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Patients with chronic non-cancer pain are referred to pain centres to improve their pain treatment. The discontinuation of pain medications in case of poor efficacy can be difficult to accept for patients, particularly opioid analgesics. Previous research has described that from the patients’ perspective, the psychological relief of a negative effect of chronic pain and withdrawal symptoms of prescription opioids represent drivers of persistent use and first stage of opioid use disorder, despite insufficient pain relief. There is no validated tool to investigate this psychological dependence. This study aimed to assess discordance between patients and pain specialists in their perception of dependence on pain medication and investigate associations with characteristics of patients, type of pain and iatrogenic pharmacodependence.

ABSTRACTMid-wavelength infrared (MWIR) imaging Fourier transform spectrometers (IFTSs) are a promising technology for measuring flare combustion efficiency (CE) and destruction removal efficiency (DRE). These devices generate spectrally resolved intensity images of the flare plume, which may then be used to infer column densities of relevant species along each pixel line-of-sight. In parallel, a 2D projected velocity field may be inferred from the apparent motion of flow features between successive images. Finally, the column densities and velocity field are combined to estimate the mass flow rates for the species needed to calculate the CE or DRE. Since the MWIR IFTS can measure key carbon-containing species in the flare plume, it is possible to measure CE without knowing the fuel flow rate, which is important for fenceline measurements. This work demonstrates this approach on a laboratory heated vent, and then deploys the technique on two working flares: a combustor burning natural gas at a known rate, and a steam-assisted flare at a petrochemical refinery. Analysis of the IFTS data highlights the potential of this approach, but also areas for future development to transform this approach into a reliable technique for quantifying flare emissions.Implications: Our research is motivated by the need to assess hydrocarbon emissions from flaring, which is a critical problem of global significance. For example, recent studies have shown that methane destruction efficiency of flaring from upstream oil may be significantly lower than the commonly assumed figure of 98%; work by Plant et al., in particular, suggest that this discrepancy amounts to CO2emissions from 2 to 8 million automobiles annually, considering the US alone. Similarly, the international energy agency (IEA) estimates a global flare efficiency of 92%,which translates in 8 million tons of CH4emitted by flares in 2020. Highlighted by these studies and supported by the World Bankinitiatives toward zero routine flaring emissions, there is an urgent need for oil and gas industry to assess their flare methane emission, and overall hydrocarbon emissions. At the very least, it is critical to identify problematic flare operating conditions and means to mitigate flare emissions. Focusing on remote quantification of plume species, the measurement technique and quantification method presented in this paper is a considerable step forward in that direction by computing combustion efficiency and key components for destruction efficiency.

Recurrent gene fusions are common in salivary gland tumors including benign tumors, such as pleomorphic adenoma (PA) and myoepithelioma (ME). In cases where chromosomal rearrangement is identified in the pleomorphic adenoma gene 1 (PLAG1)gene, different gene partners are found. Oncocytic metaplasia, characterized by oncocytes with abundant eosinophilic granular cytoplasm and hyperchromatic nuclei, is a well-known phenomenon in salivary gland neoplasms. However, the pure oncocytic variant of PA/ME showed PLAG1gene rearrangements involving various gene partners at the molecular level, without any recurrent fusion being found. Our study includes 20 cases of PA/ME, with 11 females and 9 males. The age of patients ranged from 37 to 96 years, with a median age of 62.8 years. Most tumors originate from the parotid gland. The median size of the tumor was 26.5 mm (range: 13 to 60 mm). Among the 20 cases, 14 were a pure oncocytic variant of PA/ME, whereas 6 cases showed focal oncocytic or oncocytic-like aspects. Molecular studies on 20 cases of PA/ME were conducted. A novel recurrent ZBTB47-AS1::PLAG1fusion was identified in 6 of 12 cases with pure oncocytic metaplasia, whereas the other cases had PLAG1gene fusion with different gene partners. The transcriptomic analysis of the cases harboring ZBTB47-AS1::PLAG1fusion demonstrated that these tumors have a distinct molecular profile from conventional PA/ME. This study reveals a unique subset in the oncocytic PA/ME spectrum characterized by pure oncocytic morphology with larger oncocytic cells and recurrent ZBTB47-AS1::PLAG1fusion. It also highlights the transcriptomic distinctness of salivary gland adenomas with pure oncocytic metaplasia in the spectrum of salivary gland neoplasms. Further studies are needed to better understand the oncocytic variant of PA/ME and to determine the true nature of oncocytic cells in PA/ME.

Le deuil est une expérience douloureuse et universelle qui peut avoir des effets sur la santé mentale et physique. Les soignants, en particulier les psychologues, ont pour mission d’accompagner les proches du patient décédé. La désensibilisation et retraitement par les mouvements oculaires (plus connue sous la dénomination anglaise eye-movement desensitization and reprocessing[EMDR]), une thérapie validée pour les états de stress post-traumatique, pourrait être utile dans l’accompagnement du deuil. L’objectif de notre article est de présenter la technique utilisée et l’expérience vécue par les psychologues au travers du verbatim analysé des proches accompagnés.

ABSTRACTBackgroundThe association between dental problems and sublingual/buccal buprenorphine is unclear. We conducted an analysis of dental adverse drug reactions reported with sublingual/buccal buprenorphine in VigiBase®, the pharmacovigilance database of the World Health Organization.Research design and methodsWe performed disproportionality analyses to compare the reporting rates of dental problems with sublingual/buccal buprenorphine, compared to other buprenorphine formulations and methadone. Significant signals were considered if the lower boundary of the 95% confidence interval of the Reporting Odds Ratio (ROR) was > 1; cases were ≥ 3 and p-value <0.05. We conducted sensitivity analyses by calculating the ROR according to the reporter’s qualification and the reporting continent (United States of America and Europe).ResultsWe included 30,769 reports with all buprenorphine forms. We found 20 cases of dental problems with sublingual/buccal buprenorphine. Sublingual/buccal buprenorphine was associated with an overreporting of dental problems compared to other buprenorphine formulations (ROR = 15.10; 95% CI [7.50–30.39]; p < 0.005) and compared to methadone (ROR = 6.02; 95% CI [3.21–11.30]; p < 0.005). Overreporting of dental problems was consistent in sensitivity analyses, except in Europe compared with other buprenorphine formulations and with methadone.ConclusionsSublingual/buccal buprenorphine might increase the risk of reporting dental problems. However, these results do not modify the benefits of sublingual/buccal buprenorphine in the treatment of opioid use disorders.

ABSTRACTIntroductionRespiratory depression and opioid-related death are reported when opioids are associated with gabapentinoids. Meta-analyses of randomized clinical trials investigating efficacy and safety of such association failed to assess these risks because of the lack of data. The aim of this systematic review was to investigate the risk of respiratory depression or death during this combination in the scientific literature, including case reports or series, observational studies, and clinical trials.Areas coveredPubMed®, Web of Science®, Embase®, and Google Scholar® were searched from their inception to December 2021, for original articles in English, French, and German. Data synthesis was done on a narrative approach by type of articles.Expert opinionThe review included 25 articles (4 case reports, 2 cross-sectional, 3 case–control, 14 cohort studies, and 2 clinical trials). Respiratory depression or opioid-related death and co-exposure to gabapentinoids were associated in perioperative setting/chronic pain (odds ratios around 1.3) and in opioid maintenance treatment (hazard ratio 3.4). These findings are in agreement with experimental studies showing that a single dose of gabapentinoid may reverse opioid respiratory tolerance. Because the combination gabapentinoids–opioids is highly prevalent in all clinical context, all health care professionals and patients must be aware of this risk.

Substance use disorders during pregnancy are associated with antenatal, neonatal and long-term adverse drug reactions in children. The aim of this study was to describe, using data from OPPIDUM survey, the evolution of illicit substance use or diverted prescription drug use among pregnant women visiting French addiction care centres from 2005 to 2018.

Epidemiology of substance use disorders and their complications is driven by a male predominance, and women, even if they are more and more prevalent, are never specifically represented in studies in the field. Apart from the time of pregnancy, which in itself requires specific prevention, treatment and follow-up, the importance of the sex of women in the complications of substance abuse is neglected. To illustrate, we described some characteristics of women identified in the addictovigilance information system in France and Europe, related to drug use disorders (both for illicit substances and medications). Even if the exposure to some psychoactive substances remains more prevalent in men, women, and particularly young women, seem to be more vulnerable to the adverse effects of these substances, as observed for opioid analgesics, benzodiazepines, cannabis and even nitrous oxide. It is now imperative that the female sex/gender be taken into consideration in addictovigilance expertise and in drug safety in general, even for substances for which use is predominantly male. In addition, the adequate management of the women requires the development of specific prevention and care strategies.

The French Addictovigilance Network has been using data from the French Heath insurance since the late 1990s to assess prescription drug abuse. In this narrative review, we illustrate the inputs of pharmacoepidemiology in addictovigilance based on the experience of the French Addictovigilance Network. The review focuses on pharmacoepidemiology using the French National Health Data System. We propose three examples: the MEGADOSE study, which aimed to conduct the first nation-wide, systematic, repeated assessment of doctor shopping; the DANTE study, which aimed to assess trends in analgesic use, focusing on the prevalence of use and the demographic profiles of analgesic users by age and sex; and the ZORRO study, which aimed to assess the impact of secure prescription forms on the use of zolpidem and other sedatives. These examples show how pharmacoepidemiology fits in the multifaceted monitoring conducted by the French Addictovigilance Network and complements the other data sources of this framework. This approach improves signal detection, confirmation, and quantification. It also makes it possible to overcome the limitations of each data source taken individually.

Background: Attrition continues to be a major hurdle for addiction treatment. Through the prism of the attachment theory, this phenomenon can be understood as a manifestation of the patient’s insecure attachment style, needing a highly-responsive care delivery. We developed an electronic health mobile application, co-designed with patients, aimed at helping healthcare teams respond to their patients’ needs, and fostering adherence to care. This acceptability study evaluated patients everyday use of the application for eight weeks, assessing their satisfaction with the system, and its integration within professionals’ current practice in our center. Methods: This single-center, prospective study was conducted between January 2022 and December 2022. 24 adult patients with any type of addiction were included. They were granted access to the application for eight weeks, and were invited to complete the System Usability Scale questionnaire regarding their satisfaction with application’s usability at the end of the study. The application uses active self-reports, which are later discussed with the healthcare team, and foster both the working alliance and the decision-making process. Results: 17 patients out of 24 reached the primary endpoint. On average, over the eight-weeks period, patients logged in the application 38.2 times, and sent 5.9 messages to the healthcare team. Interestingly, 64.3% of the user logins were recorded outside of our center’s working hours (either from 5 p.m. to 9 a.m., or during week-ends and bank holidays), and 70.8% of the patients logged into the application at least one time between 10 p.m. and 8 a.m. 18 patients completed the System Usability Scale questionnaire, which averaged a score of 81.8 out of 100. Healthcare professionals logged in the application’s messaging system 4.5 times a day on average. Conclusions: This preliminary study shows promising results, as patients engaged well with various components of the application. It was moreover possible for healthcare workers in our center to integrate this tool in their daily activities. More work is needed to better understand the various patients’ needs regarding the application, further strengthen their adherence to the intervention, and understand professionals’ motivations to use the application. Trial registration: ClinicalTrials.gov, Identifier: NCT04659954. Registered 09 December 2020, https://clinicaltrials.gov/study/NCT04659954.

Antenatal betamethasone is recommended before preterm delivery to accelerate fetal lung maturation. However, reports of growth and neurodevelopmental dose-related side-effects suggest that the current dose (12 mg plus 12 mg, 24 h apart) might be too high. We therefore investigated whether a half dose would be non-inferior to the current full dose for preventing respiratory distress syndrome.

Vaso-occlusive episodes (VOEs) are a major concern in patients with sickle cell disease (SCD). Exposure to systemic corticosteroids has been suspected to increase the occurrence of VOEs in case reports or series. No comparative study has been conducted to investigate this risk, which is still debated. Several clinical trials demonstrated the effectiveness of corticosteroids for the treatment of VOEs, but with increased rates of readmission. The aim of the study was to assess the risk of hospitalization for VOE associated with exposure to systemic corticosteroids in patients with SCD. We used a case-case-time-control design in a nationwide population-based cohort built in the French national health insurance database between 2010 and 2018. The population included all patients with SCD with at least 1 hospitalization for VOE. Corticosteroids were identified using out-of-hospital dispensing data. The outcome was the first hospitalization for VOE. The case-case-time-control design induces self-adjustment for time-invariant confounders, including genotype. Analyses were adjusted for time-dependent confounders (infections, red blood transfusions) and stratified by exposure to hydroxyurea. Overall, 5151 patients were included in the main analysis. Corticosteroid exposure was significantly associated with the occurrence of hospitalizations for VOEs: adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.4-5.6). In patients exposed to hydroxyurea, the adjusted odds ratio was 2.6 (95% CI, 1.1-6.4); it was 4.0 (95% CI, 2.5-6.3) in unexposed patients. These results were consistent in children and adults. In conclusion, systemic corticosteroids were associated to an increased risk of hospitalization for VOEs and should be limited in patients with SCD.

In the 2000s, newer generations of drugs appeared on the market called drugs of targeted therapy (TT) drugs. The introduction of TT in oncology has profoundly changed the prognosis of many cancers but also introduced a wide variety of adverse drugs reactions (ADR), including in particular dermatological adverse drug reactions (DADRs). We investigated the evolutions of the notifications of DADRs of anticancer drugs since 2000s in international pharmacovigilance data. For this purpose, we separated non-targeted therapy and targeted therapy. During the period from 01/01/2000 to 31/12/2017, 1,226,252 ICSRs (8.7%) were related to anticancer drugs, among them concerning anticancer drugs, 192,108 cases (15.6%) contained at least one MedDRA term for “skin and subcutaneous tissue disorders” system organ classes. The DADRs of anticancer drugs are in constant increase on the period 2000 to 2017, from 0.91% to 1.90% of the total ADR of Vigibase®. The number of DADRs drugs in the non-targeted therapies class remained stable during this period, while the DADRs of targeted therapy drugs increased and exceeded those of non-targeted therapy in recent years. Using a disproportionality analysis, we found that targeted therapy drugs are associated with a higher risk of reporting DADRs of the type: dermatitis acneiform, hair color changes, acne, and hyperkeratosis and skin toxicity. While, non-targeted therapy drugs are associated with a higher risk of reporting DADRs of the type: skin hyperpigmentation, nail discoloration, dermatitis exfoliative, Hyperhidrosis and alopecia. TT drugs are used more and more for cancer indications and even beyond. This problematic of DADR will become more and more common and should benefit from specialized support with the organization of a coordinated network of professionals.

Meteoroid impacts shape planetary surfaces by forming new craters and alter atmospheric composition. During atmospheric entry and impact on the ground, meteoroids excite transient acoustic and seismic waves. However, new crater formation and the associated impact-induced mechanical waves have yet to be observed jointly beyond Earth. Here we report observations of seismic and acoustic waves from the NASA InSight lander’s seismometer that we link to four meteoroid impact events on Mars observed in spacecraft imagery. We analysed arrival times and polarization of seismic and acoustic waves to estimate impact locations, which were subsequently confirmed by orbital imaging of the associated craters. Crater dimensions and estimates of meteoroid trajectories are consistent with waveform modelling of the recorded seismograms. With identified seismic sources, the seismic waves can be used to constrain the structure of the Martian interior, corroborating previous crustal structure models, and constrain scaling relationships between the distance and amplitude of impact-generated seismic waves on Mars, supporting a link between the seismic moment of impacts and the vertical impactor momentum. Our findings demonstrate the capability of planetary seismology to identify impact-generated seismic sources and constrain both impact processes and planetary interiors.

Anticholinergic drugs (also called antimuscarinics or atropinics) increase the risk of falls, cognitive impairment and/or mortality in older patients. These drugs belong to the lists of potentially inappropriate medications in the elderly. The aim of this review was to present and discuss the different tools available to measure the atropinic risk in drug exposure of older patients. Several scales, developed from biological and/or clinical criteria, allow to classify anticholinergic drugs according to their atropinic potency and to assign to them an atropinic burden. Total atropinic burden of patient drug exposure can be calculated as the sum of atropinic score of each drug. Other tools include drug daily doses to better estimate the atropinic risk. These different methods are a precious help to decrease atropinic exposure in the elderly. Nevertheless, they have to be considered as upgradable and it is necessary to adapt them regularly according to the introduction of new drugs in clinical practice.

In case of transtibial amputation, the deficit resulting from the loss of the lower limb can be partly compensated with a prosthetic foot and adapted rehabilitation. New prosthetic feet have been developed for transtibial amputees to mimic ankle adaptability to varying terrain. Among them, Microprocessor Prosthetic Ankles (MPA) have a microprocessor to control an electric or a hydraulic actuator to adapt ankle kinematics in stairs and slopes. The objective is to investigate parameters extracted from the moment-angle curve (MAC) and use them to compare 3 MPA during level and slope locomotion against energy storing and return (ESR) foot. Five persons with lower limb transtibial amputation successively fitted with 3 MPA (Propriofoot™, Elan™, Meridium™) compared to their ESR foot. The participants had 2 weeks of adaptation before data acquisition and then a 3 week wash-out period. Range of motion, equilibrium point, hysteresis, late stance energy released, and quasi-stiffness were computed on level ground and 12% slope (upward and downward) thanks to the MAC at the ankle. The study shows the relevance of MAC parameters to evaluate the behavior of MPA. In particular, compared to ESR, all MPA tested in the present study demonstrated a better angle adaptation between walking conditions but a decrease of available energy for the propulsion. Among MPA, main results were: (i) for the Propriofoot™: an adaptation of the ankle angle without modification of the pattern of the MAC (ii) for the Elan™: a limited adaptation of the range of motion but a modification of the energy released (iii) for the Meridium™, the highest adaptation of the range of motion but the lowest available energy of propulsion. One of the main findings of the research is to show and quantify the relationship between range of motion and energy available when using different prosthetic feet in different walking conditions.

Invasive species events related to globalization are increasing, resulting in parasitic outbreaks. Understanding of host defense mechanisms is needed to predict and mitigate against the consequences of parasite invasion. Using the honey bee Apis melliferaand the mite Varroa destructor, as a host–parasite model, we provide a comprehensive study of a mechanism of parasite detection that triggers a behavioral defense associated with social immunity. Six Varroa-parasitization-specific (VPS) compounds are identified that (1) trigger Varroa-sensitive hygiene (VSH, bees’ key defense against Varroasp.), (2) enable the selective recognition of a parasitized brood and (3) induce responses that mimic intrinsic VSH activity in bee colonies. We also show that individuals engaged in VSH exhibit a unique ability to discriminate VPS compounds from healthy brood signals. These findings enhance our understanding of a critical mechanism of host defense against parasites, and have the potential to apply the integration of pest management in the beekeeping sector.

Les équipes Ressources de soins palliatifs pédiatriques (ERRSPP) suivent de près l’actualité adulte. L’évolution de la loi Claeys-Leonetti, reconnaissant l’alimentation et l’hydratation artificielles comme des traitements à part entière pouvant être arrêtés en fin de vie a ainsi déclenché de nombreuses réflexions au sein de ces structures. Mais qu’en est-il au sein des équipes de soins de pédiatrie ? Quelle place occupe cette réflexion autour de l’alimentation et l’hydratation en fin de vie alors que le nourrissage, fonction parentale primaire, occupe une place centrale dans le développement d’un enfant ? À l’aide d’une étude qualitative princeps, et d’une démarche d’analyse originale, nous tenterons de défricher ce terrain inexploré des représentations soignantes et de la place de cette thématique dans l’accompagnement des patients de pédiatrie en fin de vie.

Background: Administrative data are used in the field of Alzheimer’s Disease and Related Syndromes (ADRS), however their performance to identify ADRS is unknown. Objective: i) To develop and validate a model to identify ADRS prevalent cases in French administrative data (SNDS), ii) to identify factors associated with false negatives. Methods: Retrospective cohort of subjects ≥ 65 years, living in South-Western France, who attended a memory clinic between April and December 2013. Gold standard for ADRS diagnosis was the memory clinic specialized diagnosis. Memory clinics’ data were matched to administrative data (drug reimbursements, diagnoses during hospitalizations, registration with costly chronic conditions). Prediction models were developed for 1-year and 3-year periods of administrative data using multivariable logistic regression models. Overall model performance, discrimination, and calibration were estimated and corrected for optimism by resampling. Youden index was used to define ADRS positivity and to estimate sensitivity, specificity, positive predictive and negative probabilities. Factors associated with false negatives were identified using multivariable logistic regressions. Results: 3360 subjects were studied, 52% diagnosed with ADRS by memory clinics. Prediction model based on age, all-cause hospitalization, registration with ADRS as a chronic condition, number of anti-dementia drugs, mention of ADRS during hospitalizations had good discriminative performance (c-statistic: 0.814, sensitivity: 76.0%, specificity: 74.2% for 2013 data). 419 false negatives (24.0%) were younger, had more often ADRS types other than Alzheimer’s disease, moderate forms of ADRS, recent diagnosis, and suffered from other comorbidities than true positives. Conclusion: Administrative data presented acceptable performance for detecting ADRS. External validation studies should be encouraged.

IntroductionThe objective was to report on the experience of the French Army Health Service in the management of blast injury of the hands related to warfare explosive devices.MethodsA retrospective study was conducted in the Percy Military Hospital (role 4 medical treatment facility) among French soldiers who presented with a combat-related blast injury of the hand between 2002 and 2018. The functional result was assessed by the disabilities of the arm, shoulder and hand (DASH) and the Orthotics and Prosthetics User Survey (OPUS, upper extremity functional status) scores. Proximal amputations (PAs) and distal amputations (DAs) were distinguished for the analysis.ResultsFifteen patients with a mean age of 31±8 years were included. They totalised 20 blasted hands. There were 16 traumatic amputations: 8 in each of the PA and DA groups. Twelve patients had additional injuries, four of which were polytraumatic. Skin closure time and flap use were higher in the DA group. Only one thumb reconstruction was performed. At a mean follow-up of 6.5±4 years, the number of amputees wearing a prosthesis was higher in the PA group. The mean DASH and OPUS scores were 35.5%±24.0% and 64.0%±19.0%, respectively, with no difference between the two groups.ConclusionThe severity of hand blasts related to warfare explosive devices requires the systematic application of damage control surgery. PAs are frequent and secondary reconstruction options are limited. The functional result is poor and similar between proximal and distal amputees.

Cet article a pour objectif de synthétiser les principales informations présentées lors des 9esAteliers de la pharmacodépendance et de l’addictovigilance de 2016 par trois professionnels de santé et spécialistes des addictions autour de la question de l’usage de substances psychoactives chez les jeunes. Les résultats des enquêtes réalisées en population générale, et celles spécifiques d’addictovigilance, apportent des données relatives à la consommation et aux pratiques d’usages dans cette population des 11–25 ans. L’offre de soins, essentiellement constituée par les consultations jeunes consommateurs, doit s’adapter à cette population aux conduites hétérogènes, allant de l’expérimentation à l’usage problématique, variables dans le temps et souvent dissimulées.

It is essential that health professionals who practice medicine in prison rely on accurate knowledge about their patients to provide them with adapted care. The use of cannabis can influence the health status of prisoners, but data are lacking regarding the potentially related adverse health consequences. The objective of this descriptive study was to describe the cardiovascular outcomes related to cannabis use in prisoners from several detention centres hospitalised in a French hospital.

La forte prévalence d’utilisation du cannabis en France, en particulier chez les adolescents et jeunes adultes, ainsi que des présentations cliniques atypiques au sein de cette population font craindre la survenue d’effets indésirables graves à risque d’être sous-diagnostiqués.

Supplemental Digital Content is available in the text.Benzodiazepines are commonly used for behavioral and psychiatric symptoms of dementia, despite their numerous adverse effects and the lack of evidence regarding their efficacy in this context. We studied longitudinal benzodiazepines exposure in incident cases of Alzheimer’s disease and related syndromes (ADRS) in France. We used a cohort of incident ADRS patients identified in 2012 within the national health data system. Benzodiazepines exposure was measured 1 year before, to 5 years after ADRS identification. Quarterly benzodiazepines prevalence and incidence were computed. We identified factors associated with long half-life benzodiazepines initiation. A total of 106 508 subjects were included. Quarterly benzodiazepines prevalence was stable (around 25%) but we saw an important decrease in long half-life benzodiazepines compensated by an increase in short half-life benzodiazepines. In most benzodiazepine initiations, the first episode lasted less than 3 months. Factors associated with initiating a long half-life benzodiazepine were young age, male gender, no registration with ADRS as a long-term disease, having consulted an ADRS specialist, antipsychotic reimbursement before the index date, no admission in nursing home. Prevalence of benzodiazepines use remains high in subjects with ADRS despite guidelines for their avoidance. However, indicators regarding benzodiazepine initiations (duration, benzodiazepine type) suggest some caution in their use.

Addictovigilance is a safety monitoring targeted at substances with potential for abuse and dependence. This vigilance was involved during the period of COVID-19 epidemic due to the significant changes in access to drugs and psychological disruption caused by the pandemic and lockdown. This article aims to present the different steps implemented by the French Addictovigilance network in collaboration with the French Health authorities from March to May 2020, including monitoring of potential harmful events, and scientific communication. The first events were identified through the continuity of the networking between the French addictovigilance centres and their partners: community pharmacies, general practitioners, specialized structures and emergency wards. As soon as the lockdown began, first cases of overdoses (lethal or not) were reported with opioids, mainly with methadone, and other opioids (heroin, oxycodone, tramadol or antitussive codeine). Lockdown-related noteworthy events consisted in clinical cases or other relevant information for which lockdown clearly played an important role: among the many substances identified at least once, pregabalin, benzodiazepines, cannabis, cocaine and nitrous oxide were the most significant in terms of prevalence, seriousness or particularly specific to the lockdown context. Despite significant decrease in the activity and travel limited to vital needs, community pharmacies continued to identify falsified prescriptions in this period, highlighting an increase in suspicious requests for pregabalin, codeine and tramadol. In parallel, the French addictovigilance network continued its communications efforts in the period, issuing a newsletter on tramadol, a press release on methadone and naloxone, and participating in the COVID-19 frequently asked questions (FAQs) of the French Society of Pharmacology and Therapeutic website (https://sfpt-fr.org/covid19). COVID-19 epidemic has been an important challenge for addictovigilance, and has proved that this monitoring is highly essential for alerting health professionals and health authorities to points of vigilance in the field of psychoactive substances.

Large electronic health records database available at a national level offer great opportunity for research in rare diseases and orphan drugs. Methods and data used in pharmacoepidemiology present a great potential for epidemiology, drug utilization studies, drug safety, drug effectiveness and pharmacoeconomics. This review presents the different sources of data in Europe, with a special focus on the French situation, with the recent implementation of SNDS (système national des données de santé[French national health data wharehouse]). Some examples are given. Development of rigorous and innovative methods must be encouraged in the future.

AbstractBackground:Lymphomas are costly diseases that suffer from a lack of detailed economic information, notably in a real-world setting. Decision-makers are increasing the search for Real-World Evidence (RWE) to assess the impact, in real-life, of healthcare management and to support their public decisions. Thus, we aimed to assess the real-world net costs of the active treatment phases of adult Hodgkin Lymphoma (HL), Follicular Lymphoma (FL) and Diffuse Large B Cell Lymphoma (DLBCL).Methods:We performed a retrospective cohort study using population-based data from a national representative sample of the French population covered by the health insurance system. Cost analysis was performed from the French health insurance perspective and took into account direct and sick leave compensation costs (€2,018). Healthcare costs were studied over the active treatment phase. We used multivariate modeling to adjust cost differences between lymphoma subtypes.Results:Analyses were performed on 224 lymphoma patients and 896 controls. The mean additional monthly costs due to HL, FL and DLBCL patients were respectively €5,188, €3,242 and €7,659 for the active treatment phase. The main additional cost driver was principally inpatient stay (hospitalization costs and costly cancer-related drugs), followed by outpatient medication and productivity loss. When adjusted, DLBCL remains significantly the most costly lymphoma subtype.Conclusion:This study provides an accurate assessment of the main lymphoma subtypes related cost with high magnitude of details in a real-world setting. We underline where potential cost saving could be realized via the use of biosimilar medication, and where lymphoma management could be improved with the early management of adverse events.KEY POINTSThis is one of the first studies which assess the additional cost of lymphoma in Europe, according the main sub-types of lymphoma and with real-world database.The additional monthly cost due to HL, FL and DLBCL patients were respectively €5,188, €3,242 and €7,659 for the active treatment phase and the main additional cost driver was principally inpatient stay (i.e. hospitalization costs and additional inpatient medicines, notably rituximab), followed by outpatient medication and productivity loss.This study provides an accurate and detailed lymphoma subtype cost description and comparison which supply data for efficiency evaluations and will allow French health policy to improve lymphoma management.

Les maladies d'Alzheimer et maladies apparentées (MAMA) sont des maladies neurodégénératives progressives et inexorables. En France, les inhibiteurs de l'acétylcholinestérase et la mémantine, dits médicaments spécifiques de la MAMA, étaient remboursés pour les sujets atteints de MAMA, avant une diminution de leur taux de remboursement en 2012 et un déremboursement total en 2018 suite à la réévaluation de leur efficacité. Notre recherche avait pour objectif d’étudier les conséquences de ces modifications de remboursement sur la prise en charge initiale de la MAMA (recherche d'un éventuel effet de report de prescription médicamenteuse).

L'utilisation du baclofène pour le traitement des troubles de l'usage de l'alcool (TUA) a considérablement augmenté en France entre 2007 et 2013, initialement par prescription hors Autorisation de mise sur le marché (AMM). En avril 2014, une autorisation temporaire d'utilisation (ATU) a été accordée dans cette indication, suivie d'une AMM en octobre 2018. Suite à une étude mettant en évidence un surrisque d'effets indésirables graves avec les fortes doses de baclofène, la dose maximale a été limitée à 80 mg/jour en juillet 2017. Notre objectif était d’évaluer l'effet de l'AMM du baclofène dans l'indication TUA sur le nombre d'initiations en France entre 2014 et 2021, et d’évaluer l'effet de la limitation de la dose maximale sur les doses quotidiennes de baclofène.

The French Addictovigilance Network aims to monitor all psychoactive substances with abuse potential including prescription drugs and other legal and illegal substances such as new psychoactive substances (NPS) and its consequences in humans. Created in 1990 through a network of regional addictovigilance centres covering the entire country, these pharmacologists with expertise in addictovigilance have developed interface with different partners (physicians, toxicologists, network of community pharmacies, addictology care centers…) and implemented several original tools of pharmacosurveillance (such as DRAMES [death related to the abuse of medicines] in strong collaboration with toxicologists or such OPPIDUM [observation of illegal products and misuse of psychotropic medications]), complementary to the spontaneous reporting. A such multidimensional approach including proactive surveillance by these tools and also among several heterogenous data sources (such as data from hospitals or claims database) is able to detect early addictovigilance signals and warnings as illustrated with three following examples: cannabis use and acute serious cardiovascular disorders, new synthetic opioids (ocfentanil, carfentanil) and severe opiate overdose or deaths, the diverted use of psychoactive drugs (codeine analgesics or sedative H1 antihistamines called purple drank) by adolescents and young adults. The choice of a broad strategy and the multifaceted system implemented by the French Addictovigilance Network using elements of pharmacology (fundamental, clinical, pharmacoepidemiology) expertise is an innovative method to detect early addictovigilance signals, and to describe its characteristics in order to increase awareness of psychoactive substances by patients, users and health professionals.

To assess and compare direct costs between patients with giant cell arteritis (GCA) that is associated or not associated with polymyalgia rheumatic (PMR), and to identify the additional cost drivers due to PMR. A population‐based, retrospective cohort study using the French National Health Insurance System Database was conducted. Cost analysis was performed from the French health insurance perspective and direct medical and nonmedical costs were taken into account (based on 2014 costs [€]). Costs were analyzed according to different components and divided into 6‐month periods to assess care consumption. Longitudinal multivariate analyses, using generalized estimating equations, were used to adjust the effect of PMR on the mean cost over time. Analyses were performed on 100 incident patients with GCA, 54 of whom had PMR. The cumulative additional cost due to PMR was €8,801 for 3 years, and €10,532 for 5 years. The significant additional costs occurred especially during the second and third years of follow‐up, amounting to €1,769 between 12 and 18 months (P= 0.02), €1,924 between 18 and 24 months (P= 0.17), €1,458 between 24 and 30 months (P= 0.08), and €1,307 between 30 and 36 months (P= 0.07). The most important cost drivers were inpatient stays, paramedic procedures, and medications. Multivariate analyses showed a significant effect of PMR on mean cost during the first 3 years of follow‐up (relative risk 1.76 [95% confidence interval 1.03–2.99], P= 0.038). To our knowledge, this study is the first to accurately assess the cost of PMR care in patients with GCA and to highlight that PMR is largely responsible for the high cost of GCA.

Benzodiazepines are a source of well-known adverse reactions related to their pharmacological properties: memory disorders, falls in the elderly, confusion and sedation, drug addiction. The impact of their chronic use on cognitive decline and dementia has been the subject of many studies for two decades.

Pharmacology is often divided in separate branches, such as molecular and cellular pharmacology, pharmacokinetics, pharmacodynamics, experimental and/or preclinical pharmacology, clinical pharmacology (and therapeutics), pharmacogenetics, pharmacogenomics, pharmacovigilance, pharmacoepidemiology, pharmacoeconomics… This enumeration gives a global picture of different scientific areas, which are however dealing with the same question. Another mindset should be a global interactive and continuous approach, which could be designed as “human pharmacology”. An original and attractive way to illustrate this continuous approach is to combine pharmacodynamics and pharmacovigilance and/or pharmacoepidemiologic data. Coupling disproportionality analyses in pharmacovigilance databases or computerized health databases, with pharmacological characteristics of drugs (receptor affinity, for example) allows investigating in humans, the mechanism of adverse drug reactions. Examples of such analyses investigating the risk of movement disorders, diabetes related to psychoactive drugs, or the risk of adverse cardiac outcomes with different drugs (classical drugs or protein kinase inhibitors) are given. The increasing number of research works investigating this topic underlines the importance of this relatively new approach, which gives significant inputs for the better knowledge of drug safety.

Some concerns have emerged about the evidence of benefits on survival outcomes or quality of life of new anticancer drugs. In parallel, the decreased cancer mortality leads to an increased number of patients exposed to cancer treatment-related consequences. In this context, pharmacoepidemiology is crucial to assess anticancer drug use, effectiveness and safety in real life conditions. We aimed to describe strengths, limitations and considerations associated with the use of the French national health insurance database (système national des données de santé[SNDS]) to conduct pharmacoepidemiological studies in oncology. The SNDS represents a powerful tool in pharmacoepidemiology owing to its extensive coverage, accurate description and quantification of drug exposure and individual data on patients. The main limitations of this database ensue from the administrative nature resulting in technical difficulties in its management and gaps in availability of data. Another limitation is the lack of accurate identification of diseases, comorbidities or outcomes and potential confounding with notably the lack of data regarding cancer stage, prognosis or risk factors. Finally, the accurate identification of the nature of chemotherapy received by patients is sometimes complex. To minimize these limitations, several approaches and statistical methods could be used as highlighted by national or international initiatives. First, the SNDS may be linked with cancer registry or clinical data. Then, several data sources could be combined using meta-analytical methods. The development of methodological tools and the use of standardized methods are crucial to enhance the quality of studies that can impact clinical practice and guide public decision. Pharmacoepidemiological approaches and pharmacovigilance represent an important cornerstone in oncology for signal detection or long-term follow up of cancer patients. In this context, validated methods to identify cancer patients and to describe chemotherapy regimens within these data should be promoted and remain too scarce despite international guidelines. Moreover, limits and strength of each data sources should be systematically discussed according to the research question. Optimized and framed use of claims database represents a future challenge in onco-pharmacoepidemiology.

Clinical evaluation of drugs before approval is based on the experimental design of clinical trial with randomization of drug exposure. Unfortunately, conclusions of clinical trials are necessarily limited to patients included into the trials. It is thus necessary to compare these experimental data coming from clinical trials with the real use of drugs in clinical practice. Pharmacoepidemiology is the study of interactions between drugs and human populations, investigating, in real conditions of life, benefits, risks and use of drugs. Pharmacoepidemiology applies to drugs the methods and/or reasoning of both pharmacology and epidemiology. The development of pharmacoepidemiology should improve the “rational drug use”.

In France, the monitoring of drug abuse and dependence is based on the implementation of national surveys and the collection of spontaneous reports of health professionals. Medico-administrative information completes these data sources through the creation of pharmacoepidemiological tools to exploit them in the field of addictovigilance. This article purposes an overview of this contribution through the presentation of several studies and/or methods developed by the French addictovigilance network to assess the psychoactive drugs diversion and its consequences at the population level. These examples underline the value of these databases and confirm that they could become a systematic routine tool for addictovigilance, particularly in complementary multi-source approaches.

The opioid epidemic has emerged in the USA in the late 1990s and widespread to Canada, Australia, and the UK to a lesser extent in the more recent years. At the European level, several studies performed in different European countries have highlighted that prescription opioid use increased substantially over the last decade, and several proxies for misuse show a parallel increasing trend. The French addictovigilance experience on opioid analgesics is a good example of a specific dedicated monitoring, taking into account in a global and multisource perspective, patterns of utilization, population involved in problematic use, ways of acquisition and health complications. The added value of this data triangulation is illustrated by the recent data on tramadol and oxycodone. The addictovigilance monitoring is particularly relevant to identify early signals of potential problematic use and to assess the impact of campaigns for opioid analgesics rational use and regulatory changes.

Le nombre d’amputations traumatiques du membre inférieur (ATMI) augmente dans le monde ces dernières années. Les personnes ATMI sont souvent jeunes et actives au moment du traumatisme, leurs attentes fonctionnelles sont élevées et elles vieilliront avec leur amputation. En 2024, il est admis que les capacités fonctionnelles, la santé physique (cardiovasculaire) et mentale, et la qualité de vie des ATMI sont altérées sur le long terme. Les cliniciens impliqués dans la prise en charge des ATMI doivent mettre en œuvre les soins médicaux et de réadaptation adaptés à la situation médicale et au projet de vie du patient. Ceci implique notamment le choix de la prothèse et de ses composants qui résulte d’un processus d’évaluation multimodal non standardisé. Un suivi médical spécialisé au long cours de cette population est indispensable. Des progrès technologiques sont attendus pour améliorer la performance et le confort des prothèses, mais également des innovations des outils de réadaptation, afin d’augmenter le niveau d’activité et la qualité de vie des patients ATMI.

Analgesics are among the most widely used drugs worldwide. The French Addictovigilance Network (FAN) established the antalgiques stupéfiants et ordonnances sécurisées(ASOS [narcotic analgesics and secure prescriptions]) survey in order to assess the dissemination of tamper-resistant prescription forms for narcotic analgesic within the medical community, as well as the nature and evolution of the prescriptions. After outlining the missions of the FAN, this article will describe the population treated with narcotic analgesics in France, their therapeutic indications and how the data have evolved since 2007.