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Symptoms improved when the patient walked on a cold floor or made contact with cold water. Dear Editor, Erythromelalgia is a recurrent and paroxysmal syndrome characterized by the clinical triad of bilateral redness, heat and paroxysmal burning pain, mostly localized on the feet.1 This disorder can be primary, resulting from mutations in the genes encoding the voltage-gated sodium channels, and can also be secondary to an underlying disease or drugs. In our patient, the following considerations can be put forward in support of a specific drug imputability: the recurrence of symptoms with each increase of platelet count, the clinical improvement after drug withdrawal or dosage adjustment, and the absence of similar symptoms after switching to another drug. [Extracted from the article]

Introduction: Rheumatoid arthritis (RA) is a systemic autoimmune disease with IL-6 as a main mediator of systemic and localized inflammation. The most often used drug for the treatment of RA is methotrexate (MTX). Aim: To explore if there is an association between the 174G/C polymorphism in IL6 gene and response to methotrexate therapy in RA patients. Materials and Methods: Study has included 131 RA patients treated and followed at the Institute of Rheumatology in Belgrade. Clinical response to the MTX therapy was conducted following the EULAR response criteria. Each patient's DNA was isolated by salting-out method. For each patient IL6 174G/C polymorphism genotype was determined by allele specific PCR method. For statistical analyses we have used SPSS program version 17.0. Results: According to EULAR response criteria 103 (78.6 %) patients were responders 12(9.2 %) good and 91 (69.5 %) moderate response) and 28 (21.4 %) were non responders. Among all patients in 47 (35.9 %) we have detected GG genotype, in 69 (52.7 %) GC genotype and in 15 (11.5 %) CC genotype. We have observed no association between genotypes or alleles and response to MTX therapy. Conclusion: No association of -174G/C IL-6 polymorphism and therapeutic response to MTX in RA patients in Serbian population was observed.

Objective: Multiregional trials are designed under the assumption that treatment effect applies to the entire target population, yet several factors may introduce geographic heterogeneity in treatment effect. We explored whether such variations exist in trials assessing the efficacy of glucagon-like peptide 1 receptor agonists (GLP-1RAs) in major cardiovascular events (MACE) in type 2 diabetes., Research Design and Methods: A systematic search of Medline and the Cochrane Library was conducted from inception until 30 June 2020. We included international randomized controlled trials comparing any GLP-1RA versus placebo, with MACE as a primary end point. Individual participant data were subsequently requested from the sponsor or through data sharing platforms. For each trial, we calculated hazard ratios (HRs) and their 95% CIs for MACE, subgrouped by region. We then performed a random-effects meta-analysis and conducted meta-regressions to assess the influence of predetermined variables of interest on treatment effect., Results: We included six trials including 45,426 patients. Baseline risk of MACE ranged from 2.9 per 100 patient-years in Southern Asia to 7.4 per 100 patient-years in Sub-Saharan Africa. HRs for MACE ranged between 0.25 (95% CI 0.05, 1.12) in Northern Africa to 0.98 (0.79, 1.22) in Western Europe. There was no significant subgroup difference across regions (P = 0.70). Baseline risk of MACE and indexes of development status (i.e., Human Development Index, gross domestic product) were independently associated with GLP-1RA efficacy., Conclusions: This study does not suggest any regional heterogeneity of GLP-1RA efficacy in MACE. However, a higher baseline risk and lower development status were associated with a greater benefit of these drugs., (© 2024 by the American Diabetes Association.)

Introduction: Pulmonary arterial hypertension (PAH) is a rare and severe disease for which most of the evidence about prognostic factors, evolution and treatment efficacy comes from cohorts, registries and clinical trials. We therefore aimed to develop and validate a new PAH identification algorithm that can be used in the French healthcare database "Système National des Données de Santé (SNDS)"., Methods: We developed and validated the algorithm using the Grenoble Alpes University Hospital medical charts. We first identified PAH patients following a previously validated algorithm, using in-hospital ICD-10 (10th revision of the International Statistical Classification of Diseases) codes, right heart catheterisation procedure and PAH-specific treatment dispensing. Then, we refined the latter with the exclusion of chronic thromboembolic pulmonary hypertension procedures and treatment, the main misclassification factor. Second, we validated this algorithm using a gold standard review of in-hospital medical charts and calculated sensitivity, specificity, positive and negative predictive value (PPV and NPV) and accuracy. Finally, we applied this algorithm in the French healthcare database and described the characteristics of the identified patients., Results: In the Grenoble University Hospital, we identified 252 unique patients meeting all the algorithm's criteria between 1 January 2010 and 30 June 2022, and reviewed all medical records. The sensitivity, specificity, PPV, NPV and accuracy were 91.0%, 74.3%, 67.9%, 93.3% and 80.6%, respectively. Application of this algorithm to the SNDS yielded the identification of 9931 patients with consistent characteristics compared to PAH registries., Conclusion: Overall, we propose a new PAH identification algorithm developed and adapted to the French specificities that can be used in future studies using the French healthcare database., Competing Interests: Conflict of interest: H. Bouvaist reports payment for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Merck, outside the submitted work. Conflict of interest: M. Humbert reports grants or contracts from Acceleron, AOP Orphan, Janssen, Merck and Shou Ti, outside the submitted work; consulting fees from 35 Pharma, Aerovate, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Keros, Merck, MorphogenIX, Shou Ti and United Therapeutics, outside the submitted work; payment 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 or advisory board for Acceleron, Altavant, Janssen, Merck and United Therapeutics, outside the submitted work. Conflict of interest: D. Montani reports grants or contracts from Acceleron, Janssen and Merck MSD, outside the submitted work; consulting fees from Acceleron, Merck MSD, Janssen and Ferrer, outside the submitted work; payment or honoraria for speakers' bureaus from Bayer, Janssen, Boerhinger, Chiesi, GSK, Ferrer and Merck MSD, outside the submitted work. Conflict of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2024.)

Introduction: Drug efficacy and effectiveness are assessed respectively through clinical trials and pharmaco-epidemiological studies. However, relative and absolute benefits of drugs are distinct measures that must be considered in relation to the baseline risk of disease incidence, complication or progression. On the other hand, adverse drug reactions are independent of the basic risk but depend on the characteristics of the population treated. Given these prerequisites, how can we balance the benefits and risks of drugs?, Areas Covered: We use the example of therapeutics evaluated during Covid to describe how assessing the benefit-risk balance of drugs is a complex process., Expert Opinion: Clinical trials are not designed to identify rare adverse events, underscoring the necessity for a pharmacovigilance system. Evaluating the balance between the benefits and risks of drugs is an ongoing process, demanding the simultaneous analysis of data from clinical trials, potential drug-drug interactions, pharmacovigilance monitoring and pharmaco-epidemiological studies, to identify potential safety concerns. In addition, pharmacologists must play a major role in educating the general public about drugs, aiding in the accurate interpretation of the benefit-risk balance and preventing misinformation.

Objectives: To evaluate whether there is evidence of efficacy of the most commonly used medications in their primary indications., Study Design and Setting: This scoping review was executed using the Cochrane Library and MEDLINE databases up to May 2023. The 10 most prescribed medications in England, France, and the United States were identified using country-specific public databases. Up to 3 common indications in primary care were defined for each medication, based on a survey of general practitioners. The outcomes were determined by the authors to be patient-important outcomes, with placebo as the comparator. Two investigators independently conducted searches, following a predefined algorithm, to identify randomized controlled trials or meta-analyses of randomized controlled trials assessing the efficacy of these medications for each indication. The risk of bias was assessed using the ROBIS or ROB 2.0 tools., Results: We identified 21 drugs, covering 56 indications and 114 outcomes. Sixty-seven percent of the evaluated medications demonstrated efficacy for at least one outcome in at least one of the sought indications. Overall, evidence of efficacy was found for 48% of the indications. There was no study evaluating the efficacy of amoxicillin and salbutamol. For other drugs such as phloroglucinol or cholecalciferol, available studies suggested an absence of efficacy in the most common indications., Conclusion: This study underscores the lack of data regarding the level of evidence for the most prescribed medications. Limitations include the choice of outcomes, and the understanding that the absence of evidence is not synonymous with the absence of efficacy., Competing Interests: Declaration of competing interest All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/disclosure-of-interest/and declare: no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years, and no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Observational studies that have reported an association between aspirin use in chronic obstructive pulmonary disease (COPD) with reductions in mortality and COPD exacerbations were shown to be affected by time-related biases. We assessed this association using a prevalent new-user study design that avoids these biases. We used the United Kingdom's Clinical Practice Research Datalink (CPRD) to form a cohort of patients with COPD. Aspirin initiators were matched on time and propensity score with nonusers during 2002-2018. The outcomes were all-cause mortality and COPD exacerbation within a one-year follow-up. Hazard ratios (HR) and 95% confidence interval (CI) of each outcome associated with aspirin use compared to nonuse were estimated using an as-treated approach. The study cohort included 10,287 initiators of aspirin and 10,287 matched nonusers. The cumulative incidence of all-cause mortality at one year was 11.5% for aspirin users and 9.2% for nonusers. The HR of all-cause mortality associated with aspirin initiation was 1.22 (95% CI: 1.08-1.37), while for severe exacerbation it was 1.21 (95% CI 1.08-1.37), compared with nonuse. The HR of a first moderate or severe exacerbation with aspirin use was 0.90 (95% CI 0.85-0.95). These estimates did not vary by platelet count. This large population-based study, designed to emulate a trial, found aspirin use in patients with COPD associated with a higher risk of all-cause mortality and severe exacerbation, but a lower risk of moderate or severe exacerbation. Further research is warranted to assess this reduction in moderate or severe exacerbations, particularly in patients with cardiovascular risk factors.

Background: Pulmonary arterial hypertension (PAH) has been described in patients treated with proteasome inhibitors (PIs). Our objective was to evaluate the association between PIs and PAH., Methods: Characteristics of incident PAH cases previously treated with carfilzomib or bortezomib were analysed from the French pulmonary hypertension registry and the VIGIAPATH programme from 2004 to 2023, concurrently with a pharmacovigilance disproportionality analysis using the World Health Organization (WHO) global database (VigiBase) and a meta-analysis of randomised controlled trials., Results: 11 incident cases of PI-associated PAH were identified (six with carfilzomib and five with bortezomib) with a female:male ratio of 2.7:1, a median age of 61 years, and a median delay between PI first exposure and PAH of 6 months. Four patients died (two from right heart failure, one from respiratory distress and one from an unknown cause). At diagnosis, six were in New York Heart Association Functional Class III/IV with severe haemodynamic impairment (median mean pulmonary arterial pressure 39 mmHg, cardiac index 2.45 L·min -1 ·m -2 and pulmonary vascular resistance 7.2 WU). In the WHO pharmacovigilance database, 169 cases of PH associated with PI were reported since 2013 with significant signals of disproportionate reporting (SDR) for carfilzomib, regardless of the definition of cases or control group. However, SDR for bortezomib were inconsistent. The systematic review identified 17 clinical trials, and carfilzomib was associated with a significantly higher risk of dyspnoea, severe dyspnoea and PH compared with bortezomib., Conclusion: PIs may induce PAH in patients undergoing treatment, with carfilzomib emitting a stronger signal than bortezomib, and these patients should be monitored closely., Competing Interests: Conflict of interest: X. Jaïs reports grants from Acceleron, Janssen, MSD and Bayer HealthCare, lecture honoraria from Janssen and MSD, and travel support from MSD, outside the submitted work. L. Savale reports grants from Acceleron, AOP Orphan, Janssen, Merck and Shou Ti, consulting fees from Acceleron, Bayer, Janssen and Merck, and lecture honoraria from Janssen and Merck, outside the submitted work. M. Jevnikar reports consulting fees from Janssen, and travel support from MSD and Janssen, outside the submitted work. A. Boucly reports grants from Acceleron, Janssen and MSD, and lecture honoraria and travel support from Janssen, Merck, AOP Orphan and Ferrer, outside the submitted work. G. Simonneau reports consulting fees and lecture honoraria from Actelion, Jansen, Bayer and MSD, travel support from Janssen, and advisory board participation with Acceleron, outside the submitted work. O. Sitbon reports grants from Acceleron (now MSD), AOP Orphan, Janssen (formerly Actelion) and MSD, consulting fees from Acceleron (now MSD), Altavant (now Enzyvant), AOP Orphan, Ferrer, Gossamer Bio, Janssen (formerly Actelion) and MSD, lecture honoraria from AOP Orphan, Janssen (formerly Actelion), Ferrer and MSD, and advisory board participation with Altavant (now Enzyvant), Gossamer Bio, Janssen (formerly Actelion) and MSD, outside the submitted work. M. Humbert reports grants from Acceleron, AOP Orphan, Janssen, Merck and Shou Ti, consulting fees from Acceleron, Aerovate, Altavant, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Merck, Morphogen-IX, Shou Ti and United Therapeutics, lecture honoraria from Janssen and Merck, and advisory board participation with Acceleron, Altavant, Janssen, Merck and United Therapeutics, outside the submitted work. D. Montani reports grants from Acceleron, Janssen and Merck MSD, consulting fees from Acceleron, Merck MSD, Janssen and Ferrer, and lecture honoraria from Bayer, Janssen, Boehringer, Chiesi, GSK, Ferrer and Merck MSD, outside the submitted work. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

In pharmacovigilance, disproportionality analyses based on individual case safety reports are widely used to detect safety signals. Unfortunately, publishing disproportionality analyses lacks specific guidelines, often leading to incomplete and ambiguous reporting, and carries the risk of incorrect conclusions when data are not placed in the correct context. The REporting of A Disproportionality analysis for drUg Safety signal detection using individual case safety reports in PharmacoVigilance (READUS-PV) statement was developed to address this issue by promoting transparent and comprehensive reporting of disproportionality studies. While the statement paper explains in greater detail the procedure followed to develop these guidelines, with this explanation paper we present the 14 items retained for READUS-PV guidelines, together with an in-depth explanation of their rationale and bullet points to illustrate their practical implementation. Our primary objective is to foster the adoption of the READUS-PV guidelines among authors, editors, peer reviewers, and readers of disproportionality analyses. Enhancing transparency, completeness, and accuracy of reporting, as well as proper interpretation of their results, READUS-PV guidelines will ultimately facilitate evidence-based decision making in pharmacovigilance., (© 2024. The Author(s).)

Background and Aim: Disproportionality analyses using reports of suspected adverse drug reactions are the most commonly used quantitative methods for detecting safety signals in pharmacovigilance. However, their methods and results are generally poorly reported in published articles and existing guidelines do not capture the specific features of disproportionality analyses. We here describe the development of a guideline (REporting of A Disproportionality analysis for drUg Safety signal detection using individual case safety reports in PharmacoVigilance [READUS-PV]) for reporting the results of disproportionality analyses in articles and abstracts., Methods: We established a group of 34 international experts from universities, the pharmaceutical industry, and regulatory agencies, with expertise in pharmacovigilance, disproportionality analyses, and assessment of safety signals. We followed a three-step process to develop the checklist: (1) an open-text survey to generate a first list of items; (2) an online Delphi method to select and rephrase the most important items; (3) a final online consensus meeting., Results: Among the panel members, 33 experts responded to round 1 and 30 to round 2 of the Delphi and 25 participated to the consensus meeting. Overall, 60 recommendations for the main body of the manuscript and 13 recommendations for the abstracts were retained by participants after the Delphi method. After merging of some items together and the online consensus meeting, the READUS-PV guidelines comprise a checklist of 32 recommendations, in 14 items, for the reporting of disproportionality analyses in the main body text and four items, comprising 12 recommendations, for abstracts., Conclusions: The READUS-PV guidelines will support authors, editors, peer-reviewers, and users of disproportionality analyses using individual case safety report databases. Adopting these guidelines will lead to more transparent, comprehensive, and accurate reporting and interpretation of disproportionality analyses, facilitating the integration with other sources of evidence., (© 2024. The Author(s).)

Background: Despite its known cardiac and lung toxicities, the chemotherapy drug gemcitabine has only rarely been associated with pulmonary hypertension (PH), and the underlying mechanism remains unclear. The objective of the present study was to assess the association between gemcitabine and PH., Methods: We identified incident cases of precapillary PH confirmed by right heart catheterisation in patients treated with gemcitabine from the French PH Registry between January 2007 and December 2022. The aetiology, clinical, functional, radiological and haemodynamic characteristics of PH were reviewed at baseline and during follow-up. A pharmacovigilance disproportionality analysis was conducted using the World Health Organization (WHO) pharmacovigilance database., Results: We identified nine cases of pulmonary arterial hypertension, either induced (in eight patients) or exacerbated (in one patient) by gemcitabine. Patients exhibited severe precapillary PH, with a median mean pulmonary arterial pressure of 40 (range 26-47) mmHg, a cardiac index of 2.4 (1.6-3.9) L·min -1 ·m -2 and a pulmonary vascular resistance of 6.3 (3.1-12.6) Wood units. The median time from the initiation of gemcitabine to the onset of PH was 7 (4-50) months, with patients receiving a median of 16 (6-24) gemcitabine injections. Six patients showed clinical improvement upon discontinuation of gemcitabine. In the WHO pharmacovigilance database, we identified a significant signal with 109 cases reporting at least one adverse event related to PH with gemcitabine., Conclusion: Both clinical cases and pharmacovigilance data substantiate a significant association between gemcitabine use and the onset or worsening of precapillary PH. The observed improvement following the discontinuation of treatment underscores the importance of PH screening in gemcitabine-exposed patients experiencing unexplained dyspnoea., Competing Interests: Conflict of interest: X. Jais reports grants or contracts from Acceleron, Janssen, MSD and Bayer HealthCare, outside the submitted work; and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Janssen and MSD, outside the submitted work. Conflict of interest: L. Savale reports grants or contracts from Bayer, Janssen and Merck, outside the submitted work; and speaker fees from Janssen, outside the submitted work. Conflict of interest: O. Sitbon reports grants or contracts from Acceleron, AOP Orphan, Janssen, GSK and MSD, outside the submitted work; consulting fees from Altavant, Gossamer Bio, Janssen and MSD, outside the submitted work; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events for AOP Orphan, Janssen, Ferrer and MSD, outside the submitted work; and participation on a Data Safety Monitoring Board or Advisory Board for Acceleron, Altavant, Gossamer Bio, Janssen, MSD and Ferrer, outside the submitted work. Conflict of interest: 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 for 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. Conflict of interest: P. Bonniaud reports a research grant from AstraZeneca, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Sanofi and AstraZeneca, outside the submitted work; support for attending medical and research meetings from AstraZeneca, Novartis, Sanofi, Roche and Boehringer, outside the submitted work; and personal fees for advisory boards from AstraZeneca, Novartis, Sanofi, GSK, Roche and Boehringer, outside the submitted work. Conflict of interest: D. Montani reports grants or contracts from Acceleron, Janssen and Merck MSD, outside the submitted work; consulting fees from Acceleron, Merck MSD, Janssen and Ferrer, outside the submitted work; and speaker fees from Bayer, Janssen, Boehringer, Chiesi, GSK, Ferrer and Merck MSD, outside the submitted work. Conflict of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2024.)

Objectives: Measurement of digital perfusion, sometimes coupled with a cold challenge, has been widely used as an objective outcome in trials evaluating drug therapies in RP, in addition to patient-reported outcomes or to establish the proof-of-concept in preliminary studies. However, whether digital perfusion is a valid surrogate for clinical outcomes in RP trials has never been explored. The principal aim of this study was to evaluate the potential surrogacy of digital perfusion, by combining individual-level and trial-level data., Methods: We used individual data from a series of n-of-1 trials, and trial data from a network meta-analysis. We estimated individual-level surrogacy through coefficients of determination between digital perfusion and clinical outcomes (R2ind). We further calculated the coefficients of determination between treatment effect on the clinical outcomes and on digital perfusion, at the individual level (R2TEind) and at the trial level (R2trial), using non-weighted linear regression, with their 95% CI calculated through bootstrapping., Results: Results from 33 patients and 24 trials were included in the final analysis. At the individual level, there was no correlation between digital perfusion and clinical outcomes at rest and in response to various cooling tests (the highest R2ind was 0.03 [-0.07, 0.09]), and R2TEind was also very low 0.07 (0, 0.29). At the trial level, the highest value of R2trial was 0.1 (0, 0.477)., Conclusions: Digital perfusion, at rest or in response to a cold challenge, and whatever the method used, does not fulfil the criteria of a valid surrogate for existing patient-reported outcomes in RP trials., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: To report of a case of bilateral ocular hypotony associated with ciliary detachments and macula edema as an uncommon troublesome side-effect of pembrolizumab (an immune checkpoint inhibitor) treatment., Methods: A 56-year-old man with a history of metastatic axillary melanoma (bone, lung, spleen and lymph node lesions) treated with pembrolizumab complained of visual deterioration at his first-year anti-PD1 follow-up visit. Visual acuity in both eyes was 20/32. The patient presented bilateral ocular hypotony (7 mmHg in the right eye, 3mmHg in the left eye), ciliary detachments and macula edema. Several treatments were sequentially tried including systemic steroid therapy, subconjunctival injections of triamcinolone, an intravitreal dexamethasone implant, and leaving some cohesive viscoelastic agent during cataract surgery., Results: None of the treatments tried were effective in reducing the ocular hypotony and stopping pembrolizumab was not an option due to its efficacy in controlling the cancer., Conclusion: Pembrolizumab treatment carries a risk of ocular hypotony which can be bilateral, presenting a challenging risk - benefit dilemma, particularly if pembrolizumab is effective in controlling the cancer., Competing Interests: Declaration of interest / financial disclosures: No author has a proprietary interest or conflict of interest

Introduction: In refining drug safety signals, defining the object of study is crucial. While research has explored the effect of different event definitions, drug definition is often overlooked. The US FDA Adverse Event Reporting System (FAERS) records drug names as free text, necessitating mapping to active ingredients. Although pre-mapped databases exist, the subjectivity and lack of transparency of the mapping process lead to a loss of control over the object of study., Objective: We implemented the DiAna dictionary, systematically mapping individual free-text instances to their corresponding active ingredients and linking them to the World Health Organization Anatomical Therapeutic Chemical (WHO-ATC) classification., Methods: We retrieved all drug names reported to the FAERS (2004-December 2022). Using existing vocabularies and string editing, we automatically mapped free text to ingredients. We manually revised the mapping and linked it to the ATC classification., Results: We retrieved 18,151,842 reports, with 74,143,411 drug entries. We manually checked the first 14,832 terms, up to terms occurring over 200 times (96.88% of total drug entries), to 6282 unique active ingredients. Automatic unchecked translations extend the standardization to 346,854 terms (98.94%). The DiAna dictionary showed a higher sensitivity compared with RxNorm alone, particularly for specific drugs (e.g., rimegepant, adapalene, drospirenone, umeclidinium). The most prominent drug classes in the FAERS were immunomodulating (37.40%) and neurologic drugs (29.19%)., Conclusion: The DiAna dictionary, as a dynamic open-source tool, provides transparency and flexibility, enabling researchers to actively shape drug definitions during the mapping phase. This empowerment enhances accuracy, reproducibility, and interpretability of results., (© 2024. The Author(s).)

Background: Diabetic foot ulcers (DFUs) are a common complication of diabetes, associated with important morbidity. Appropriate animal models of DFUs may improve drug development, and subsequently the success rate of clinical trials. However, while many models have been proposed, they are extremely heterogeneous, and no standard has emerged. We thus propose a systematic review with a network meta-analysis (NMA) to gather direct and indirect evidence, and compare the different mouse models of diabetes-related ulcers., Methods: The systematic search was performed in Pubmed and Embase. The main outcomes were wound size measurement at days 3, 7, 11 and 15 (±1 day). The risk of bias and methodological quality of all included studies was assessed by using the Systematic Review Center for Laboratory animal Experimentation (SYRCLE) risk of bias tool. Meta-regressions were done on prespecified variables, including mouse strain, type of ulcer, sex, age, and use of a splint., Findings: We included 295 studies. Among all models, only db/db, ob/ob, streptozotocin (STZ), and STZ + high fat diet mice showed a significantly delayed wound healing, compared with controls, at each time point. Age, sex and ulcer type had influence on wound healing, although not at all time points., Interpretation: In conclusion, the db/db model is associated with the largest delay in wound healing The STZ model also exhibits significantly decreased wound healing. STZ + high fat diet and ob/ob mice may also be relevant models of diabetes-related ulcers, although the results rely on a more limited number of studies., Funding: This work was funded by the Agence Nationale de la Recherche (grant ANR-18-CE17-0017)., Competing Interests: Declaration of interests The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: We hypothesized that during the Christmas season the safety profile and the toxicity of some drugs may be exacerbated. We therefore assessed and characterized changes in drug safety profiles over the Christmas period., Design: We performed a retrospective longitudinal analysis of adverse events reported in the World Health Organization (WHO) pharmacovigilance database between April 1st 2017 to March 31th 2023., Setting: We extracted cases reported by the 5 main contributors' countries of the WHO pharmacovigilance database with a Christmas tradition: USA, France, Germany, Italy and UK., Participants: We analyzed 4,999,459 individual case safety reports from USA (n=3,498,961), France (n=419,018), Germany (n=398,763), Italy (n=251,641) and UK (n=431,076), reported between April 1st 2017 to March 31th 2023., Main Outcome Measures: Monthly reports of adverse events were analyzed. Time trend, seasonal effect a Christmas effect (December-January) were explored., Results: We found 91 adverse events significantly more frequently reported during the Christmas period, independently after controlling for winter effect and general tendency. The main type of adverse events were psychiatric disorders, infections and skin and subcutaneous disorders. The highest numbers of attributable cases to Christmas were found for drug dependence, emotional distress, and drug withdrawal syndrome. The most involved drugs were oxycodone in psychiatric disorders (n=47,527), docetaxel in skin disorders (n=9440) and social circumstances (n=1940), olmesartan in gastrointestinal disorders (n=1263), fentanyl in cardiac disorders (n=929), adalimumab in infections (n=11,316) and immune system disorders (n=3781), and collagenase clostridium histolyticum in reproductive system disorders (n=318)., Conclusions: Our study shows that a range of drugs adverse events are more frequently reported at Christmas compared to other periods of the year, notably psychiatric disorders, infections, and skin disorders., (Copyright © 2023 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)