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The ATP-sensitive potassium channels and their regulatory subunits, sulfonylurea receptor 1 (SUR1/Kir6.2) and SUR2/Kir6.1, contribute to the pathophysiology of pulmonary hypertension (PH). Loss-of-function pathogenic variants in the ABCC8 gene, which encodes for SUR1, have been associated with heritable pulmonary arterial hypertension. Conversely, activation of SUR1 and SUR2 leads to the relaxation of pulmonary arteries and reduces cell proliferation and migration. Diazoxide, a SUR1 activator, has been shown to alleviate experimental PH, suggesting its potential as a therapeutic option. However, there are paradoxical reports of diazoxide-induced PH in infants. This review explores the role of SUR1/2 in the pathophysiology of PH and the contradictory effects of diazoxide on the pulmonary vascular bed. Additionally, we conducted a comprehensive literature review of cases of diazoxide-associated PH and analysed data from the World Health Organization pharmacovigilance database (VigiBase). Significant disproportionality signals link diazoxide to PH, while no other SUR activators have been connected with pulmonary vascular disease. Diazoxide-associated PH seems to be dose-dependent and potentially related to acute effects on the pulmonary vascular bed. Further research is required to decipher the differing pulmonary vascular consequences of diazoxide in different age populations and experimental models., Competing Interests: Conflict of interest: D. Montani reports grants or contracts from Acceleron, Janssen and Merck MSD, outside the submitted work, consulting fees from Acceleron, Janssen, Merck MSD and Ferrer, outside the submitted work, and payment or honoraria for speakers’ bureaus from Bayer, Janssen, Boehringer, Chiesi, GSK, Ferrer and Merck MSD, outside the submitted work. E-M. Jutant reports consulting fees from Chiesi, outside the submitted work, payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from GSK and Chiesi, outside the submitted work, and support for attending meetings and/or travel from Janssen, outside the submitted work. M. Humbert reports grants or contracts from Acceleron, AOP Orphan, Janssen, Merck and Shou Ti, outside the submitted work, consulting fees from Acceleron, Aerovate, Altavant, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Merck, MorphogenIX, Shou Ti, Tiakis and United Therapeutics, outside the submitted work, payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Janssen and Merck, outside the submitted work, and participation on a data safety monitoring board or advisory board for Acceleron, Altavant, Janssen, Merck and United Therapeutics, outside the submitted work. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2023.)

Introduction: Previous pre-clinical and pharmacovigilance disproportionality analyses highlighted a safety signal of cutaneous ulcer with bisphosphonate use. Therefore, our objective is to evaluate this risk and assess whether unmeasured confounding factors could explain this association., Methods: This study is a population-based cohort study from a representative sample (1/97th) of the French health insurance claims database: Echantillon Généraliste des Bénéficiaires (EGB) from 2006 to 2019. To limit the impact of our study design and methodological choices on any association between skin ulceration and exposure to bisphosphonates, we used several methods: a Cox proportional hazards analysis and a prior event rate ratio (PERR) analysis, using two propensity matched control groups, and either the first episode of incident ulceration or multiple event-time outcomes., Results: There were 7402 individuals newly exposed to bisphosphonates matched to 29,605 unexposed individuals on propensity score. The primary outcome was skin ulcer occurrence assessed by at least 2 deliveries of wound dressing during the period of one month. Among 6911 individuals newly exposed to bisphosphonates and 28,072 unexposed individuals with no previous skin ulcer, the Cox regression yielded a hazard ratio (HR) of 1.40 (95% CI 1.26-1.56) for newly exposed individuals. Among 7402 exposed and 29,605 unexposed individuals, the PERR analysis found a non-significant HR of 1.03 (95% CI 0.87-1.24). Results were similar on the different sensitivity analyses., Conclusion: No association between bisphosphonate and skin ulcers was found in the French population. The association observed in previous pharmacovigilance studies and in the Cox regression analysis is likely due to unmeasured confounding factors., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background and Objective: Observational studies have shown that a significant proportion of patients interchanging between tumor necrosis factor-α inhibitor biosimilars withdraws from the new treatment because of adverse effects. We aim to analyze adverse events related to interchanging from tumor necrosis factor-α (TNF-α) inhibitor reference products to biosimilars and between biosimilars reported in the World Health Organization pharmacovigilance database., Methods: We extracted all cases reporting the Medical Dictionary for Regulatory Activities term "Product substitution issue (PT)" for TNF-α inhibitors. Then, we analyzed and categorized all adverse events reported in more than 1% of cases. We compared the adverse events reported according to reporter qualification, type of switch, and type of TNF-α inhibitor using Chi 2 tests. We conducted a network analysis coupled with a clustering approach to identify syndromes of co-reported adverse events., Results: In the World Health Organization pharmacovigilance database, 2543 cases and 6807 adverse events related to TNF-α inhibitor interchangeability have been reported up to October 2022. Injection-site reactions were the most reported adverse events with 940 cases (37.0%), followed by modifications in drug effect in 607 cases (23.9%). Musculoskeletal, cutaneous, and gastrointestinal disorders linked to the underlying disease were reported in 505 (20.0%), 145 (5.7%), and 207 (8.1%) cases, respectively. Adverse events non-related to the underlying disease were nonspecific (n = 458, 18.0%), neurologic (n = 224, 8.8%), respiratory (n = 132, 5.2%), and psychological disorders (n = 64, 2.5%). Injection-site reactions and infection-related symptoms (e.g., nasopharyngitis, urinary tract infection, lower respiratory tract infection) were more reported by non-healthcare professionals while adverse events related to reduced clinical efficacy (e.g., drug ineffective, arthralgia, psoriasis) were more reported by healthcare professionals. The proportions of injection-site reactions were higher when switching between biosimilars of the same reference product, but the proportions of adverse events related to reduced clinical efficacy (e.g., psoriasis, arthritis, psoriatic arthropathy) were more reported when switching from a reference product. The main differences in the proportions of reported cases between adalimumab, infliximab, and etanercept were driven by symptoms related to the underlying targeted diseases, except for a higher reporting rate of injection-site pain with adalimumab. Adverse events evocative of hypersensitivity reactions were reported in 192 (7.6%) cases. Most of the network clusters concerned non-specific adverse events or were related to reduced clinical efficacy., Conclusions: This analysis highlights the burden of patient-reported adverse events when interchanging between TNF-α inhibitor biosimilars, notably injection-site reactions, non-specific adverse events, and symptoms related to reduced clinical efficacy. Our study also highlights differences in reporting patterns between patients and healthcare professionals and depending on the type of switch. The results are limited by missing data, the lack of precision of the coded Medical Dictionary for Regulatory Activities terms, and by the variability of reporting rate of adverse events. Thus, incidence rates of adverse events cannot be inferred from these results., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background and Aim: Disproportionality analysis is traditionally used in spontaneous reporting systems to generate working hypotheses about potential adverse drug reactions: the so-called disproportionality signals. We aim to map the methods used by researchers to assess and increase the validity of their published disproportionality signals., Methods: From a systematic literature search of published disproportionality analyses up until 1 January 2020, we randomly selected and analyzed 100 studies. We considered five domains: (1) rationale for the study, (2) design of disproportionality analyses, (3) case-by-case assessment, (4) use of complementary data sources, and (5) contextualization of the results within existing evidence., Results: Among the articles, multiple strategies were adopted to assess and enhance the results validity. The rationale, in 95 articles, was explicitly referred to the accrued evidence, mostly observational data (n = 46) and regulatory documents (n = 45). A statistical adjustment was performed in 34 studies, and specific strategies to correct for biases were implemented in 33 studies. A case-by-case assessment was complementarily performed in 35 studies, most often by investigating temporal plausibility (n = 26). Complementary data sources were used in 25 articles. In 78 articles, results were contextualized using accrued evidence from the literature and regulatory documents, the most important sources being observational (n = 45), other disproportionalities (n = 37), and case reports (n = 36)., Conclusions: This meta-research study highlighted the heterogeneity in methods and strategies used by researchers to assess the validity of disproportionality signals. Mapping these strategies is a first step towards testing their utility in different scenarios and developing guidelines for designing future disproportionality analysis., (© 2023. The Author(s).)

Objectives: The literature on vaccine hesitancy has widely commented on the various factors leading some to feel particularly at risk of disease infection while others do not. But little attention has been paid to whether we also see such differences regarding people's assessment of their personal vulnerability towards vaccine adverse events (AEs)., Methods: We designed two cross-sectional online surveys among representative samples of the French mainland population (n = 2015 and 3087). We asked participants if they felt, more than others, at risk of severe vaccine related side effects and to explain why. We performed two separate mixed effect binomial regressions models: 1) to explore the link between the feeling of being particularly at risk of severe vaccine related AEs and socio-demographic characteristics, source of information, trust in health agencies and partisan orientation; 2) to explore the link between the fear of side effects and vaccine hesitancy., Results: We found that 15% of respondents felt to be, more than others, at risk of severe vaccine-related adverse events and that this feeling was associated to negative attitudes to vaccines. This feeling was particularly prevalent among women, those with a lower income, lower educational attainment and lower trust in public health institutions. The vast majority of the reasons given by responders are unrelated to genuine risk factors of vaccine related adverse events., Conclusions: These findings suggest that vaccine hesitancy is at least partly grounded in a feeling of vulnerability towards vaccine adverse events., Competing Interests: Declaration of Competing Interest All authors have completed the Unified Competing Interest form and declare that J.K.W. is a member of the Commission Technique des Vaccinations at the Haute Autorité de la Santé.”, (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Home noninvasive ventilation (NIV), targeting a reduction of carbon dioxide with a combination of sufficient inspiratory support and backup-rate improves outcomes in patients with chronic obstructive pulmonary disease. The aim of this systematic review with individual participant data (IPD) meta-analysis was to evaluate the effects of intensity of home NIV on respiratory outcomes in individuals with slowly progressive neuromuscular (NMD) or chest-wall disorders (CWD)., Methods: Controlled, non-controlled and cohort studies indexed between January-2000 and December-2020 were sought from Medline, Embase and the Cochrane Central Register. Outcomes were diurnal PaCO 2 , PaO 2 , daily NIV usage, and interface type (PROSPERO-CRD 42021245121). NIV intensity was defined according to the Z-score of the product of pressure support (or tidal volume) and backup-rate., Results: 16 eligible studies were identified; we obtained IPD for 7 studies (176 participants: 113-NMD; 63-CWD). The reduction in PaCO 2 was greater with higher baseline PaCO 2 . NIV intensity per se was not associated with improved PaCO 2 except in individuals with CWD and the most severe baseline hypercapnia. Similar results were found for PaO 2 . Daily NIV usage was associated with improvement in gas exchange but not with NIV intensity. No association between NIV intensity and interface type was found., Conclusion: Following home NIV initiation in NMD or CWD patients, no relationship was observed between NIV intensity and PaCO 2 , except in individuals with the most severe CWD. The amount of daily NIV usage, rather than intensity, is key to improving hypoventilation in this population during the first few months after introduction of therapy., (Copyright © 2023 SEPAR. Published by Elsevier España, S.L.U. All rights reserved.)

The objective of this study is to examine the potential association between drug use and adverse event reporting in France. A number of drug users and cases reported were extracted from the French Health Care Insurance database (Open Medic) and the French pharmacovigilance database. We performed two separate mixed-effect models (with a drug used or reporting rate as dependent variables) with a random intercept for drug classes. We selected 62 drugs from 10 drug classes, for which 177 364 cases were reported in the French pharmacovigilance database in 2020. The results showed a strong association between drug users and the number of reported cases in France among each drug class (P < 0.01). Within a drug class, the number of reported cases is, therefore, a proxy for the exposure to a given drug in the population. This finding could be useful to approximate and compare drug exposure from pharmacovigilance databases., (© 2023 The Authors. Fundamental & Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of Société Française de Pharmacologie et de Thérapeutique.)

Background: A common complaint of people with aphasia and their families is their inability to find information about current aphasia treatment research (Hinckley, Boyle, Lombard & Bartels-Tobin, 2014; Hinckley & El-Khouri, 2021). Plain language summaries, video summaries, and graphical summaries are three ways to disseminate research results that are more accessible to a broader audience. The purpose of this tutorial is to discuss the motivations for disseminating research in understandable ways, and to provide information and resources on how aphasia-friendly dissemination can be done., Method: We report an overview of evidence on the importance of and characteristics of dissemination. Next, we provide specific characteristics and resources for producing plain language summaries, video summaries, and graphical abstracts. Finally, we conducted a systematic search for journals in the area of stroke rehabilitation after consultation with a research librarian. The publication webpages of each journal were inspected to gather information about whether and how the journal published plain language summaries, video summaries, or graphical abstracts. Editors were contacted as needed to complete the information. Sixty journals in stroke rehabilitation were identified, and a total of 43 journals (71%) publish video abstracts, graphical summaries, and/or plain language summaries either independently or through third-party platforms., Conclusions: The findings are discussed in the context of the importance of making research consumer-friendly. We offer specific recommendations for aphasia researchers, and future directions for publishing research in ways that will have an impact on the broader public are suggested., (Copyright © 2023. Published by Elsevier Inc.)

Competing Interests: Conflict of interest: None declared.

Background and Aims: The current opioid epidemic in the United States began 20 years ago and has become the leading cause of accidental deaths in the country. This crisis prompted us to explore trends in opioid abuse and dependence worldwide. We sought to identify other countries at high-risk of opioid use disorders, using the World Health Organization's (WHO) pharmacovigilance database., Methods: We performed a disproportionality analysis using VigiBase, the WHO Global Individual Case Safety Report (ICSR) database. Five opioids used worldwide were included: oxycodone, fentanyl, morphine, tramadol, and codeine. We extracted all ICSRs associated with the drugs of interest, considered as suspect medication and recorded up until 5 June 2021, using the narrow Standardised MedDRA Query (SMQ) for drug abuse and dependence. Countries with at least one ICSR for each of the five opioids were retained. The relationship between the use of a drug (i.e. an opioid) and the occurrence of an adverse drug reaction (i.e. drug abuse and dependence) for each country was assessed by calculating the information component (IC) and its 99.9% CI [IC 0005 ; IC 9995 ], using a quasi-Bayesian confidence propagation neural network (BCPNN). A hierarchical cluster analysis (Ward's method) of the IC 0005 value for each of the five opioids was performed to identify subgroups of countries with similar reported risks of opioid abuse and dependence., Results: Among 21 countries, the optimal number of clusters was calculated to be four, each with a Jaccard index >0.5 (0.95, 0.78, 0.65 and 0.75, respectively). Six countries with the highest signals of drug abuse and dependence were identified in cluster 1, with significant CIs for the five opioids of interest (IC 0005  > 0), ranging from 0.9 to 5.8 for the lower endpoint., Conclusions: There appear to be four distinct clusters of countries with similar opioid abuse and dependence profiles. The group with the highest reported risk for the opioids oxycodone, fentanyl, morphine, tramadol and codeine includes Australia, Canada, France, Germans, the United Kingdom and the United States., (© 2022 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Since the 1960s, several drugs have been linked to the onset or aggravation of pulmonary arterial hypertension (PAH): dasatinib, some amphetamine-like appetite suppressants (aminorex, fenfluramine, dexfenfluramine, benfluorex) and recreational drugs (methamphetamine). Moreover, in numerous cases, the implication of other drugs with PAH have been suggested, but the precise identification of iatrogenic aetiologies of PAH is challenging given the scarcity of this disease and the potential long latency period between drug intake and PAH onset. In this context, we used the World Health Organization's pharmacovigilance database, VigiBase, to generate new hypotheses about drug associated PAH., Methods: We used VigiBase, the largest pharmacovigilance database worldwide to generate disproportionality signals through the Bayesian neural network method. All disproportionality signals were further independently reviewed by experts in pulmonary arterial hypertension, pharmacovigilance and vascular pharmacology and their plausibility ranked according to World Health Organization causality categories., Results: We included 2184 idiopathic PAH cases, yielding a total of 93 disproportionality signals. Among them, 25 signals were considered very likely, 15 probable, 28 possible and 25 unlikely. Notably, we identified 4 new protein kinases inhibitors (lapatinib, lorlatinib, ponatinib and ruxolitinib), 1 angiogenesis inhibitor (bevacizumab), and several chemotherapeutics (etoposide, trastuzumab), antimetabolites (cytarabine, fludarabine, fluorouracil, gemcitabine) and immunosuppressants (leflunomide, thalidomide, ciclosporin)., Conclusion: Such signals represent plausible adverse drug reactions considering the knowledge of iatrogenic PAH, the drugs' biological and pharmacological activity and the characteristics of the reported case. Although confirmatory studies need to be performed, the signals identified may help clinicians envisage an iatrogenic aetiology when faced with a patient who develops PAH., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Substantial placebo response has been observed in trials assessing treatments in Raynaud's Phenomenon (RP), which makes any treatment effect difficult to detect. However, whether this response is due to a real placebo effect or to other nonspecific effects, such as regression towards the mean (RTM), has not been explored. Our objectives were to explore and quantify placebo response in RP, and to evaluate the magnitude of RTM contribution., Methods: We combined trial-level and individual-level data from a series of n-of-1 trials and a network meta-analysis, respectively. Main outcomes were the daily frequency and the mean duration of RP attacks, as well as the Raynaud's Condition Score (RCS). We estimated the placebo response by the mean difference between the placebo period (or arm) and the baseline. RTM was estimated by the relationship between placebo response and baseline, and with Galton squeeze plots. Finally, we simulated the effect of the threshold used for inclusion in clinical trials on RTM., Findings: We observed a large and significant placebo response from both individual and trial data for RCS [-1.20 (-1.63, -0.77) and -0.65 (-0.89, -0.41)] and the daily frequency of RP [-0.61 (-0.85, -0.37) and -0.75 (-0.95, -0.54)]. Outcome at baseline was significantly associated with placebo response, suggesting the presence of RTM. The latter was confirmed on individual data, through Galton squeeze plots., Interpretation: Placebo response is large in RP trials, and likely due to regression towards the mean rather than 'true' placebo effect. This should be carefully considered when designing future trials., Funding: This work has been partially supported by MIAI @ Grenoble Alpes (ANR-19-P3IA-0003)., Competing Interests: Declaration of Competing Interest The authors declare no competing interest for this work., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Little is known about the impact of mandatory vaccination on people who are reluctant to be vaccinated, despite the potential importance in terms of public health policy., Objective: We aimed to explore the relationship between vaccine hesitancy and onset, severity and characteristics of self-reported adverse events., Methods: We used a cross-sectional online survey conducted in 2021 among a representative sample of the French population aged 18 years and older (n = 1593). All reported adverse events were analyzed and categorized by trained experts in drug safety and pharmacovigilance. Multivariate binomial regressions on the onset of self-reported adverse events, vaccine hesitancy categories and predefined responders' characteristics were performed., Results: Overall, 590 (37.0%) participants reported at least one adverse event, with 121 (20.5%) considered it to be severe. Proportions of reported adverse events, ranging from 18% (in non-reluctant responders) to 65% (in very reluctant responders), and their severity, ranging from 5% (non-reluctant responders) to 41% (very reluctant responders), depended highly on attitudes toward vaccination. The adverse events profile remained similar between groups. In the multivariate regression model, beyond attitude toward vaccination, younger age and female gender were significantly associated with higher reporting of vaccine adverse events., Conclusions: Our results suggest that vaccine hesitancy could be a major driver of patient-reported vaccine-related adverse events and their perceived severity. In this context, vaccinators must pay special attention to reluctant patients and inform them on the possible nocebo nature of these adverse events so as to prevent them., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: To provide a qualitative view and quantitative measure of sleep disturbances across and between early stages - clinical ultra high-risk and first episode - of psychotic and bipolar disorders., Methods: Electronic databases (PubMed, Cochrane, Embase, PsychINFO) were searched up to March 2021 for studies comparing sleep measures between individuals with an early stage and controls. Standard mean deviations (Cohen's d effect sizes) were calculated for all comparisons and pooled with random-effects models. Chi-square tests were used for direct between-subgroups (ultra high-risk vs first episode) comparisons of standard mean deviations. The effects of age, sex ratio, symptoms and treatment were examined in meta-regression analyses., Results: A database search identified 13 studies that contrasted sleep measures between individuals with an early stage ( N  = 537) and controls ( N  = 360). We observed poorer subjective sleep quality (standard mean deviation = 1.32; 95% confidence interval, [1.01, 1.62]), shorter total sleep time (standard mean deviation =-0.44; 95% confidence interval, [-0.67, -0.21]), lower sleep efficiency (standard mean deviation = -0.72; 95% confidence interval, [-1.08, -0.36]), longer sleep onset latency (standard mean deviation = 0.75; 95% confidence interval, [0.45, 1.06]) and longer duration of wake after sleep onset (standard mean deviation = 0.49; 95% confidence interval, [0.21, 0.77]) were observed in early stages compared to controls. No significant differences were observed for any of the reported electroencephalographic parameters of sleep architecture. No significant between-subgroups differences were observed. Meta-regressions revealed a significant effect of the age and the antipsychotic status on subjective measures of sleep., Conclusion: The early stage population presents with significant impairments of subjective sleep quality continuity, duration and initiation. Systematic assessments of sleep in early intervention settings may allow early identification and treatment of sleep disturbances in this population.

Background and Objective: The concern surrounding the association between Guillain-Barré syndrome (GBS) and vaccination has increased with the widespread use of COVID-19 vaccines. The aim of this study was to assess the potential association of GBS with mRNA-based or adenovirus-vectored COVID-19 vaccines., Methods: Reports of GBS associated with mRNA-based or adenovirus-vectored COVID-19 vaccines were extracted from the WHO pharmacovigilance database, exposure data from the Our World in Data website, and the background rates of GBS from published data. For countries contributing to VigiBase and with available data on COVID-19 vaccine exposure, reporting rates were estimated and observed-to-expected (OE) analyses were performed., Results: A total of 2499 cases were included: 1157 (46.3%) cases with adenovirus-vectored COVID-19 vaccines and 1342 (53.7%) with mRNA-based COVID-19 vaccines. The male-to-female sex ratio was 1.09 and the median (IQR) age was 57 (45-66) years. The reporting rates (95% CI) per 100,000 person-years within the 42-day window were 5.57 (5.13-6.03) for adenovirus-vectored COVID-19 vaccines and 1.39 (1.31-1.47) for mRNA-based COVID-19 vaccines, while the background incidence was 1.2-3.1 per 100,000 person-years. For mRNA-based COVID-19 vaccines, the OE ratio was <1 for both time windows in all European countries and slightly elevated for the 21-day window in the USA. For adenovirus-vectored COVID-19 vaccines, the OE ratio was consistently > 2.0 for all countries. Sensitivity analyses minimally altered these results., Conclusions: These findings suggest both the absence of safety concern for GBS with mRNA-based COVID-19 vaccines and an increased risk with adenovirus-vectored COVID-19 vaccines. Back to top., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Classifications of impaction based on panoramic radiographs such as the ones of Pell and Gregory and Winter are essential to allow a better understanding of third molar position regarding depth and bone coverage of the impacted tooth and to evaluate the difficulties of the surgical procedures. The aim of the study was to classify upper and lower third molars teeth in a sample of a Lebanese population and compare the data to results from other studies., Materials and Methods: Digital panoramic radiographs of 71 patients with a total of 181 wisdom teeth from patients that had been subjected for third molars extraction, from November 2016 to November 2018, were collected and analyzed. The mean age was 26.25 years. All third molars were categorized according to Pell and Gregory by using A, B, C scores for depth in upper and lower third molars, and angulations were classified according to Winter's classification. Nonparametric normality tests evaluating age group and gender distribution were conducted by utilizing the Chi-square test for age distribution and the binomial and Kruskal-Wallis tests for gender., Results: In the Pell and Gregory classification, the lower third molars showed type B impaction as the most frequent with 66.1% for the right side and 60.3% for the left side; the maxillary third molars both showed the type C impaction as the most frequent with 63.3% for the right side and 59.2% for the left side. According to the Winter classification, lower third molars showed mesio-angulation as the most frequent angle of impaction with 41.1% for right mandibular side and 46.5% for mandibular left side; As for the maxillary third molars, the disto-angulation was the most frequent angulation seen in both maxillary right and left side teeth 53.3% and 43.2%., Conclusions: Comparison of our results with other populations has shown similarities in certain criteria like angulation and relation to ramus, but most results varied. Thus, the current study can be taken as a baseline for further studies., Competing Interests: Conflict of interestThe authors declared that they have no conflict of interest., (© The Association of Oral and Maxillofacial Surgeons of India 2020.)

Coronary microvascular dysfunction (CMVD) is common and associated with poorer outcomes in patients with ST Segment Elevation Myocardial Infarction (STEMI). The index of microcirculatory resistance (IMR) and the index of hyperemic microvascular resistance (HMR) are both invasive indexes of microvascular resistance proposed for the diagnosis of severe CMVD after primary percutaneous coronary intervention (pPCI). However, these indexes are not routinely assessed in STEMI patients. Our main objective was to clarify the association between IMR or HMR and long-term major adverse cardiovascular events (MACE), through a systematic review and meta-analysis of observational studies. We searched Medline, PubMed, and Google Scholar for studies published in English until December 2020. The primary outcome was a composite of cardiovascular death, non-cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and rehospitalization for heart failure occurring after at least 6 months following CMVD assessment. We identified 6 studies, reporting outcomes in 1094 patients (mean age 59.7 ± 11.4 years; 18.2% of patients were women) followed-up from 6 months to 7 years. Severe CMVD, defined as IMR > 40 mmHg or HMR > 3mmHg/cm/sec was associated with MACE with a pooled HR of 3.42 [2.45; 4.79]. Severe CMVD is associated with an increased risk of long-term adverse cardiovascular events in patients with STEMI. Our results suggest that IMR and HMR are useful for the early identification of severe CMVD in patients with STEMI after PCI, and represent powerful prognostic assessments as well as new therapeutic targets for clinical intervention., Competing Interests: The authors have declared that no competing interests exist.

Aim: Intermittent hypoxia (IH) is considered to be a major contributor to obstructive sleep apnoea-related cardiovascular consequences. The present meta-analysis aimed to assess the effects of IH on cardiac remodelling, function and infarct size after myocardial ischaemia across different rodent species and IH severities., Methods and Results: Relevant articles from PubMed, Embase and Web of Science were screened. We performed a random effect meta-analysis to assess the effect of IH on myocardium in rodents by using standardised mean difference (SMD). Studies using rodents exposed to IH and outcomes related to cardiac remodelling, contractile function and response to myocardial ischaemia-reperfusion were included. 5217 articles were screened and 92 were included, demonstrating that IH exposure induced cardiac remodelling, characterised by cardiomyocyte hypertrophy (cross-sectional area: SMD=2.90, CI (0.82-4.98), I 2 =94.2%), left ventricular (LV) dilation (LV diameter: SMD=0.64, CI (0.18-1.10), I 2 =88.04%), interstitial fibrosis (SMD=5.37, CI (3.22-7.53), I 2 =94.8) and apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labelling: SMD=6.70, CI (2.96-10.44), I 2 =95.9). These structural changes were accompanied by a decrease in LV ejection fraction (SMD=-1.82, CI (-2.52--1.12), I 2 =94.22%). Importantly, most of the utilised IH protocols mimicked extremely severe hypoxic disease. Concerning infarct size, meta-regression analyses highlighted an ambivalent role of IH, depending on its severity. Indeed, IH exposure with inspiratory oxygen fraction ( F IO 2 ) <7% was associated with an increase in infarct size, whereas a reduced infarct size was reported for F IO 2 levels above 10%. Heterogeneity between studies, small study effect and poor reporting of methods in included articles limited the robustness of the meta-analysis findings., Conclusion: This meta-analysis demonstrated that severe IH systematically induces cardiac remodelling and contractile dysfunction in rodents, which might trigger or aggravate chronic heart failure. Interestingly, this meta-analysis showed that, depending on stimulus severity, IH exhibits both protective and aggravating effects on infarct size after experimental ischaemia-reperfusion procedures., Competing Interests: Conflict of interest: E. Belaidi has nothing to disclose. Conflict of interest: C. Khouri has nothing to disclose. Conflict of interest: O. Harki has nothing to disclose. Conflict of interest: S. Baillieul has nothing to disclose. Conflict of interest: G. Faury has nothing to disclose. Conflict of interest: A. Briançon-Marjollet has nothing to disclose. Conflict of interest: J.-L. Pépin has nothing to disclose. Conflict of interest: C. Arnaud. has nothing to disclose., (Copyright ©The authors 2022.)

Background: Obstructive sleep apnoea and the related intermittent hypoxia (IH) are widely recognised as risk factors for incident cardiovascular diseases. Numerous studies support the deleterious vascular impact of IH in rodents but an overall interpretation is challenging owing to heterogeneity in rodent species investigated and the severity and duration of IH exposure. To clarify this major issue, we conducted a systematic review and meta-analysis to quantify the impact of IH on systemic artery structure and function depending on the different IH exposure designs., Methods: We searched PubMed, Embase and Web of Science, and included 125 articles in a meta-analysis, among them 112 using wild-type rodents and 13 using apolipoprotein E knockout (ApoE -/- ) mice. We used the standardised mean difference (SMD) to compare results between studies., Results: IH significantly increased mean arterial pressure (+13.90 (95% CI 11.88-15.92) mmHg), and systolic and diastolic blood pressure. Meta-regressions showed that mean arterial pressure change was associated with strain and year of publication. IH altered vasodilation in males but not in females and increased endothelin-1-induced but not phenylephrine-induced vasoconstriction. Intima-media thickness significantly increased upon IH exposure (SMD 1.10 (95% CI 0.58-1.62); absolute values +5.23 (2.81-7.84) µm). This increase was observed in mice but not in rats and was negatively associated with age. Finally, IH increased atherosclerotic plaque size in ApoE -/- mice (SMD 1.08 (95% CI 0.80-1.37))., Conclusions: Our meta-analysis established that IH, independently of other confounders, has a strong effect on vascular structure and physiology. Our findings support the interest of identifying and treating sleep apnoea in routine cardiology practice., Competing Interests: Conflict of interest: O. Harki has nothing to disclose. Conflict of interest: Q. Boete has nothing to disclose. Conflict of interest: J-L. Pépin has nothing to disclose. Conflict of interest: C Arnaud has nothing to disclose. Conflict of interest: E. Belaidi has nothing to disclose. Conflict of interest: G. Faury has nothing to disclose. Conflict of interest: C. Khouri has nothing to disclose. Conflict of interest: A. Briançon-Marjollet has nothing to disclose., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Protein kinase inhibitors experienced their advent in the 2000s. Their market introduction made it possible to constitute a class of targeted therapies administered orally. This name was chosen to mark a break with conventional chemotherapy drugs, but it is important to stress that these are multi-target drugs with complex affinity profiles. Adverse effects can be explained by direct interactions with their targets of interest, chosen for their indications (on-target) but also interactions with other targets (off-target). The adverse effect profiles of these drugs are therefore varied and it is possible to identify common profiles related to inhibitions of common targets. Identification of these targets has improved the global understanding of the pathophysiological mechanisms underlying the onset of adverse drug reactions as well as of the related diseases, and makes it possible to predict the adverse effect profile of new protein kinase inhibitors based on their affinities. In this review, we describe the main adverse drug reactions associated with protein kinase inhibitors, their frequency and their plausible mechanisms of action., (Copyright © 2021 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

We report the case of a 77-year-old man with Parkinson's disease (PD) who experimented for the first time gout crisis after the initiation of levodopa. Levodopa was withdrawn, and colchicine and allopurinol were initiated to treat the gout crisis. Because of PD progression, levodopa was reintroduced, and the patient presented relapse of gout flare. To further explore the association between gout and levodopa, we extracted and synthetized all Individual Case Safety Reports of gout associated with levodopa in the World Health Organization pharmacovigilance database, VigiBase ® , up to April 2021. 43 cases of gout were reported in VigiBase ® with drugs from N04BA ATC class. Levodopa was suspected in fifteen cases among which improvement was noticed in six cases (two after levodopa withdrawal, two despite treatment continuation, and two cases lacking details about action taken with levodopa); three cases did not recover; in the remaining six cases, evolution was not known. "Hyperuricemia" was not mentioned in the Summary of Product Characteristics of medicine containing levodopa; however, "abnormality biologics test with uric acid" was mentioned. Despite few cases of recovery after reduced doses of levodopa, the above-described case of positive reintroduction was an argument in favor of the role of levodopa in gout flare. This study highlights a potential association between levodopa and gout through an analysis of the cases reported in the WHO pharmacovigilance database., (© 2021 Société Française de Pharmacologie et de Thérapeutique.)

Background: A particularly high burden of sleep apnoea is reported in patients treated with cardiac implants such as pacemakers and defibrillators. Sleep apnoea diagnosis remains a complex procedure mainly based on sleep and respiratory indices captured by polysomnography (PSG) or respiratory polygraphy (PG)., Aim: We aimed to evaluate the performance of implantable cardiac devices for sleep apnoea diagnosis compared to reference methods., Method: Systematic structured literature searches were performed in PubMed, Embase and. Cochrane Library was performed to identify relevant studies. Quantitative characteristics of the studies were summarized and a qualitative synthesis was performed by a randomized bivariate meta-analysis and completed by pre-specified sensitivity analyses for different implant types and brands., Results: 16 studies involving 999 patients met inclusion criteria and were included in the meta-analysis. The majority of patients were men, of mean age of 64 ± 4.6 years. Sensitivity of cardiac implants for sleep apnoea diagnosis ranged from 60 to 100%, specificity from 50 to 100% with a prevalence of sleep apnoea varying from 22 to 91%. For an apnoea-hypopnoea index threshold ≥30 events/h during polysomnography (corresponding to severe sleep apnoea), the overall performance of the implants was relevant with a sensitivity of 78% and a specificity of 79%. Subgroup analyses on implant type and brand provided no additional information owing to the small number of studies., Conclusion: The respiratory disturbance index provided by cardiac implants is clinically relevant and might improve access to sleep apnoea diagnosis in at-risk cardiovascular populations. PROSPERO Registration number: CRD42020181656., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aim of the Study: The use of nefopam is constantly increasing in France. The objectives of this study were to quantify the intensity of the drug dependence signal, to identify the populations at risk and the risk factors of dependence., Methods: All serious and non-serious cases of misuse, abuse, drug dependence, overdose and withdrawal syndrome reported to the French Addictovigilance Network since 1988 were reviewed. An analysis of nefopam reimbursement data from the French national EGB (échantillon généraliste des bénéficiaires) database for the period 2006-2017 was also performed., Results: The drug dependence profile of nefopam is close to that of a psychostimulant. Our literature review and the analysis of spontaneous reports confirm the risk of abuse and dependence of nefopam. In addition to a frequent psychiatric history (depression, psychosis, anxiety), nearly half of the patients also present addictive disorders, including more than one-third with opioid-dependence. In almost half of the 120 reported cases, the main adverse reaction was dependence and the frequency of serious effects was greater than 40%. In nearly 70% of the reported cases, the use was associated with chronic pain, which might explain the prolonged use. Moreover, the analysis of data on the reimbursement of nefopam in the general population showed that one French person out of two, having a prescription for nefopam, presented chronic pain. However, nefopam is only indicated in the treatment of acute painful conditions. Although it does not seem to be associated with a greater risk of abuse or dependence, taking the drug orally is another very frequent off-label use that needs to be regulated., Conclusion: In France, the prescription of nefopam outside of its marketing authorization is regrettable, because it contributes to the development of abuse and drug dependence., (Copyright © 2021 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Background: The optimal interface for the delivery of home non-invasive ventilation (NIV) to treat chronic respiratory failure has not yet been determined. The aim of this individual participant data (IPD) meta-analysis was to compare the effect of nasal and oronasal masks on treatment efficacy and adherence in patients with COPD and obesity hypoventilation syndrome (OHS)., Methods: We searched Medline and Cochrane Central Register of Controlled Trials for prospective randomised controlled trials (RCTs) of at least 1 month's duration, published between January 1994 and April 2019, that assessed NIV efficacy in patients with OHS and COPD. The main outcomes were diurnal PaCO 2 , PaO 2 and NIV adherence (PROSPERO CRD42019132398)., Findings: Of 1576 articles identified, 34 RCTs met the inclusion criteria and IPD were obtained for 18. Ten RCTs were excluded because only one type of mask was used, or mask data were missing. Data from 8 RCTs, including 290 IPD, underwent meta-analysis. Oronasal masks were used in 86% of cases. There were no differences between oronasal and nasal masks for PaCO 2 (0.61 mm Hg (95% CI -2.15 to 3.38); p=0.68), PaO 2 (-0.00 mm Hg (95% CI -4.59 to 4.58); p=1) or NIV adherence (0·29 hour/day (95% CI -0.74 to 1.32); p=0.58). There was no interaction between the underlying pathology and the effect of mask type on any outcome., Interpretation: Oronasal masks are the most used interface for the delivery of home NIV in patients with OHS and COPD; however, there is no difference in the efficacy or tolerance of oronasal or nasal masks., Competing Interests: Competing interests: ML has no conflict of interest to declare related to the present work. He received speaker fees from Air Liquide Medical System, and Sefam, and non-financial support from Nomics outside the context of the submitted work. He received a salary from Air Liquide Medical System as a medical trainer. A Léotard has no conflict of interest to declare related to the present work. JC Borel is salaried by AGIR à dom, a home-care provider. JL Pépin and his department has received research support and personal fees from Philips Respironics, Sefam, Fisher and Paykel, and ResMed. JLP is supported by the French National Research Agency in the framework of the "Investissements d’avenir” program (ANR-15-IDEX-02) and the “e-health and integrated care and trajectories medicine and MIAI artificial intelligence” Chairs of excellence from the Grenoble Alpes University Foundation. This work has been partially supported by MIAI @ Grenoble Alpes (ANR-19-P3IA-0003). M Dreher has received speaking and advisor fees from companies in the field of mechanical ventilation; in addition, his study group received an open research grant from ResMed. JH Storre reports grants and personal fees for lectures from Heinen und Löwenstein and VitalAire, grants, personal fees for lectures and non-financial support for meeting attendance from Vivisol GmbH, grants from Weinmann Deutschland, personal fees for consultancy/advisory board work from Breas Medical AB regarding the submitted work; personal fees for consultancy and lectures, and non-financial support for meeting attendance from Boehringer Ingelheim Pharma, personal fees for consultancy and lectures from SenTec AG, Keller Medical GmbH, Linde Deutschland and Santis GmbH, outside the submitted work. M Patout reports personal fees from Resmed, Philips Respironics, grants and non-financial support from Fisher & Paykel, non-financial support and personal fees from Asten, research grants from B& D Electromedical and Fisher & Paykel, personal fees and non-financial support from Chiesi outside the submitted work. GC Funk received speaker fees from Draeger and Getinge. PJ Wijkstra reports grants and personal fees from Philips, grants and personal fees from RESMED, grants from Vital Air, grants from VIVISOL, grants from Goedegebuure, personal fees from Synapse, personal fees from Bresotec, outside the submitted work., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To review and appraise methods and reporting characteristics of pharmacovigilance disproportionality analyses., Study Design and Setting: We randomly selected 100 disproportionality analyses indexed in Medline found during a systematic literature search. We then extracted and synthetized methodological and reporting characteristics using seven key items: (1) title transparency; (2) protocol pre-registration; (3) date of data extraction and analysis; (4) outcome, population, exposure and comparator definitions; (5) adjustment and stratification of results; (6) method and threshold for signal detection; (7) secondary and sensitivity analyses., Results: We found that methods used to generate disproportionality signals were extremely heterogeneous; there were nearly as many unique analyses as studies. The authors used various populations, methods, signal detection thresholds, adjustment or stratification variables, generally without justification for their choice or pre-specification in protocols. Moreover, 78% of studies failed to report methods for case, adverse drug reactions or comparator selection and 32 studies did not define the threshold for signal generation., Conclusion: Our survey raises major concerns regarding all aspects of disproportionality analyses that could lead to misleading results and generate unjustified alarms. We advocate for a strong and transparent rationale for variable selection, choice of population and comparators pre-specified in a protocol and assessed by sensitivity analyses., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Millions of Americans have been infected with COVID-19 and communities of color have been disproportionately burdened. We investigated the relationship between demographic characteristics and COVID-19 positivity, and comorbidities and severe COVID-19 illness (use of mechanical ventilation and length of stay) within a racial/ethnic minority population. Patients tested for COVID-19 between March 2020 and January 2021 (N = 14171) were 49.9% (n = 7072) female; 50.1% (n = 7104) non-Hispanic Black; 33.2% (n = 4698) Hispanic; and 23.6% (n = 3348) aged 65+. Overall COVID-19 positivity was 16.1% (n = 2286). Compared to females, males were 1.1 times more likely to test positive (p = 0.014). Compared to non-Hispanic Whites, non-Hispanic Black and Hispanic persons were 1.4 (p = 0.003) and 2.4 (p<0.001) times more likely, respectively, to test positive. Compared to persons ages 18-24, the odds of testing positive were statistically significantly higher for every age group except 25-34, and those aged 65+ were 2.8 times more likely to test positive (p<0.001). Adjusted for race, sex, and age, COVID-positive patients with chronic obstructive pulmonary disease were 1.9 times more likely to require a ventilator compared to those without chronic obstructive pulmonary disease (p = 0.001). Length of stay was not statistically significantly associated with any of the comorbidity variables. Our findings emphasize the importance of documenting COVID-19 disparities in marginalized populations., Competing Interests: The authors have declared that no competing interests exist.

Objective: To systematically review and appraise misinterpretation of pharmacovigilance disproportionality analysis results in published studies., Study Design and Setting: We randomly selected 100 studies that performed disproportionality analyses and indexed in Medline identified during a systematic literature search. Titles, abstracts and main texts (results, discussion and conclusion) were evaluated for spin independently by two reviewers. Spin in pharmacovigilance studies was classified according to three main categories: inappropriate interpretation, inappropriate extrapolations and misleading reporting., Results: Of the 100 studies evaluated, we found that 63%, 56% and 51% had at least one type of spin in their abstract, main text or conclusion respectively, and 40% used causal language to interpret their results in the abstract or conclusion. Spin in titles and results were exclusively represented by inappropriate interpretations of findings (12% and 21% respectively), with terms such as "risk of" or "risks associated with" or results erroneously presented as regular Odds Ratios. Spin in discussion sections mostly concerned inappropriate interpretations (38%)and misleading reporting (12%). Misleading reporting, notably failing to acknowledge the limitations of disproportionality analyses, was the most frequent type of spin in abstracts (55%) and conclusion sections (37%)., Conclusion: We found that spin is frequent in publications of pharmacovigilance disproportionality analyses, notably in abstracts. This consisted notably in an over-interpretation of the results suggesting a proven causative link between a drug use and the risk of an event., (Copyright © 2021. Published by Elsevier Inc.)

Rationale: Pulmonary hypertension (PH) has been described in patients treated with leflunomide. Objectives: To assess the association between leflunomide and PH. Methods: We identified incident cases of PH in patients treated with leflunomide from the French PH Registry and through the pharmacoVIGIlAnce in Pulmonary ArTerial Hypertension (VIGIAPATH) program between September 1999 to December 2019. PH etiology, clinical, functional, radiologic, and hemodynamic characteristics were reviewed at baseline and follow-up. A pharmacovigilance disproportionality analysis using the World Health Organization's global database was conducted. We then investigated the effect of leflunomide on human pulmonary endothelial cells. Data are expressed as median (min-max). Results: Twenty-eight patients treated with leflunomide before PH diagnosis was identified. A total of 21 (75%) had another risk factor for PH and 2 had two risk factors. The median time between leflunomide initiation and PH diagnosis was 32 months (1-120). Right heart catheterization confirmed precapillary PH with a cardiac index of 2.37 L⋅min -1 ⋅m -2 (1.19-3.1) and elevated pulmonary vascular resistance at 9.63 Wood Units (3.6-22.1) without nitric oxide reversibility. Five patients (17.9%) had no other risk factor for PH besides exposure to leflunomide. No significant hemodynamic improvement was observed after leflunomide withdrawal. The pharmacovigilance disproportionality analysis using the World Health Organization's database revealed a significant overrepresentation of leflunomide among reported pulmonary arterial hypertension-adverse drug reactions. In vitro studies showed the dose-dependent toxicity of leflunomide on human pulmonary endothelial cells. Conclusions: PH associated with leflunomide is rare and usually associated with other risk factors. The pharmacovigilance analysis suggests an association reinforced by experimental data.

Objective: We aimed at testing if a correlation between adverse drug reactions relative risks estimated from meta-analyses and disproportionality analyses calculated from pharmacovigilance spontaneous reporting systems databases exist, and if methodological choices modify this correlation., Study Design: We extracted adverse drug reactions (ADR) odds ratios (ORs) from meta-analyses used as reference and calculated corresponding Reporting Odds Ratios (RORs) from the WHO pharmacovigilance database according to five different designs. We also calculated the relative bias and agreement of ROR compared to ORs., Results: We selected five meta-analyses which displayed a panel of 13 ADRs. A significant correlation for 7 out of the 13 ADRs studied in the primary analysis was found. The methods for ROR calculation impacted the results but none systematically improved the correlations. Whereas correlation was found between OR and ROR, agreement was poor and relative bias was important., Conclusion: Despite the large variation in disproportionality analyses results due to design specification, this study provides further evidence that relative risks obtained from meta-analyses and from disproportionality analyses correlate in most cases, in particular for objective ADR not associated with the underlying pathology., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Bariatric surgery is the most effective treatment of severe obesity. However, this surgery can have an impact on the bioavailability and metabolism of oral drugs as it modifies absorption, intestinal, and hepatic metabolism, and efflux transporter activity. The clinical impact of such modifications often remains unknown. To investigate, we extracted and summarized all reports of changes in drug efficacy associated with bariatric surgery registered in the WHO pharmacovigilance database. We identified 165 drug reports affecting 128 patients. The majority involved gastric bypass surgery (77.3%). Most reports concerned drug ineffectiveness (74.7%). The most frequent modifications concerned psychotropic drugs with a reduction in efficacy. This study underlines the urgent need for more research to better characterize the impact of bariatric surgery on drug pharmacokinetics and clinical efficacy.

Background: A plethora of methods and models of disproportionality analyses for safety surveillance have been developed to date without consensus nor a gold standard, leading to methodological heterogeneity and substantial variability in results. We hypothesized that this variability is inversely correlated to the robustness of a signal of disproportionate reporting (SDR) and could be used to improve signal detection performances. Methods: We used a validated reference set containing 399 true and false drug-event pairs and performed, with a frequentist and a Bayesian disproportionality method, seven types of analyses (model) for which the results were very unlikely to be related to actual differences in absolute risks of ADR. We calculated sensitivity, specificity and plotted ROC curves for each model. We then evaluated the predictive capacities of all models and assessed the impact of combining such models with the number of positive SDR for a given drug-event pair through binomial regression models. Results: We found considerable variability in disproportionality analysis results, both positive and negative SDR could be generated for 60% of all drug-event pairs depending on the model used whatever their truthfulness. Furthermore, using the number of positive SDR for a given drug-event pair largely improved the signal detection performances of all models. Conclusion: We therefore advocate for the pre-registration of protocols and the presentation of a set of secondary and sensitivity analyses instead of a unique result to avoid selective outcome reporting and because variability in the results may reflect the likelihood of a signal being a true adverse drug reaction., 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 © 2021 Khouri, Nguyen, Revol, Lepelley, Pariente, Roustit and Cracowski.)

Few studies have simultaneously investigated the impact of inflammation and genetic polymorphisms of cytochromes P450 2C19 and 3A4 on voriconazole trough concentrations. We aimed to define the respective impact of inflammation and genetic polymorphisms on voriconazole exposure by performing individual data meta-analyses. A systematic literature review was conducted using PubMed to identify studies focusing on voriconazole therapeutic drug monitoring with data of both inflammation (assessed by C-reactive protein level) and the pharmacogenomics of cytochromes P450. Individual patient data were collected and analyzed in a mixed-effect model. In total, 203 patients and 754 voriconazole trough concentrations from six studies were included. Voriconazole trough concentrations were independently influenced by age, dose, C-reactive protein level, and both cytochrome P450 2C19 and 3A4 genotype, considered individually or through a combined genetic score. An increase in the C-reactive protein of 10, 50, or 100 mg/L was associated with an increased voriconazole trough concentration of 6, 35, or 82%, respectively. The inhibitory effect of inflammation appeared to be less important for patients with loss-of-function polymorphisms for cytochrome P450 2C19. Voriconazole exposure is influenced by age, inflammatory status, and the genotypes of both cytochromes P450 2C19 and 3A4, suggesting that all these determinants need to be considered in approaches of personalization of voriconazole treatment.

Vancomycin is a tricyclic glycopeptide antibiotic produced from Streptococcus orientalis . There is much variation in the literature with regard to the recommended dose, dilution rate and type of infusion. Given the vesicant properties of vancomycin at supratherapeutic doses (>10mg/ml), tissue damage including blistering and necrosis have been reported. We report a rare case of bilateral cutaneous necrosis induced by accidental extravasation of vancomycin when being intravenously administered. The skin surrounding the injection site was marked by the appearance of subcutaneous calcifications. The development of iatrogenic skin calcinosis has not yet been described for the extravasation of vancomycin. The mechanism underlying the calcinosis observed in our case remains unclear, but we hypothesised a form of localised calciphylaxis induced by a local triggering factor. The ulcers progressed to re-epithelialisation following necrosis debridement and local conservative treatments. Given the increased prevalence of meticillin-resistant Staphylococcus aureus , which has prompted clinicians to gradually increase vancomycin dosage, clinicians should be aware of the high risk of skin toxicity in cases of vancomycin high-dose extravasation.