = 741, aROR = 1.37 (95% CI: 1.27–1.47); exemestane: n = 316, aROR = 1.37 (95% CI: 1.22–1.53); tamoxifen: n = 311, aROR = 1.25 (95% CI: 1.12–1.40); and fulvestrant: n = 319, aROR = 1.19 (95% CI: 1.06–1.33)] and only with palbociclib for iCDK4/6s [ n = 1,542, aROR = 1.41 (95% CI: 1.34–1.48)]. Conclusion: These findings suggest that in females treated for breast cancer, all ETs may be associated with NCI. However, amongst iCDK4/6s, NCI may be specific to palbociclib. NCI most frequently involved learning and memory as well as language. Neurocognitive impact of treatments requires better consideration and management.

Letter to Blood| August 25, 2022 An updated list of drugs suspected to be associated with immune thrombocytopenia based on the WHO pharmacovigilance database Clinical Trials & Observations Ségolène Fuentes, Ségolène Fuentes Department of Internal Medicine, Normandie University, Université de Caen Normandie (UNICAEN), Centre Hospitalo-Universitaire (CHU) de Caen Normandie, Caen, France; Search for other works by this author on: This Site PubMed Google Scholar Basile Chrétien, Basile Chrétien Department of Pharmacology, CHU de Caen Normandie, Caen, France; https://orcid.org/0000-0002-7483-2489 Search for other works by this author on: This Site PubMed Google Scholar Charles Dolladille, Charles Dolladille Department of Pharmacology, CHU de Caen Normandie, Caen, France;Normandie University, UNICAEN, INSERM U1086 ANTICIPE, Caen, France; Search for other works by this author on: This Site PubMed Google Scholar Joachim Alexandre, Joachim Alexandre Department of Pharmacology, CHU de Caen Normandie, Caen, France;Normandie University, UNICAEN, INSERM U1086 ANTICIPE, Caen, France; Search for other works by this author on: This Site PubMed Google Scholar Anaël Dumont, Anaël Dumont Department of Internal Medicine, Normandie University, Université de Caen Normandie (UNICAEN), Centre Hospitalo-Universitaire (CHU) de Caen Normandie, Caen, France; Search for other works by this author on: This Site PubMed Google Scholar Alexandre Nguyen, Alexandre Nguyen Department of Internal Medicine, Normandie University, Université de Caen Normandie (UNICAEN), Centre Hospitalo-Universitaire (CHU) de Caen Normandie, Caen, France; Search for other works by this author on: This Site PubMed Google Scholar Hubert de Boysson, Hubert de Boysson Department of Internal Medicine, Normandie University, Université de Caen Normandie (UNICAEN), Centre Hospitalo-Universitaire (CHU) de Caen Normandie, Caen, France;Normandie University, UNICAEN, UR4650 PSIR, CHU de Caen Normandie, Caen, France; and Search for other works by this author on: This Site PubMed Google Scholar Stéphane Chèze, Stéphane Chèze Department of Hematology, CHU de Caen Normandie, Caen, France Search for other works by this author on: This Site PubMed Google Scholar Gwénola Maigné, Gwénola Maigné Department of Internal Medicine, Normandie University, Université de Caen Normandie (UNICAEN), Centre Hospitalo-Universitaire (CHU) de Caen Normandie, Caen, France; Search for other works by this author on: This Site PubMed Google Scholar Achille Aouba, Achille Aouba Department of Internal Medicine, Normandie University, Université de Caen Normandie (UNICAEN), Centre Hospitalo-Universitaire (CHU) de Caen Normandie, Caen, France;Normandie University, UNICAEN, UR4650 PSIR, CHU de Caen Normandie, Caen, France; and Search for other works by this author on: This Site PubMed Google Scholar Samuel Deshayes Samuel Deshayes Department of Internal Medicine, Normandie University, Université de Caen Normandie (UNICAEN), Centre Hospitalo-Universitaire (CHU) de Caen Normandie, Caen, France;Normandie University, UNICAEN, UR4650 PSIR, CHU de Caen Normandie, Caen, France; and https://orcid.org/0000-0001-8887-3233 Search for other works by this author on: This Site PubMed Google Scholar Blood (2022) 140 (8): 922–927. https://doi.org/10.1182/blood.2022015936 Article history Submitted: February 14, 2022 Accepted: June 29, 2022 First Edition: July 8, 2022 Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Request Permissions Cite Icon Cite Search Site Citation Ségolène Fuentes, Basile Chrétien, Charles Dolladille, Joachim Alexandre, Anaël Dumont, Alexandre Nguyen, Hubert de Boysson, Stéphane Chèze, Gwénola Maigné, Achille Aouba, Samuel Deshayes; An updated list of drugs suspected to be associated with immune thrombocytopenia based on the WHO pharmacovigilance database. Blood 2022; 140 (8): 922–927. doi: https://doi.org/10.1182/blood.2022015936 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBlood Search Subjects: Clinical Trials and Observations, Platelets and Thrombopoiesis, Thrombocytopenia TO THE EDITOR: Iatrogenic thrombocytopenia is a common adverse drug reaction (ADR) that can be caused by various mechanisms, including drug-associated immune thrombocytopenia (DITP), whose prognosis is generally favorable when the suspected drug is withdrawn.1-4 However, the diagnosis of DITP remains challenging for several reasons. First, there is limited evidence about this rare disease because of a lack of recent powerful studies.2-6 Second, the involved patients frequently have comorbidities and are thereby often exposed to several drugs, which may be possible causes of secondary immune thrombocytopenia (ITP) leading to frequent misdiagnoses.2,7,8 Moreover, the withdrawal of some drugs can be highly challenging a…

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.

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.

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: = 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.

BACKGROUND: Problem-Based Learning (PBL) requires active communication and learner autonomy, which can be challenging in cultural contexts that emphasize group harmony and indirect communication, such as Japan. This challenge is often amplified when PBL is conducted in a non-native language (English), potentially inducing "foreign language anxiety." While the COVID-19 pandemic necessitated a shift to online learning, the specific impact of this format on psychological barriers and student engagement in high-context cultures remains underexplored. We investigated whether the online format could reduce these transactional distances and enhance learning outcomes compared to traditional in-person PBL. METHODS: We conducted a naturalistic, historical control study comparing fourth-year medical students at Nagoya University during a Child and Adolescent Psychiatry curriculum. The 2019 cohort (n = 109) participated in-person, while the 2021 cohort (n = 100) participated online. We administered a 15-item questionnaire assessing satisfaction, engagement, and case suitability. Beyond standard descriptive comparisons, we applied a novel multidimensional statistical framework. This included Ordered Logistic Regression adjusted for age and sex to identify predictors of satisfaction, Exploratory Factor Analysis (EFA) to validate the instrument's latent structure, and K-means Clustering to identify distinct student "phenotypes" based on response patterns. RESULTS: The online cohort reported significantly higher satisfaction across most domains (Odds Ratios 0.36-0.51, p < 0.05). Factor analysis identified two primary dimensions-"Perceived Learning Efficacy" and "Engagement"-while "Communication Skills" (Question 4) emerged as an independent outlier, failing to load on either dimension. Cluster analysis identified two distinct student phenotypes: a "Traditional/Dissatisfied" profile (Cluster 1: n = 77, 69% from the in-person group, predominantly male and older) and a "Digital/Satisfied" profile (Cluster 2: n = 127, 57% from the online group, predominantly female and younger). CONCLUSIONS: Online delivery of PBL was associated with significantly higher student satisfaction and engagement scores in this Japanese context. Because the study is observational (historical-cohort comparison with no randomisation), this association cannot be attributed causally to the modality, and the role of reduced foreign-language anxiety is an interpretive hypothesis that the present design does not directly test. The identification of distinct student phenotypes suggests that demographic factors (gender, age) and delivery modality interact to shape the learning experience. These findings advocate for a tailored pedagogical approach, where digital formats serve as a "safe harbor" for students with high communication apprehension.

Perform the analysis of the World Health Organization (WHO) Pharmacovigilance database 'VigiBase' (Extract Case Level version), <https://who-umc.org/> e.g., load data, perform data management, disproportionality analysis, and descriptive statistics. Intended for pharmacovigilance routine use or studies. This package is NOT supported nor reflect the opinion of the WHO, or the Uppsala Monitoring Centre. Disproportionality methods are described by Norén et al (2013) <doi:10.1177/0962280211403604>.