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Introduction: Improving adverse events following immunisation (AEFI) detection is vital for vaccine safety surveillance, as an early safety signal can help minimize risks. In February 2022, the World Health Organization reported a preliminary signal on sudden sensorineural hearing loss (SSNHL) following coronavirus disease 2019 (COVID-19) vaccination, 54 million persons in France received at least one dose, covering 78.8% of the population within a year., Objective: The primary objective of this study was to identify a method of disproportionality analysis capable to detect a safety signal for hearing impairment (HI) as early as possible during the initial phases of the COVID-19 vaccination campaign. Secondly, we described all cases of SSNHL reported during vaccine booster campaigns in France., Methods: Data from January 2011 to February 2022 were extracted from the French pharmacovigilance database. Cases were all spontaneous reports of AEFI for elasomeran and tozinameran, while non-cases were AEFI reported for other vaccines. Disproportionality analysis for HI was performed monthly during 2021, to estimate a reporting odds ratio (ROR). Four different methods were used for ROR estimation. Furthermore, we reviewed cases of SSNHL following messenger RNA COVID-19 vaccinations reported during booster campaigns, from 2 February 2022 to 1 March 2023, based on a comprehensive medical evaluation., Results: Using a standard methodology, we identified a signal on 31 July 2021 (ROR 1.50, 95% confidence interval [CI] [1.06-2.18]). Multivariate analysis adjusted for sex, age, ototoxic drugs and excluding reference reports of common AEFI for vaccines allowed us to detect the HI signal as early as 31 March 2021 (ROR 2.67, 95% CI [1.36-5.57]). The SSNHL reporting rate was estimated to be 0.83/1,000,000 doses for tozinameran and 4.3/1,000,000 for elasomeran during the booster campaigns., Conclusion: Using a well-structured disproportionality analysis could have enhanced early detection of safety signals and contribute to risk minimizing measures. According to descriptive data, HI following mRNA COVID-19 vaccines remains rare., Competing Interests: Declarations. Funding: Open access funding provided by Université Toulouse III - Paul Sabatier. The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors. Conflict of interest: No commercial organizations had any role in the writing of this paper for publication. All authors declare they have no conflicts of interest. Ethics approval: The study was conducted in accordance with the principles of the Declaration of Helsinki. Patient consent was not required because the analysis was carried out on the French Pharmacovigilance DataBase, an anonymized database. Consent to participate: Patient consent was waived as the French Pharmacovigilance database contains anonymised data that cannot allow patients’ identification. Consent for publication: Not applicable. Availability of data and material: Data sharing is not applicable to this article, as the datasets used are based on anonymised data that are protected by agreements with the French Data Protection Commission (CNIL; Commission Nationale de l’Informatique et Liberté). Code availability: The code will be made available upon reasonable request to the corresponding author. Authors’ contributions: D.B., H.B. and H.T.-V. contributed equally to this study. They had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. D.B. and H.B. conceptualized the study. D.B., H.B. and F.S. designed the study. All authors were involved in acquisition, analysis, and interpretation of the data. M.B.R., H.G., M.L., F.R., J.M. and A.G. provided administrative, technical or material support. D.B., H.B. and H.T.-V. drafted the manuscript. All authors read and approved the final version., (© 2024. The Author(s).)

In March 2020, World Health Organization recognized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emergence as a public health emergency of international concern. One of the major preventative measures developed against coronavirus disease 2019 (COVID-19) was vaccines. To monitor their use and safety of vaccines from the first utilization in humans during clinical development phases to implementation for the general population, an enhanced national pharmacovigilance system was enabled by the French National Agency for Medicines and Health Products Safety in collaboration with the 30 Regional Pharmacovigilance Centres. Here, we review the significant outcomes from a 2-year collaboration experience between the French National Agency for Medicines and Health Products Safety, the 30 Regional Pharmacovigilance Centres, disease-related experts and the pharmacovigilance and risk assessment committee at the European medicine agency. In France, until January 2023, over 155 million doses of COVID-19 vaccines were administrated, and 190,000 adverse events following immunizations (25% classified as serious) were analysed. Altogether 53 potential safety signals were reported to the Pharmacovigilance and Risk Assessment Committee at the European Medicine Agency by the French National Agency for Medicines and Health Products Safety: 13 were confirmed, 24 are still under investigation and 16 were not confirmed. The enhanced national PV system contributed actively better to define the safety profile of the newly developed vaccines, and the French National Agency for Medicines and Health Products Safety continues to monitor the benefit and risks of the COVID-19 vaccines., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Objective: In recent years, safety concerns about modafinil exposure during pregnancy have emerged. In particular, increased risks for major congenital anomalies (MCA) and impaired fetal growth were reported, although study results were conflicting. Our investigation aims to examine previously reported safety signals., Method: Multicenter case series based on data from 18 Teratology Information Services from 12 countries. Modafinil exposed pregnancies with an estimated date of birth before August 2019 were included in this study. For prospectively ascertained pregnancies, cumulative incidences of pregnancy outcomes, rate of nonchromosomal MCA in first trimester exposed pregnancies and percentiles of neonatal/infant weight and head circumference (HC) were calculated. Potential dose-dependent effects on fetal growth were explored by linear regression models. Retrospectively ascertained cases were screened for pattern of MCA and other adverse events., Results: One hundred and seventy-five prospectively ascertained cases were included, of which 173 were exposed at least during the first trimester. Cumulative incidences for live birth, spontaneous abortion and elective termination of pregnancy were 76.9% (95% CI, 68.0%-84.8%), 9.3% (95% CI, 5.0%-16.9%), and 13.9% (95% CI, 8.1%-23.1%), respectively. Nonchromosomal MCA was present in 3/150 live births, corresponding to an MCA rate of 2.0% (95%CI, 0.6%-6.1%), none were reported in pregnancy losses. Compared to reference standards, birth weight (BW) tended to be lower and neonatal HC to be smaller in exposed newborns (data available for 144 and 73 of 153 live births, respectively). In nonadjusted linear regression models, each 100 mg increase of average dosage per pregnancy day was associated with a decrease in standard deviation score (SDS) of -0.28 SDS (95% CI, -0.45 to -0.10) for BW and of -0.28 SDS (95% CI, -0.56 to 0.01) for HC. Screening of 22 retrospectively reported cases did not reveal any specific pattern of MCA or other adverse outcomes., Conclusion: The results do not indicate an increased risk of MCA after in utero exposure to modafinil, but a tendency toward lower BW and reduced neonatal HC. However, these findings should be regarded as preliminary. Until further studies allow for a definite conclusion, modafinil should not be used during pregnancy., (© 2023 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Coffea arabica, an allotetraploid hybrid of Coffea eugenioides and Coffea canephora, is the source of approximately 60% of coffee products worldwide, and its cultivated accessions have undergone several population bottlenecks. We present chromosome-level assemblies of a di-haploid C. arabica accession and modern representatives of its diploid progenitors, C. eugenioides and C. canephora. The three species exhibit largely conserved genome structures between diploid parents and descendant subgenomes, with no obvious global subgenome dominance. We find evidence for a founding polyploidy event 350,000-610,000 years ago, followed by several pre-domestication bottlenecks, resulting in narrow genetic variation. A split between wild accessions and cultivar progenitors occurred ~30.5 thousand years ago, followed by a period of migration between the two populations. Analysis of modern varieties, including lines historically introgressed with C. canephora, highlights their breeding histories and loci that may contribute to pathogen resistance, laying the groundwork for future genomics-based breeding of C. arabica., (© 2024. The Author(s).)

As part of the COVID-19 vaccination campaign, the National Agency for the Safety of Medicines and Health Products and all 31 regional pharmacovigilance centers were mobilized in an exceptional reinforced vaccine pharmacovigilance surveillance system. Concerning adenovirus vaccines, Vaxzévria® and Jcovden®, this national system, based on the daily analysis of notified cases of adverse events, has allowed the early identification of safety signals, some of which have been validated, others still under analysis, common to mRNA vaccines or more specific of adenovirus vaccines such as Vaccine Induced Immune Thrombocytopenia. Complementing european and international actions, this follow-up has contributed to a better definition of the safety profile of these vaccines and has led to redefine the vaccine strategy in our country. Although today these two vaccines have no longer place in the national vaccine strategy, they are still used in other countries, where the experience acquired could be useful and will contribute to fuel the reflection on future therapies involving viral vectors., (Copyright © 2023 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

The association between vaccines and peripheral facial palsy (PFP), an issue that has been the subject of debate for many years, has been raised again following results of clinical trials assessing mRNA based COVID-19 vaccines. To review the available literature on this topic, PubMed was searched from inception until February 25, 2022. Inclusion criteria were case reports with documented rechallenge and comparative epidemiological studies. Cases of COVID-19 vaccine-induced PFP with available data on vaccine rechallenge were also identified from Vigibase until December 31, 2021. Of the 347 articles retrieved, 32 comparative epidemiological studies, 1 meta-analysis and 4 case reports met our criteria, of which 13 involved COVID-19 vaccines. Eight studies found an association between at least one vaccine and the occurrence of PFP, whereas 24 did not. Positive studies involved seasonal or pandemic H1N1 influenza vaccines administered parenterally (4 studies) or intranasally (1 study with a toxin-adjuvanted vaccine), BNT162b2, a mRNA COVID-19 vaccine (1 disproportionality analysis and 1 observed-to-expected analysis) and an inactivated virus COVID-19 vaccine (CoronaVac®) (1 study combining a case-control and an observed-to-expected approach). Strong evidence was found only for the intranasal influenza vaccine while other positive studies detected only a marginal association between PFP and vaccination. Of the four case reports with documented rechallenge, only two were positive and involved an influenza vaccine and tozinameran in one case each. In Vigibase, rechallenge was documented in 49 reports with 29 (59.2%) cases being negative and 20 (40.8%) positive. The available data did not confirm an excess risk of PFP after vaccination in most studies. Moreover, of the eight epidemiological studies suggesting a possible excess risk of PFP after any vaccine, three were disproportionality analyses and two observed-to excepted analyses, suggesting great caution should be taken when interpreting these results., (Copyright © 2022 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Background: Somatic embryogenesis (SE) is one of the most promising processes for large-scale dissemination of elite varieties. However, for many plant species, optimizing SE protocols still relies on a trial and error approach. We report the first global scale transcriptome profiling performed at all developmental stages of SE in coffee to unravel the mechanisms that regulate cell fate and totipotency., Results: RNA-seq of 48 samples (12 developmental stages × 4 biological replicates) generated 90 million high quality reads per sample, approximately 74% of which were uniquely mapped to the Arabica genome. First, the statistical analysis of transcript data clearly grouped SE developmental stages into seven important phases (Leaf, Dedifferentiation, Primary callus, Embryogenic callus, Embryogenic cell clusters, Redifferentiation and Embryo) enabling the identification of six key developmental phase switches, which are strategic for the overall biological efficiency of embryo regeneration. Differential gene expression and functional analysis showed that genes encoding transcription factors, stress-related genes, metabolism-related genes and hormone signaling-related genes were significantly enriched. Second, the standard environmental drivers used to control SE, i.e. light, growth regulators and cell density, were clearly perceived at the molecular level at different developmental stages. Third, expression profiles of auxin-related genes, transcription factor-related genes and secondary metabolism-related genes were analyzed during SE. Gene co-expression networks were also inferred. Auxin-related genes were upregulated during dedifferentiation and redifferentiation while transcription factor-related genes were switched on from the embryogenic callus and onward. Secondary metabolism-related genes were switched off during dedifferentiation and switched back on at the onset of redifferentiation. Secondary metabolites and endogenous IAA content were tightly linked with their respective gene expression. Lastly, comparing Arabica embryogenic and non-embryogenic cell transcriptomes enabled the identification of biological processes involved in the acquisition of embryogenic capacity., Conclusions: The present analysis showed that transcript fingerprints are discriminating signatures of cell fate and are under the direct influence of environmental drivers. A total of 23 molecular candidates were successfully identified overall the 12 developmental stages and can be tested in many plant species to optimize SE protocols in a rational way., (© 2023. The Author(s).)

Purpose: To provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARP inhibitors (PARPi)., Experimental Design: In a French cancer center, we identified and described the profiles of 13 t-MN diagnosed among 37 patients with ovarian cancer referred to hematology consultation for cytopenia under PARPi. Next, we described these 13 t-MN post-PARPi among 37 t-MN post ovarian cancer according to PARPi exposure. Finally, we described 69 t-MN post-PARPi in a national cohort., Results: From 2016 to 2021, cumulative incidence of t-MN was 3.5% (13/373) among patients with ovarian cancer treated with PARPi. At time of hematologic consultation, patients with t-MN had a longer PARPi exposure (9 vs. 3 months, P = 0.01), lower platelet count (74 vs. 173 G/L, P = 0.0005), and more cytopenias (2 vs. 1, P = 0.0005). Compared with t-MN not exposed to PARPi, patients with t-MN-PARPi had more BRCA1/2 germline mutation (61.5% vs. 0%, P = 0.03) but similar overall survival (OS). In the national cohort, most t-MN post-PARPi had a complex karyotype (61%) associated with a high rate of TP53 mutation (71%). Median OS was 9.6 months (interquartile range, 4-14.6). In multivariate analysis, a longer time between end of PARPi and t-MN (HR, 1.046; P = 0.02), olaparib compared with other PARPi (HR, 5.82; P = 0.003) and acute myeloid leukemia (HR, 2.485; P = 0.01) were associated with shorter OS., Conclusions: In a large series, we described a high incidence of t-MN post-PARPi associated with unfavorable cytogenetic and molecular abnormalities leading to poor OS. Early detection is crucial, particularly in cases of delayed cytopenia., (©2022 American Association for Cancer Research.)

Background: Janus kinase (JAK) inhibitors are targeted therapies with a potential imunomodulatory and anti-inflammatory effect, indicated in various dysimmune pathologies. Skin cancers have been reported to occur in patients treated with JAK inhibitors. However, drug safety in clinical trials did not confirm that risk, but these studies are performed on controlled population and in a limited time of follow up., Objectives: The aim of this study is to evaluate in real life condition if a disproportionality signal exists between JAK inhibitors treatment and skin cancers., Methods: We performed cases/non cases analysis in VigiBase® (the World Health Organization international database of suspected adverse drug reaction) using information component to search for a disproportionality signal of skin cancers from JAK inhibitor. We extracted all reports of skin cancers from the French Pharmacovigilance database occurring since 1978 up to 31 st December 2019 for the three existing JAK inhibitors on market: ruxolitinib, tofacitinib and baricitinib. Only melanoma, squamous cell carcinoma and Merkel cell carcinoma were analyzed, according to the pathophysiology of these cancers and their link with immunosuppression., Results: A disproportionality signal was found positive for squamous cell carcinoma with ruxolitinib (IC025=3.92) and tofacitinib (IC025=0.82), for melanoma with ruxolitinib (IC025=0.81) and tofacitinib (IC025=0.74), and Merkel cell carcinoma with ruxolitinib (IC025=4) and tofactinib (IC025=1.01) and only for Merkel cell carcinoma with baricitinib (IC025=0.53). Moreover, Merkel cell carcinoma, a very rare skin cancer more prevalent in immunodepressed patients was particularly represented in our sample and was associated with a significant disproportionality signal with all the studied JAK inhibitors., Conclusion: Our study shows that JAK inhibitors could be associated with an extra risk to develop skin cancers. Could an anti-viral or immunovigilance disruption mechanism brought by JAK inhibitors explain an over-risk with Merkel cell carcinoma, which were notably represented in our sample? Considering pharmacovigilance method limitations, further pharmacoepidemiological studies are required to assess a causal link between JAK inhibitors treatment and skin cancers development., (Copyright © 2022 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Diarrhoea is an adverse drug reaction of the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril + valsartan. It was also described with olmesartan and more recently with other angiotensin receptor blockers. The study was performed to compare diarrhoea reports in pharmacovigilance databases with sacubitril + valsartan and valsartan. The study used reports of diarrhoea with the ARNI sacubitril + valsartan registered: first in the French PharmacoVigilance Database (FPVD) and second in Vigibase®, the WHO Global Individual Case Safety Report database. After description of the main characteristics, disproportionality analyses were performed. Results are reported as reporting odds ratios (ROR) with 95% confidence interval. We found 29 reports of diarrhoea with sacubitril + valsartan in the FPVD and 686 in Vigibase®. With sacubitril + valsartan, diarrhoea occurred more frequently in males around 70 years with a median delay of 3 days. With valsartan, diarrhoea occurred more frequently in females around 68 years with a median delay of 0.5 days. In the FPVD, a significant association was found with sacubitril + valsartan in comparison with valsartan alone before (ROR = 8.78 [5.19-14.85]) and after (ROR = 11.19 [5.89-21.25]) exclusion of concomitant drugs known to be associated with diarrhoea. A significant association was also found in Vigibase® after adjustment on age, sex, reporter and its location (ROR = 1.31 [1.14-1.50]). Diarrhoea reported with sacubitril + valsartan has marked differences in gender, delay of occurrence and frequency of reporting in comparison with diarrhoea with valsartan. From a pharmacodynamic point of view, these results suggest a specific role of sacubitril in diarrhoea., (© 2021 Société Française de Pharmacologie et de Thérapeutique.)

Understanding vulnerabilities of plant populations to climate change could help preserve their biodiversity and reveal new elite parents for future breeding programmes. To this end, landscape genomics is a useful approach for assessing putative adaptations to future climatic conditions, especially in long-lived species such as trees. We conducted a population genomics study of 207 Coffea canephora trees from seven forests along different climate gradients in Uganda. For this, we sequenced 323 candidate genes involved in key metabolic and defence pathways in coffee. Seventy-one single nucleotide polymorphisms (SNPs) were found to be significantly associated with bioclimatic variables, and were thereby considered as putatively adaptive loci. These SNPs were linked to key candidate genes, including transcription factors, like DREB-like and MYB family genes controlling plant responses to abiotic stresses, as well as other genes of organoleptic interest, such as the DXMT gene involved in caffeine biosynthesis and a putative pest repellent. These climate-associated genetic markers were used to compute genetic offsets, predicting population responses to future climatic conditions based on local climate change forecasts. Using these measures of maladaptation to future conditions, substantial levels of genetic differentiation between present and future diversity were estimated for all populations and scenarios considered. The populations from the forests Zoka and Budongo, in the northernmost zone of Uganda, appeared to have the lowest genetic offsets under all predicted climate change patterns, while populations from Kalangala and Mabira, in the Lake Victoria region, exhibited the highest genetic offsets. The potential of these findings in terms of ex situ conservation strategies are discussed., (© 2022 John Wiley & Sons Ltd.)

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.)

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.)

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.)

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.)

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.)

Caffeine is the most consumed alkaloid stimulant in the world. It is synthesized through the activity of three known N-methyltransferase proteins. Here we are reporting on the 422-Mb chromosome-level assembly of the Coffea humblotiana genome, a wild and endangered, naturally caffeine-free, species from the Comoro archipelago. We predicted 32,874 genes and anchored 88.7% of the sequence onto the 11 chromosomes. Comparative analyses with the African Robusta coffee genome (C. canephora) revealed an extensive genome conservation, despite an estimated 11 million years of divergence and a broad diversity of genome sizes within the Coffea genus. In this genome, the absence of caffeine is likely due to the absence of the caffeine synthase gene which converts theobromine into caffeine through an illegitimate recombination mechanism. These findings pave the way for further characterization of caffeine-free species in the Coffea genus and will guide research towards naturally-decaffeinated coffee drinks for consumers.

The antiretroviral drug lopinavir/ritonavir has been recently repurposed for the treatment of COVID-19. Its empirical use has been associated with multiple cardiac adverse reactions pertaining to its ancillary multi-channel blocking properties, vaguely characterized until now. We aimed to characterize qualitatively the cardiotoxicity associated with lopinavir/ritonavir in the setting of COVID-19. Spontaneous notifications of cardiac adverse drug reactions reported to the national Pharmacovigilance Network were collected for 8 weeks since March 1st 2020. The Nice Regional Center of Pharmacovigilance, whose scope of expertise is drug-induced long QT syndrome, analyzed the cases, including the reassessment of all available ECGs. QTc ≥ 500 ms and delta QTc > 60 ms from baseline were deemed serious. Twenty-two cases presented with 28 cardiac adverse reactions associated with the empirical use of lopinavir/ritonavir in a hospital setting. Most adverse reactions reflected lopinavir/ritonavir potency to block voltage-gated potassium channels with 5 ventricular arrhythmias and 17 QTc prolongations. An average QTc augmentation of 97 ± 69 ms was reported. Twelve QTc prolongations were deemed serious. Other cases were likely related to lopinavir/ritonavir potency to block sodium channels: 1 case of bundle branch block and 5 recurrent bradycardias. The incidence of cardiac adverse reactions of lopinavir/ritonavir was estimated between 0.3% and 0.4%. These cardiac adverse drug reactions offer a new insight in its ancillary multi-channel blocking functions. Lopinavir/ritonavir cardiotoxicity may be of concern for its empirical use during the COVID-19 pandemic. Caution should be exerted relative to this risk where lopinavir/ritonavir summary of product characteristics should be implemented accordingly., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Several cases of Pneumocystosis pneumonia (PCP) have been reported in patients with hypercortisolism, mainly in patients with severe ectopic ACTH syndrome (EAS). We report 2 cases of PCP that did not develop until after starting treatment with metyrapone, one of which occurred in an outpatient with Cushing's disease (CD) without pulmonary symptoms before medical treatment for CD. Patient 1 presented as an outpatient with CD and severe hypercortisolism but nonetheless in good general condition. Treatment with metyrapone was started before pituitary surgery. Patient 2 had EAS due to prostate cancer. Respiratory failure in the two patients occurred 4 days and 30 days, respectively, after the start of metyrapone treatment. In both cases, chest CT showed bilateral interstitial infiltrates, and Pneumocystis jirovecii was found on bronchoalveolar lavage (BAL). A literature review was performed to identify risk factors for PCP in patients with CD: we identified 20 other cases of PCP in patients treated for hypercortisolism, including 16 patients with EAS. Ninety percent of patients had free urinary cortisol greater than 6 times the upper limit of normal (ULN). In conclusion, onset of PCP after initiation of anticortisolic therapy is not limited to patients with EAS, and may occur in CD patients with elevated cortisol levels, even if the patient remains in good general condition and has no pulmonary symptoms before treatment. In such patients, routine prophylactic treatment with trimethoprim/sulfamethoxazole (TMP/SMX) should be considered., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Objectives: Lung transplant (LT) recipients require multidisciplinary care because of the complexity of therapeutic management. Pharmacists are able to detect drug-related problems and provide recommendations to physicians through pharmacists' interventions (PIs). We aimed at assessing the clinical impact of PIs on therapeutic management in LT outpatients., Design: Data were collected prospectively from an LT recipients cohort during 7 years. A multidisciplinary committee assessed retrospectively the clinical impact of accepted PIs., Setting: French University Hospital., Participants: LT outpatients followed from 2009 to 2015., Primary Outcome Measures: Clinical impact of PIs performed by pharmacists using the CLEO tool and the Pareto chart., Results: 1449 PIs led to a change in patient therapeutic management and were mainly related to wrong dosage (39.6%) and untreated indication (19.6%). The clinical impact of PIs was 'avoids fatality', 'major' and 'moderate', in 0.1%, 7.0% and 57.9%, respectively. Immunosuppressants, antimycotics for systemic use and antithrombotic agents had the greatest clinical impact according to the Pareto chart. PIs related to drug-drug interactions (10%) mainly had a moderate and major clinical impact (82.3%, p<0.0001)., Conclusion: Clinical pharmacists play a key role for detecting drug-related problems mostly leading to a change in therapeutic management among LT outpatients. Our study provides a new insight to analyse the clinical impact of PIs in order to target PIs which have most value and contribute to patient care through interdisciplinary approach., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Several clusters of encephalopathy occurred after the market change from Holoxan® (ifosfamide lyophilized powder) to Ifosfamide EG® (liquid formulation) and justified a formal survey in 2015. In June 2016, the regulatory authority decided to apply a precautionary measure in reducing the shelf life of Ifosfamide EG® at 7 months. One-year study from spontaneous reports lead to suspect a potential residual risk. Due to the many limitations associated with spontaneous notifications, we performed a multicentric observational study, aiming to better explore this pharmacovigilance signal., Methods: We performed a case-control study in pediatric oncology Departments of 25 university hospitals between July 1st, 2016 and July 1st, 2018. All children (<18 y.o.) receiving liquid formulation or lyophilized powder formulation during the study period were included. Patients with at least one occurrence of encephalopathy were considered as cases. Logistic regression model was used to estimate the odds ratio of encephalopathy between exposure groups., Results: During the study period, 52 cases and 495 controls were included. A residual over-risk of encephalopathy was associated with ifosfamide 7-month shelf-life liquid formulation compared to lyophilized powder (adjusted OR 1.91, 95% CI: 1.03-3.53)., Conclusions: Observed difference does not seem to be related to the pathology treated, the doses used, the co-medications, a meningeal localization and/or an irradiation of the central nervous system. This study confirms data from spontaneous reports that led to the precautionary measure for the liquid formulation. Even if the risk of encephalopathy seems reduced, our study suggests the persistence of a residual risk of encephalopathy associated with liquid formulation compared to the lyophilized powder., (Copyright © 2019 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

On March 16, 2020, the French Society of Pharmacology and Therapeutics put online a national Question and Answer (Q&A) website, https://sfpt-fr.org/covid19 on the proper use of drugs during the COVID-19 pandemic. The working group 'Drugs and COVID-19' was composed of a scientific council, an editorial team, and experts in the field. The first questions were posted online during the first evening of home-confinement in France, March 17, 2020. Six weeks later, 140 Q&As have been posted. Questions on the controversial use of hydroxychloroquine and to a lesser extent concerning azithromycin have been the most consulted Q&As. Q&As have been consulted 226 014 times in 41 days. This large visibility was obtained through an early communication on Twitter, Facebook, traditional print, and web media. In addition, an early communication through the French Ministry of Health and the French National Agency for Medicines and Health Products Safety ANSM had a large impact in terms of daily number of views. There is a pressing need to sustain a public drug information service combining the expertise of scholarly pharmacology societies, pharmacovigilance network, and the Ministry of Health to quickly provide understandable, clear, expert answers to the general population's concerns regarding COVID-19 and drug use and to counter fake news., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

Introduction: Idiosyncratic drug-induced agranulocytosis is a rare but potentially serious haematological disorder. The pathophysiological mechanisms are complex and poorly understood. We aimed at investigating agranulocytosis drug related causes from the myelograms with "myeloid maturation arrest" performed in our university hospital over the last seven years., Methods: A retrospective analysis of myelograms collected for agranulocytosis was performed from 1st January 2010 to 31th December 2016. We used the method of Bégaud et al. for drug causality assessment., Results: Among the 104 myelograms analysed, 41 agranulocytosis were drug-induced, whose 28 were idiosyncratic. Among these 28 cases, 26 different drugs were involved. Agranulocytosis was a known adverse reaction in the summary of the product characteristics for 24 drugs, mainly associated with undetermined frequency (n=7). Mean onset latency was 38.1 days after starting the drug (calculated for n=23 cases) and granulocyte growth factors were used in 50% of cases without shortening the mean delay of blood count recovery. Bone marrow presented hypereosinophilia in 29% of cases. Pharmacovigilance reporting rate was 48%., Conclusion: A "maturation arrest" in the myelogram is not pathognomonic for idiosyncratic drug-induced agranulocytosis. This rare event require multidisciplinary care involving haematologists, biologists and pharmacovigilance experts. Agranulocytosis reporting rate was high compared with usual adverse drug reaction reporting rate (5 to 10%), probably related to the potential severity of this event., (Copyright © 2020 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Medication errors (ME) are frequently encountered and present at every step of the therapeutic process. This study's aims were to take stock of the ME reported to the region's pharmacovigilance (CRPV) and poison control centers (CAPTV) and to identify potential regional actions. A 2-months (January and February 2017) prospective gathering of the calls to the CAPTV regarding the ME and of the ME declarations to the region's CRPV (Clermont-Ferrand, Grenoble, Lyon, Saint-Etienne) has been carried out. The place of occurrence, the event's description and its consequences and data regarding the patient were collected. In addition to that, the regional drug observatory OMEDIT analysis has allowed to determine the ME's types (REMED characterization, never event?) and to look for the results of a potential thorough analysis. The study reported 580 calls for 590 ME and 583 patients. ME mostly affected the ambulatory/domicile sector (76%), the medico-social sector (14%) and the healthcare facilities sector (7%). It usually was about dose errors, medication errors and patient errors with a different profile in each sector. The majority of errors (85%) occurred at the administration step. Almost all the observed ME were confirmed errors having reached the patient (99.5%) but only a few had serious consequences. One out of 5 ME was eligible for a thorough analysis but even less were subjected to that kind of analysis. The main never event concerned the unidose in the ambulatory sector. The health products involved were mostly a single medication (75%) and then the patient's full treatment (12%). The CRPV/CAPTV/OMEDIT's skills are complementary for the gathering, the analysis and the management of the ME. Training campaigns and support are to be considered for the professionals and especially within the medico-social facilities., (Copyright © 2019 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Bradykinin-mediated angioedema is a rare disease, due to vasodilation and increased vascular permeability resulting from bradykinin. This kind of angioedema affects abdominal and/or upper airways. It differs clinically from histamine-mediated angioedema by the absence of urticaria or skin rash. Antihistamines and corticosteroids are not effective. Delayed diagnosis can lead to inadequate and potentially fatal management by asphyxiation. Bradykinin-mediated angioedema results from either overproduction of bradykinin or inhibition of its degradation. Etiology can be hereditary or acquired. Deficiency of C1 inhibitor and drug induced are the main causes of bradykinin-mediated angioedema. Its diagnosis is clinical (presentation, family history, seriousness, frequency, etc.) and biological (dosage of C1-INH level, C1-INH activity, and complement protein 4 level). Acute attack treatment is based on C1-inhibitor concentrates and icatibant, a bradykinin receptor antagonist. Long-term prophylaxis can be necessary, especially before surgical and dental procedures. New drugs, including gene therapy, are being tested., (Copyright © 2020 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Background: Pharmacists play a key role in ensuring the safe use of injectable antineoplastics, which are considered as high-alert medications. Pharmaceutical analysis of injectable antineoplastic prescriptions aims to detect and prevent drug related problems by proposing pharmacist interventions (PI). The impact of this activity for patients, healthcare facilities and other health professionals is not completely known. This study aimed at describing the clinical, economic, and organizational impacts of PIs performed by pharmacists in a chemotherapy preparation unit., Methods: A prospective 10-week study was conducted on PIs involving injectable antineoplastic prescriptions. Each PI was assessed by one of the four multidisciplinary expert committees using a multidimensional tool with three independent dimensions: clinical, economic and organizational. An ancillary quantitative evaluation of drug cost savings was conducted., Results: Overall, 185 patients were included (mean age: 63.5 ± 13.7 years; 54.1% were male) and 237 PIs concerning 10.1% prescriptions were recorded. Twenty one PIs (8.9%) had major clinical impact (ie: prevented hospitalization or permanent disability), 49 PIs (20.7%) had moderate clinical impact (ie: prevented harm that would have required further monitoring/treatment), 62 PIs (26.2%) had minor clinical impact, 95 PIs (40.0%) had no clinical impact, and 9 PIs (3.8%) had a negative clinical impact. For one PI (0.4%) the clinical impact was not determined due to insufficient information. Regarding organizational impact, 67.5% PIs had a positive impact on patient management from the healthcare providers' perspective. A positive economic impact was observed for 105 PIs (44.3%), leading to a saving in direct drug costs of 15,096 €; 38 PIs (16.0%) had a negative economic impact, increasing the direct drug cost by 11,878 €. Overall cost saving was 3218€., Conclusions: PIs are associated with positive clinical, economic and organizational impacts. This study confirms the benefit of pharmacist analysis of injectable antineoplastic prescriptions for patient safety with an overall benefit to the healthcare system.

Background: Several pharmacological treatments are available for secondary Raynaud's phenomenon, but there is uncertainty regarding the best options. We aimed to assess and compare the benefits and harms of treatments available for secondary Raynaud's phenomenon., Method: We did a systematic review and network meta-analysis of randomised controlled trials (RCTs) of pharmacological treatments. We searched for systematic reviews published in MEDLINE and the Cochrane Database of Systematic Reviews up to Jan 31, 2017, and for RCTs published from inception to Sept 24, 2019 in MEDLINE, Embase, and ClinicalTrials.gov. We included double-blind RCTs (parallel or crossover) that compared two or more pharmacological treatments or placebo in patients with secondary Raynaud's phenomenon. Individual patient data were obtained for one unpublished RCT. Three researchers independently screened the texts and extracted the data. Efficacy outcomes included severity (on a ten-point scale), daily frequency, and mean duration of Raynaud's phenomenon attacks. We also examined tolerability and acceptability. Pairwise meta-analyses and Bayesian random-effects network meta-analyses were used to synthesise data. This study is registered with PROSPERO (CRD42017057518)., Findings: We included 58 RCTs in the analysis, comprising 3867 patients (3540 [91·5%] with secondary Raynaud's phenomenon) and 15 classes of drugs. Phosphodiesterase 5 (PDE5) inhibitors were more effective than placebo for frequency (mean difference -0·36 [95% credibility interval -0·69 to -0·04]), severity (-0·34 [-0·66 to -0·03]), and duration (-3·42 [-6·62 to -0·29]) of attacks (low to moderate level of evidence). Calcium channel blockers (CCBs) were superior to placebo for frequency (-0·35 [-0·67 to -0·02]) and severity (-0·84 [-1·25 to -0·45]) of attacks (low level of evidence). For severity of attacks, selective serotonin-reuptake inhibitors (-1·54 [-2·68 to -0·41]; very low level of evidence) and oral prostacyclin receptor agonists (-0·48 [-0·80 to -0·16]; low level of evidence) were superior to placebo. No other drug classes were significantly superior to placebo with regard to efficacy outcomes. Compared with placebo, tolerability was lower for PDE5 inhibitors (incidence rate ratio for serious adverse events or early study exit due to adverse events 3·30 [95% CrI 1·49 to 7·55]) and CCBs (3·13 [1·33 to 7·04]). For all outcomes, global heterogeneity and between-study variance ranged from low (I 2 =0% and τ 2 =0·0 for attack severity and duration) to moderate (I 2 =41% and τ 2 =0·2 for tolerability). The overall risk of bias was judged to be low in 22 (38%), high in ten (17%), and unclear in 26 (45%) RCTs., Interpretation: PDE5 inhibitors and CCBs are the most effective pharmacological options, albeit with moderate efficacy and a low level of evidence. Current evidence does not support the use of any other drug in secondary Raynaud's phenomenon., Funding: None., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Somatic embryogenesis (SE) is one of the most promising processes for large-scale dissemination of elite varieties. However, for many plant species, optimizing SE protocols still relies on a trial-and-error approach. Using coffee as a model plant, we report here the first global analysis of metabolome and hormone dynamics aiming to unravel mechanisms regulating cell fate and totipotency. Sampling from leaf explant dedifferentiation until embryo development covered 15 key stages. An in-depth statistical analysis performed on 104 metabolites revealed that massive re-configuration of metabolic pathways induced SE. During initial dedifferentiation, a sharp decrease in phenolic compounds and caffeine levels was also observed while auxins, cytokinins and ethylene levels were at their highest. Totipotency reached its highest expression during the callus stages when a shut-off in hormonal and metabolic pathways related to sugar and energetic substance hydrolysis was evidenced. Abscisic acid, leucine, maltotriose, myo-inositol, proline, tricarboxylic acid cycle metabolites and zeatin appeared as key metabolic markers of the embryogenic capacity. Combining metabolomics with multiphoton microscopy led to the identification of chlorogenic acids as markers of embryo redifferentiation. The present analysis shows that metabolite fingerprints are signatures of cell fate and represent a starting point for optimizing SE protocols in a rational way.