Use of sodium-glucose cotransporter-2 inhibitors in France: Analysis of French nationwide health insurance database.

AIM: Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have been commercialized in France for type 2 diabetes since April 2020 and later for heart and renal diseases. Given the recent developments in treating diabetes and the widening of SGLT-2i indications, we aimed to study changes in the use of glucose-lowering drugs in France and to characterize SGLT-2i new users. METHODS: We performed a nationwide utilization study using the French health insurance database. Trends in incidence and prevalence of glucose-lowering drug use were assessed by a repeated cross-sectional study in 2019 and 2021. A cohort study of incident SGLT-2i users was then conducted to describe patient characteristics and the strategy for treating diabetes. RESULTS: The prevalence of SGLT-2i use gradually reached 0.1% in the third quarter of 2021 and increased more significantly to 0.2% thereafter. SGLT-2i became the second most prescribed glucose-lowering drug class after metformin at the end of 2021 (0.1%). Among the cohort of 125 387 SGLT-2i new users (mean age 65.0 years; 60.1% of men), 87.6% presented a diabetic comorbidity. The patient profile changed over the study period with an increasing proportion of patients with cardiovascular (28.7% in 2020 vs. 40.2% in 2021) or renal (7.7% in 2020 vs. 11.8% in 2021) comorbidities at initiation. The main combinations used at SGLT-2i initiation were metformin (12.5%) and metformin plus dipeptidyl peptidase-4 inhibitors (8.1%). One-year probability of SGLT-2i persistence was estimated to be 55%. CONCLUSION: The expansion of indications for SGLT-2i and the broadening of the target population make it essential to assess the reasons for discontinuation and review their safety profile.

Estimating individualized treatment effects using an individual participant data meta-analysis.

BACKGROUND: One key aspect of personalized medicine is to identify individuals who benefit from an intervention. Some approaches have been developed to estimate individualized treatment effects (ITE) with a single randomized control trial (RCT) or observational data, but they are often underpowered for the ITE estimation. Using individual participant data meta-analyses (IPD-MA) might solve this problem. Few studies have investigated how to develop risk prediction models with IPD-MA, and it remains unclear how to combine those methods with approaches used for ITE estimation. In this article, we compared different approaches using both simulated and real data with binary and time-to-event outcomes to estimate the individualized treatment effects from an IPD-MA in a one-stage approach. METHODS: We compared five one-stage models: naive model (NA), random intercept (RI), stratified intercept (SI), rank-1 (R1), and fully stratified (FS), built with two different strategies, the S-learner and the T-learner constructed with a Monte Carlo simulation study in which we explored different scenarios with a binary or a time-to-event outcome. To evaluate the performance of the models, we used the c-statistic for benefit, the calibration of predictions, and the mean squared error. The different models were also used on the INDANA IPD-MA, comparing an anti-hypertensive treatment to no treatment or placebo ( N = 40 237 , 836 events). RESULTS: Simulation results showed that using the S-learner led to better ITE estimation performances for both binary and time-to-event outcomes. None of the risk models stand out and had significantly better results. For the INDANA dataset with a binary outcome, the naive and the random intercept models had the best performances. CONCLUSIONS: For the choice of the strategy, using interactions with treatment (the S-learner) is preferable. For the choice of the method, no approach is better than the other.

Clinical improvement after Essure® devices removal: a systematic review.

PURPOSE: Essure® implant is a permanently implanted minimally invasive birth control device for women (female sterilisation) widely used between 2002 and 2018. Many adverse events were reported by patients. Increasingly removal procedures have been performed in symptomatic patients. However, there is a lack of in-depth studies on clinical improvement after Essure® removal. We aimed to review all clinical studies about symptoms and quality of life (QoL) after removal procedures. MATERIALS AND METHODS: A review of literature in electronic search in Medline and Embase databases from January 2002 to January 2022 using the following keywords: Essure; Essure removal; quality of life; symptomatology improvement. RESULTS: Out of 764 articles in the initial database, 18 clinical studies were eligible for inclusion in our literature review. Overall clinical improvement rates after removal ranged from 21% to 98%. All symptoms were less frequent after Essure® removal, although with large discrepancies between studies. Lack of improvement was reported between 1% to 15% of patients. Rate of patients with improvement of QoL after removal ranged from 58 to 98%. The pain was reported as significantly reduced after the surgery. CONCLUSIONS: In the available literature, Essure® removal in symptomatic patients may improve symptoms and quality of life. This should be discussed in the benefits and risks ratio before deciding on the best option of management.

Essure® removal in symptomatic patients may improve symptoms and quality of life.

SGLT2 inhibitors in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials balancing their risks and benefits.

AIMS/HYPOTHESIS: Cardiovascular outcome trials (CVOTs) have demonstrated the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i). However, serious adverse drug reactions have been reported. The risk/benefit ratio of SGLT2i remains unquantified. We aimed to provide an estimation of their risk/benefit ratio in individuals with type 2 diabetes. METHODS: We conducted a systematic review (MEDLINE, up to 14 September 2021) and meta-analysis. We included randomised CVOTs assessing SGLT2i in individuals with type 2 diabetes with or without other diseases. We used the Cochrane 'Risk of bias' assessment tool. The primary outcomes were overall mortality, major adverse cardiovascular events (MACE), hospitalisation for heart failure (HHF), end-stage renal disease (ESRD), amputation, diabetic ketoacidosis (DKA) and reported genital infections. For each outcome, we estimated the incidence rate ratio (IRR) with a 95% CI; we then computed the number of events expected spontaneously and with SGLT2i. RESULTS: A total of 46,969 participants from five double-blind, placebo-controlled international trials (weighted mean follow-up 3.5 years) were included. The prevalence of previous CVD ranged from 40.6% to 99.2%. The definition of reported genital infections ranged from 'genital mycotic infection' to 'genital infections that led to discontinuation of the trial regimen or were considered to be serious adverse events'. The number of included studies for each outcomes was five. The use of SGLT2i decreased the risk of all-cause death (IRR 0.86 [95% CI 0.78, 0.95]), MACE (IRR 0.91 [95% CI 0.86, 0.96]), HHF (IRR 0.69 [95% CI 0.62, 0.76]) and ESRD (IRR 0.67 [95% CI 0.53, 0.84]), and increased the risk of DKA (IRR 2.59 [95% CI 1.57, 4.27]) and genital infection (IRR 3.50 [95% CI 3.09, 3.95]) but not of amputation (IRR 1.23 [95% CI 1.00, 1.51]). For 1000 individuals treated over 3.5 years, SGLT2i are expected, on average, to decrease the number of deaths from 70 to 61, to prevent nine MACE, 11 HHF and two cases of ESRD, while inducing two DKA occurrences and 36 genital infections; 778 individuals are expected to avoid all the following outcomes: MACE, HHF, ESRD, amputation, DKA and genital infection. CONCLUSIONS/INTERPRETATION: Our study is limited to aggregate data. In a population of individuals with type 2 diabetes and a high CVD risk, the cardiovascular and renal benefits of SGLT2i remain substantial despite the risk of DKA and even the hypothetical risk of amputation. TRIAL REGISTRATION: OSF Registries: https://doi.org/10.17605/OSF.IO/J3R7Y FUNDING: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Efficacy and safety of topiramate in binge eating disorder: a systematic review and meta-analysis.

BACKGROUND: To assess the efficacy and safety of topiramate in treating binge eating disorder (BED), using a systematic review and meta-analysis of the available randomized clinical trials (RCTs). METHODS: The RCTs assessing topiramate vs placebo with or without adjunctive psychotherapy in BED were reviewed using a systematic search in the PubMed, Web of Science, PsycINFO, Cochrane Database of Systematic Review, and ClinicalTrials.gov search Websites, from inception to November 2019. Main outcomes were the changes in binge frequency, quality of life, and weight, respectively. Effect estimates were pooled using random-effect models and presented as risk ratios (RRs) or mean differences (MDs) and their 95% confidence interval (95% CI). Data extraction was performed by two independent reviewers. RESULTS: Three studies were eligible for inclusion, involving 528 BED patients. Topiramate was found to be significantly more efficacious than placebo in reducing: (a) the number of binge episodes per week (MD = -1.31; 95% CI = -2.58 to -0.03; I2 = 94%); (b) the number of binge days per week (MD = -0.98; 95% CI = -1.80 to -0.16; I2 = 94%); and (c) weight (MD = -4.91 kg; 95% CI = -6.42 to -3.41; I2 = 10%). However, participants in the topiramate groups withdrew significantly more frequently for safety reasons, relative to placebo participants (RR = 1.90; 95% CI = 1.13-3.18, I2 = 0%). CONCLUSIONS: Preliminary findings support a possible efficacy of topiramate for the treatment of BED, even if safety concerns could limit the practical use of this treatment in BED subjects.

Minoxidil versus placebo in the treatment of arterial wall hypertrophy in children with Williams Beuren Syndrome: a randomized controlled trial.

BACKGROUND: Insufficient elastin synthesis leads to vascular complications and arterial hypertension in children with Williams-Beuren syndrome. Restoring sufficient quantity of elastin should then result in prevention or inhibition of vascular malformations and improvement in arterial blood pressure. METHODS: The aim of this study was to assess the efficacy and safety of minoxidil on Intima Media Thickness (IMT) on the right common carotid artery after twelve-month treatment in patient with Williams-Beuren syndrome. We performed a randomized placebo controlled double blind trial. All participants were treated for 12 months and followed for 18 months. The principal outcome was assessed by an independent adjudication committee blinded to the allocated treatment groups. RESULTS: The principal outcome was available for 9 patients in the placebo group and 8 patients in the minoxidil group. After 12-month treatment, the IMT in the minoxidil group increased by 0.03 mm (95% CI -0.002, 0.06) compared with 0.01 mm (95%CI - 0.02, 0.04 mm) in the placebo group (p = 0.4). Two serious adverse events unrelated to the treatment occurred, one in the minoxidil and 1 in the placebo group. After 18 months, the IMT increased by 0.07 mm (95% CI 0.04, 0.10 mm) in the minoxidil compared with 0.01 mm (95% CI -0.02, 0.04 mm) in the placebo group (p = 0.008). CONCLUSION: Our results suggest a slight increase after 12 and 18-month follow-up in IMT. More understanding of the biological changes induced by minoxidil should better explain its potential role on elastogenesis in Williams-Beuren syndrome. TRIALS REGISTRATION: US National Institutes of Health Clinical Trial Register (NCT00876200). Registered 3 April 2009 (retrospectively registered).

Reducing waste in pediatric clinical research.

The importance of reducing waste and increasing value when conducting research has been emphasized by a series of articles published in the Lancet in 2014. A survey indicates that, one year later, these articles have not influenced how research is conducted. In this review, we explore four stages described by Moher et al. in research production that lead to waste. We show that all four stages including, questions relevant to users, appropriate design conduct and analysis, accessible full research, unbiased and usable reports, efficient research regulation and management of biomedical research are also producing an important waste in pediatric research. We conclude that methods to improve research quality and limit waste need to be implemented in pediatric research and recognized by authorities as a priority.

Use of available clinical evidence to extrapolate drug effects from adults to children.

The extrapolation of the benefit risk ratio from adults to children is performed during drug development and often implicitly used by many paediatricians when prescribing off-label drugs in children. This is due to the specific constraints of paediatric clinical research leading to a lack of safety and efficacy data in children. Extrapolation frameworks for drug development have been proposed by several regulatory agencies. Using a meta-epidemiological approach, we explored the similarities and differences of the benefit, the benefit risk ratio and the perceived placebo effect between adults and children from meta-analyses including randomized double-blinded placebo-controlled trials evaluating a drug intervention in an indication in adults and children with separate data for both populations. We also explored the use of the effect model using adult data to predict the treatment effect in children and to calibrate future paediatric clinical trials. Our research highlights the importance of using all available evidence and quantitative methods before extrapolating the benefit risk ratio from adults to children and carrying out new studies in the context of the existing evidence. More generally, this should be applied to any research to avoid a waste of time and resources invested.

Mushroom Poisoning-Related Cardiac Toxicity: A Case Report and Systematic Review.

We encountered a case of mushroom intoxication complicated by "toxic-like" myocarditis. Because of the lack of systematized knowledge on this subject, we performed a systematic review of the literature on cardiac toxicity in mushroom poisoning (MP). The aim of this study was to identify and describe the severity, the causal relationship, and the mushroom species involved in other reported cardiac events associated with MP. We included 39 studies in our review. We found 106 cases of cardiac events associated with MP, including 18 deaths. A wide variety of cardiac manifestations were reported, ranging from the simple elevation of cardiac enzymes (n = 61) to ventricular tachycardia (n = 14), acute heart failure (n = 18), and myocarditis (n = 7). Causal relationship between cardiac manifestations and mushroom poisoning was assessed for 42 patients, applying the algorithm validated by the French Toxicovigilance Coordination Committee. Twenty-three cases (54.8%) had a "possible" causal relationship, eight cases (19%) a "probable" relationship, and ten cases (23.8%) a "very probable" relationship. Several fungal genera were involved in reported cases, including Amanita but also rarer ones like Russula and Tricholoma. In conclusion, we showed that cases of cardiac toxicity following MP have been documented in the existing literature, and for some of them, we assessed a strong causal relationship.

Unlicensed/Off-Label Drug Prescriptions at Hospital Discharge in Children: An Observational Study Using Routinely Collected Health Data.

BACKGROUND: Unlicensed and off-label (UL/OL) prescriptions have been associated with an increased risk of drug-related problems. Data of their prevalence at hospital discharge remain insufficient. We aimed to describe the prevalence of UL/OL drugs in outpatient prescriptions at discharge in children. METHODS: We conducted a retrospective study using the routinely collected health data of children at discharge from 2014 to 2016. The primary reference source for determining licensed labelling was the summaries of product characteristics (SPCs) in a French industry-independent formulary named Thériaque. We described the characteristics of UL/OL prescriptions at discharge and looked for predictors of UL/OL prescriptions. RESULTS: We included 2536 prescriptions of 479 children. Licensed, OL, and UL prescriptions accounted for 58.6% (95% CI: 56.7-60.5), 39.2% (95% CI: 37.3-41.1), and 2.3% (95% CI: 1.7-2.9), respectively. A total of 323 (74%) children received at least one UL/OL drug. Among the licensed drugs, bronchodilators (8.8%) and analgesics (8.6%), and among the OL drugs, antibiotics (2.8%), were the most prescribed. The younger age of the children and higher number of drugs they received increased the probability of UL/OL prescriptions (unadjusted p-value of ≤0.05). CONCLUSION: The prevalence of UL/OL prescriptions is about 40% at discharge from a pediatric university hospital in France.

Deaths induced by compassionate use of hydroxychloroquine during the first COVID-19 wave: an estimate.

BACKGROUND: During the first wave of COVID-19, hydroxychloroquine (HCQ) was used off-label despite the absence of evidence documenting its clinical benefits. Since then, a meta-analysis of randomised trials showed that HCQ use was associated with an 11% increase in the mortality rate. We aimed to estimate the number of HCQ-related deaths worldwide. METHODS AND FINDINGS: We estimated the worldwide in-hospital mortality attributable to HCQ use by combining the mortality rate, HCQ exposure, number of hospitalised patients, and the increased relative risk of death with HCQ. The mortality rate in hospitalised patients for each country was calculated using pooled prevalence estimated by a meta-analysis of published cohorts. The HCQ exposure was estimated using median and extreme estimates from the same systematic review. The number of hospitalised patients during the first wave was extracted from dedicated databases. The systematic review included 44 cohort studies (Belgium: k = 1, France: k = 2, Italy: k = 12, Spain: k = 6, Turkey: k = 3, USA: k = 20). HCQ prescription rates varied greatly from one country to another (range 16-84%). Overall, using median estimates of HCQ use in each country, we estimated that 16,990 HCQ-related in-hospital deaths (range 6267-19256) occurred in the countries with available data. The median number of HCQ-related deaths in Belgium, Turkey, France, Italy, Spain, and the USA was 240 (range not estimable), 95 (range 92-128), 199 (range not estimable), 1822 (range 1170-2063), 1895 (range 1475-2094) and 12739 (3244- 15570), respectively. CONCLUSIONS: Although our estimates are limited by their imprecision, these findings illustrate the hazard of drug repurposing with low-level evidence.

Exposure to ammonia solution due to substance use: a retrospective study from the French poison centres database (2009-2018).

INTRODUCTION: Ammonia solution (ammonium hydroxide) is used to convert cocaine hydrochloride to freebase cocaine. Due to its causticity, unintentional exposure to ammonia in a substance use context can result in injury. The objective of this study was to describe the characteristics of unintentional oral and buccal ammonia solution exposure in a substance use context. METHODS: A retrospective study was conducted using the French poison centres database over a 10-year period (2009-2018). RESULTS: A total of 1,546 files were extracted, and 263 substance users were included. There was a significant increase in the number of these exposures between 2009 and 2018. Unintentional ingestion of ammonia solution was linked to product decanting in 89 per cent of cases. Substance use prior to the exposure and a festive context, such as free parties or teknivals, were identified in 25 per cent and 21 per cent of cases, respectively. Patients received a hospital examination in 87 per cent of cases. The severity of intoxication in substance users was graded as moderate (33 per cent) or severe (15 per cent) using the Poisoning Severity Score. DISCUSSION: The increased number of ammonia solution cases reported was consistent with an increase in the number of crack users in Europe in the same period. Ammonia solution exposure can suggest the possibility of substance use disorders. In such cases, patients can be referred to receive appropriate treatment and support. This study had some limitations, such as the lack of available information due to the retrospective nature of the study and the non-standardized questions asked by the poison centre during the medical phone interviews. CONCLUSION: Oral and buccal ammonia solution exposure in known substance users in France increased between 2009 and 2018. These users were mostly young men. A festive context and decanting were frequent. Patients were mainly referred to emergency departments to receive clinical examination and care. The potential severity of oral or buccal ammonia solution exposure in substance users requires increased vigilance among all healthcare professionals involved in the management of these intoxication cases.

Drug-related risk of hospital readmission in children with chronic diseases, a systematic review.

BACKGROUND: Drug-related problems (DRPs) are one of the leading causes of hospital readmissions. Children with chronic diseases are more likely to experience DRPs than adults. The burden and characteristics of drug-related readmissions at and after hospital discharge in children remain unclear. OBJECTIVE: We aimed to summarize the impact of DRPs at and after hospital discharge on the risk of readmissions in children with chronic diseases. METHODS: We conducted a systematic review searching PubMed from inception until January 2022. Study selection criteria were studies assessing the impact of different factors at discharge and after discharge on the risk of hospital readmissions in children with chronic diseases, reporting an assessment of DRPs. DRP could be the only risk factor assessed or one among others. Included studies were assessed with the Risk of Bias in Non-Randomized Studies - of Exposure (ROBINS-E) tool. We summarized the qualitative impact of the reported DRPs on hospital readmission as conclusive (significant association) or inconclusive. RESULTS: Of the 4734 studies initially identified, 13 met inclusion criteria. Eleven studies were retrospective, using electronic health records. The studies assessed the impact of DRPs at or after discharge according to the type of medication (in 6 studies), number of medication (in 5 studies) and medication nonadherence (in 2 studies). From the 44 reported associations between DRPs and the risk of readmission 26 (59% [95% CI, 43%-73%]) were conclusive, of which 81% increased the risk and 19% decreased the risk, and 17 (39% [95% CI, 24%-55%]) were inconclusive. CONCLUSION: The impact of DRPs on hospital readmissions in children with chronic diseases displayed conflicting results, estimated associations having potentially a serious risk of bias. We need more evidence with a lower risk of bias.

Vaccines and Bell's palsy: A narrative review.

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.

Population designations in biomedical research: Limitations and perspectives.

In biomedical research, population differences are of central interest. Variations in the frequency and severity of diseases and in treatment effects among human subpopulation groups are common in many medical conditions. Unfortunately, the practices in terms of subpopulation labeling do not exhibit the level of rigor one would expect in biomedical research, especially when studying multifactorial diseases such as cancer or atherosclerosis. The reporting of population differences in clinical research is characterized by large disparities in practices, and fraught with methodological issues and inconsistencies. The actual designations such as "Black" or "Asian" refer to broad and heterogeneous groups, with a great discrepancy among countries. Moreover, the use of obsolete concepts such as "Caucasian" is unfortunate and imprecise. The use of adequate labeling to reflect the scientific hypothesis needs to be promoted. Furthermore, the use of "race/ethnicity" as a unique cause of human heterogeneity may distract from investigating other factors related to a medical condition, particularly if this label is employed as a proxy for cultural habits, diet, or environmental exposure. In addition, the wide range of opinions among researchers does not facilitate the attempts made for resolving this heterogeneity in labeling. "Race," "ethnicity," "ancestry," "geographical origin," and other similar concepts are saturated with meanings. Even if the feasibility of a global consensus on labeling seems difficult, geneticists, sociologists, anthropologists, and ethicists should help develop policies and practices for the biomedical field.

[Does aspirin have a place in primary cardiovascular prevention by the polypill ? Simulation study on a realistic virtual population]. / L'aspirine a-t-elle une place dans la prévention cardiovasculaire primaire par la polypill ? Étude de simulation sur une population virtuelle réaliste.

BACKGROUND: The polypill strategy could become widely accepted in cardiovascular prevention due to reduced costs and its simplicity, which promote compliance. Aspirin is often included as a component of the polypill for primary prevention, but three powerful recent trials failed to show any favorable net benefit even in high-risk subgroups. Our objective is to estimate the net benefit associated with aspirin in primary cardiovascular prevention. METHODS: We simulated the impact of different polypill compositions combining pravastatin, ramipril, hydrochlorothiazide, with or without aspirin, on a realistic French virtual population between 35 and 65 years old. We assessed how this impact on myocardial infarction and stroke varied according to gender, diabetes, and arterial hypertension. We identified the subgroup of individuals whose specific benefit from aspirin was greater than twice the risk of serious bleeding it induced. RESULTS: The absolute benefit associated with aspirin was reduced by co-prescriptions. No subgroup of women benefited from aspirin, and the subgroup of women with a clear net benefit represented 128 women out of 529,421. Men at high risk of cardiovascular death, or with diabetes and hypertension, had a benefit from aspirin exceeding the risk of bleeding induced, but this risk represented more than half of the benefit. No subgroup analyzed did show a benefit greater than twice the risk of bleeding. The proportion of men whose expected benefit from aspirin was greater than twice the risk of bleeding represented 3% of all men. An optimal polypill strategy in primary prevention between the ages of 35 and 65, combining three drugs but not aspirin, can hope to save two out of three strokes and more than one out of two myocardial infarctions. It would prevent a major cardiovascular accident every 16 to 193 individuals treated according to the subgroups considered. CONCLUSION: Until proven otherwise, aspirin has only a limited place in individuals between 35 and 65 years without a cardiovascular history. We showed how simulating therapeutic strategies on a realistic virtual population could be used for best applying available evidence.

A revisited version of the disputatio for pharmacological training: An educational study.

OBJECTIVE: The disputatio is a pedagogical method existing since the Middle-Ages where students had to debate about a question asked by a "master", exercising their thinking and oratory skills. To move away from traditional vertical teaching methods, the disputatio has been revived by pharmacologists. Thus, for almost three successive years, several groups of young French pharmacologists and therapists confronted their ideas concerning a medical question at a therapeutic impasse. The aim here is to describe the initial feedback received from participants. METHODS: An anonymous questionnaire was sent by email in May 2023 to the participants of the different disputationes of 2019, 2022 and 2023. Participants were asked about different aspects of their feelings before, during and after the disputatio, using the 5-point Likert scale. They were also asked to describe the event in 2 to 5 words. Finally, participants could leave their comments in a free-field and were asked to give an overall satisfaction score out of 10. RESULTS: Out of the 39 participants, 27 (69.2%) answered the questionnaire. Although 50% of respondents reported a feeling of anxiety before participating, most enjoyed the expert talks as well as working with people they did not know. Besides, over 66% reported having underestimated the skills they could share with colleagues from different backgrounds. Over 55% of respondents reported progress in methodology, and over 83% in pharmacology and/or therapeutics. Participants reported an overall satisfaction score of 8.6/10, and the main terms used to describe the event were "sharing", "enriching" and "meeting". CONCLUSION: The disputatio is an innovative training program whose pedagogical and human values were underlined by most of the participants. Beyond pharmacology and therapeutics, the principle of disputatio could be extended to other disciplines, spanning the centuries.

Bites by Non-Native Reptiles in France: Species, Circumstances and Outcome.

We aimed to make an exhaustive assessment of circumstances of bites by exotic reptiles bred in France. A retrospective observational study was conducted in all the reported cases from 2000 to 2020 in French poison control centers (PCCs). Two hundred and eighteen cases of bites were recorded. The sex ratio (M/F) of the patients was 1.79 and the mean age of the patients was 29.0 ± 15.8 years. Twenty-two cases (10.1%) occurred during the deep night. One hundred and eighty-six bites (85.7%) occurred in a private context; however, there were more cases of high severity when it occurred in a professional setting (60.0% vs. 11.2%, p < 0.01). The feeding/nursing activity accounted for 54.7% cases. Forty-three species of snake were identified; 28 were considered venomous. There were no deaths among the patients in the study. Most of the cases (85.8%) were of mild severity. All of the patients bitten by a venomous reptile were hospitalized: 10 patients received an antivenom; and 2 required surgery. Bites occurred at home and by a small number of popular non-venomous reptile species (pythons and boas, colubrids). These occurred mainly when handling the animals. The rare envenomations were mainly by Asian and American crotalids, followed by elapids. One-third of them were treated with antivenom when available.

Reappraisal of the efficacy of intensive glycaemic control on microvascular complications in patients with type 2 diabetes: A meta-analysis of randomised control-trials.

OBJECTIVE: To re-assess the effect of tight glycaemic control on diabetic microvascular complications. METHOD: Meta-analysis and trial sequential analyses of randomised trials included in Hemmingsen et al that specifically assessed glycaemic control with a specific HbA1c level targeted in the intervention group, and compared intensive glycaemic control versus standard glycaemic control. RESULTS: Seven clinical trials that randomised 28,614 participants with type 2 diabetes (15,269 to intensive control and 13,345 to conventional control), including 3 sub-studies, were included. Strict control of blood glucose levels is associated with a reduction of retinopathy progression (RR=0.77, 95% CI: 0.66-0.89, I2=33%), incidence or progression of macular oedema (RR=0.66, 95% CI: 0.40-0.99, I2=0%), number of photocoagulations (RR=0.84, 95% CI: 0.73-0.97, I2=0%), risk of microalbuminuria (RR=0.76, 95% CI: 0.64-0.9, I2=76%) and risk of "macroalbuminuria or proteinuria" (RR=0.68, 95% CI: 0.55-0.85, I2=36%). CONCLUSION: This meta-analysis has shown that a tight control of blood glucose levels is associated with a decrease of specific microvascular complication of diabetes: photocoagulation, progression of diabetic retinopathy, incidence or progression of macular oedema, risk of microalbuminuria and risk of macroalbuminuria or proteinuria. Regarding all the other outcomes (vision loss, surgery of cataract, proliferative or non-proliferative retinopathy, death related to kidney disease, development of kidney disease, doubling of serum creatinine, neuropathy), no significant result was found.

Publication bias in pharmacogenetics of adverse reaction to antiseizure drugs: An umbrella review and a meta-epidemiological study.

Publication bias may lead to a misestimation in the association between pharmacogenetic biomarkers (PGx) and antiseizure drug's adverse effects (AEs). We aimed to assess its prevalence in this field. We searched for systematic reviews assessing PGx of antiseizure drug's AEs. For each unique association between a PGx, a drug and its AE, we used the available odds ratio (ORs) to generate corresponding funnel plots. We estimated the prevalence of publication bias using visual inspections and asymmetry tests. We explored the impact of publication bias using ORs adjusted for potential publication bias. Twenty-two associations were available. Our visual analysis suggested a publication bias in five out twenty-two funnel plots (23% [95%CI: 8; 45]). The Egger's test showed a significant publication bias in one (HLA-B*15:02 and phenytoin-induced Stevens-Johnson syndrome or toxic epidermal necrolysis, p = 0.03) out of nine (11% [95%CI: 0; 48]) and the Begg's test in one (HLA-B*15:02 and carbamazepine-induced serious cutaneous reactions, p = 0.02) out of ten (10% [95%CI: 0; 45]) assessable funnel plots. Adjusting for publication bias may reduce by half the ORs of the pharmacogenetics associations. Publication bias in the pharmacogenetic of antiseizure drug's AEs is not uncommon and may affect the estimation of the effect of such biomarkers. When conducting pharmacogenetic studies, it is critical to publish also the negative one.