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Tramadol (TR) metabolism is mainly dependent on the enzymatic activity of CYP2D6, which is controlled by genetic polymorphisms. Individuals are classified as poor (PMs), intermediate (IMs), extensive (EMs) or ultrarapid metabolizers (UMs) according to their genotype or phenotype. The determination of the metabolic phenotype for CYP2D6 can be of utmost importance in forensic and clinical contexts that involve TR intake. The present study aimed to describe CYP2D6 genetic variants in cases of TR-related deaths and to assess which metabolic ratio(s) (MRs) would allow to determine CYP2D6 phenotype without having to perform genetic analyses. Forty-eight postmortem blood samples were selected from TR-related death cases previously analyzed in a forensic context in North of France between 2013 and 2019. Initial available data included blood concentrations of TR and its two main metabolites (M1 & M2) determined using an LC--MS-MS method. TR metabolism was expressed as various MRs comprising TR/M1, TR/M2 and M2/M1. After DNA extraction, sequencing was used for genetic variant detections that affect CYP2D6 activity/expression. In the present study, the allelic variants with the higher frequency were CYP2D6*1 (68%), followed by *4 (21%). The most frequent phenotype is EMs (59.6%), followed by IMs (23.4%), PMs (12.8%) and UMs (6.4%). There was no significant correlation between each calculated MR and the genotypically predicted phenotypes, except for M2/M1 which appears related to the PM phenotype. The observed distribution of CYP2D6 genetic variants in this TR-related death population was similar to that found in the general Caucasian population. The present study displayed that the blood M2/M1 ratio could be the best-correlated TR MR to the PM phenotype, and could thus be used in forensic contexts where genetic analyses are not possible or poorly informative. For the other phenotypes, especially the UM phenotype, genetic analysis appears to be the only reliable method to predict the CYP2D6 phenotype. [ABSTRACT FROM AUTHOR]

Aldicarb, a carbamate pesticide banned in France since 2008, represents a persistent risk of human poisoning. There is no up-to-date picture of aldicarb intentional poisonings associated to detailed diagnosis and clinical management of cases to evaluate the effect of its ban on intoxication risk reduction, including suicide. This retrospective epidemiological study describes cases of suicidal intoxication from the Hauts-de-France region between 2012 and 2021 and illustrates this situation through one analytically documented case. 60 cases were collected, mostly presenting a pathognomonic symptomatology. Thirty-five victims presented a muscarinic syndrome (58.3%), 14 a nicotinic syndrome (23.3%), and 37 a central nervous system impairment (61.7%). Hospitalization was necessary for 44 cases (73.3%), with 2 fatal evolutions. Diagnosis was based on the blood cholinesterase activities. Among the 25 cases with toxicology results, 45.8% presented a moderate decrease of acetylcholinesterase activity, whereas 87.5% presented a strong decrease of butyrylcholinesterase activity. Blood or urine detection of aldicarb and its metabolites may be considered in therapeutic management, although their quantification is unlikely to change the emergency medical care. Our study updates epidemiology of aldicarb poisoning at a regional level, highlighting a persisting health threatening situation with banned pesticides. More than 65% of national cases occurred in this agricultural area, aldicarb remaining available from storage of previously purchased products. Robust evidence is presented that acute poisoning is an ongoing major global public health challenge. There is a need for continued international efforts in risk reduction, knowledge, and information strategies. [ABSTRACT FROM AUTHOR]

• Chemical submission can affect victims of all ages not only youngest. • Toxicological analyzes using appropriate methods are mandatory for diagnosis. • The name "date-rape drug" is wrongly attributed to GHB (less than 4 % of our cohort) • Benzodiazepines deserve this naming due to their highest prevalence each year. Drug facilitated-crime or chemical submission (DFC/CS) is defined as the concealed or forced administration of psychoactive substances to a victim for criminal purposes. This is a national program set up in the early 2000 s in the form of a prospective multicenter survey, the results of which this manuscript presents. Over this 19-year period, 5487 cases were collected, analyzed and classified into 54 % of suspected cases, 29 % of chemical vulnerability (CV) cases and 17 % of proven DFC/CS cases. In the overall data, the most prevalent victims were female (81 %), with an average age of 27 years. Sexual assault was the most frequent aggression (77 %), followed by theft (14 %). Victims of proven DFC/CS cases were from of all ages including children and elderly. In 934 victims of DFC/CS, 100 various psychoactive substances were detected mostly represented by benzodiazepines and z-drugs (55 %), various sedatives including antihistamines (16 %) and non-therapeutic substances (16 %). Gamma-hydroxybutyric acid (GHB) was found in 4 % cases. In CV cases, alcohol (90 %) and cannabis (32 %) intake were mainly involved. In France, despite prevention messages, DFC/CS has been an epidemic for many years and has been proven by our national study. This national program has the aim to identifying the substances used but unfortunately not the goal to fight against this phenomenon. Since 2009, we observed a new modus operandi of the aggressors who pose as taxi drivers facilitating the reception of the victims leaving nightclubs. We can emphasize that GHB is not the "date rape drug" but rather the benzodiazepine class is. [ABSTRACT FROM AUTHOR]

The French trade balance deteriorated almost continuously from the late 1990s to the early 2010s. At the macroeconomic level, French export market share deteriorated while domestic sales kept pace with domestic demand. Does this assessment apply to individual firms? Using microlevel data for French industrial firms over the period 2002–12, we explore the link between domestic and export sales. We show that export and domestic sales have a tendency, albeit slight, to move in opposite directions. This may be due to factors such as deliberate strategies to target a specific market or the presence of production constraints. Addressing the resulting endogeneity issue, our analysis shows that a positive demand shock in the domestic market also leads to an increase in exports. In particular, a 10% increase in domestic demand leads to a 4% increase in exports. This complementarity between markets seems to be driven by small firms and could reflect the existence of liquidity constraints. Increased sales in one market could lessen these constraints by facilitating funding for company development in the export market. [ABSTRACT FROM AUTHOR]

In contrast to a large strand of the literature that focuses on multi-product firms, this paper examines multi-destinations firms and the effects of financial constraints on newly served and newly exited destinations. Intuitively, financial constraints have a negative impact on firm expansion in new destinations by limiting firm ability to finance entry costs. The effect on exit from existing destinations is ambiguous. Due to financial constraints, a firm may face difficulties financing the recurrent costs of maintaining her market presence. But if financial constraints also affect entry, the firm may have strong incentives to stay in a given destination since it may not be able to fund the fixed entry costs associated to the reallocation of her portfolio of destinations. We develop a simple theoretical model which includes these two effects. We use a unique longitudinal dataset on French firms that contains information on export destinations of individual firms and allows to construct various firm-level measures of financial constraints to test these predictions. The empirical results suggest that financial constraints hamper a firms's ability to cover fixed entry costs as well as recurrent costs associated with maintaining the presence in a foreign market, thereby reducing the probability of entering into a new foreign markets and increasing the probability of exiting from an existing foreign market. [ABSTRACT FROM AUTHOR]

Methoxetamine (MXE) is increasingly used and abused, as it is frequently presented as being safer than ketamine, and legal. Cases of only MXE consumption being associated with the occurrence of seizures are rarely reported. A single MXE intoxication case by inhalation is described concerning a 21-year-old man, not known to be epileptic, who was found collapsed in his bedroom, supposedly after an epileptic seizure. He was transferred to the Emergency Department of the Henri Mondor Hospital, Aurillac, France. He was conscious, but with a sinus bradycardia (48/min) and an ST-segment elevation on the electrocardiogram, and a slightly increased creatine kinase level (270 U/L) and hyponatremia (127 mmol/L). New seizure activity occurred during hospitalization, but the clinical course in the intensive care unit was favorable. Quantitation of MXE in serum and urine using gas chromatography coupled to mass spectrometry (GC–MS) was developed, as well as a liquid chromatography coupled to tandem mass spectrometry (LC–MS-MS) method for the determination of MXE in hair. Limits of detection and quantification were, respectively, 2 and 10 µg/L for the GC–MS method and both 0.5 pg/mg for the LC–MS-MS method. Concentrations of 30 and 408 µg/L were, respectively, measured in serum and urine. Concentrations of 135 and 145 pg/mg were detected in two 2.5 cm hair strands, consistent with one or several consumptions during the 2 ½ months prior to sampling. A sample of the powder consumed was available and also analyzed. This case illustrates the dangers of this drug, which justify its classification as a narcotic in France since August 2013. [ABSTRACT FROM AUTHOR]

After the exploitation of coal mines in the 19th and 20th centuries in northern France, many mining slag heaps (SH) were left without any particular management or monitoring. Currently, the influence of these SHs on the quality of surrounding wetlands is hardly known. The purpose of this work is to determine the water quality in the neighbourhood of two SHs located near the city of Douai and its influence on the distribution of aquatic invertebrates in local wetlands. Our approach involves (1) the spatial and temporal characterization of the water composition (anions, major elements, sulphide, DOC and alkalinity) and of the biological diversity (aquatic invertebrates) and (2), based on this chemical and biological screening, the establishment of relationships between water quality and biodiversity distribution through multivariate data analysis. The results clearly indicate that substantial leaching from the slag heaps occurs, given the very high concentrations of dissolved sulphates (in the range of 2 g L−1). While the pH remains weakly basic, indicating that the leaching water has been neutralized by the highly carbonated regional substratum, high levels of biodegradable organic matter and sulphate contents have been noticed. They sporadically cause significant drops in dissolved oxygen and the occurrence of dissolved sulphides that massively reduce biodiversity, qualitatively and quantitatively. In Summer, oxygen saturation is generally lower due to the higher rate of organic matter degradation, and the risk of anoxic episodes therefore increases. Finally, as wetlands are vulnerable environments, these preliminary results suggest that monitoring and management of these sites must be attempted quickly to avoid the degradation of those valuable habitats. Image 1 • Wetlands are widely enriched in sulphates, caused by slag heap leaching. • Impact of leaching on wetlands was assessed using chemical & biological approaches. • The water composition reveals a typical example of a neutralized acid mine drainage. • Combination of high S2−, low O 2 and pH may lead to a loss of biodiversity. • Variations in DOC and lixiviate composition induce spatio-temporal changes. Leaching of slag heaps introduces in the surrounding wetlands high amounts of sulphates that influences the aquatic biodiversity through redox processes. [ABSTRACT FROM AUTHOR]

The quantification of tectonic and eustatic factors in the control of the sedimentary record is one of the main questions in sedimentary basin dynamics. We propose two methods allowing: (i) 3D measurement of accommodation at basin scale and (ii) to decipher between local (10–100 km wavelength) and basin-scale accommodation. The local signal is necessarily of tectonic origin, the basin-scale signal is of both eustatic and large tectonic origin. The measurement of accommodation requires (a) high-resolution time-lines calibrated in ages (sequence stratigraphy on well-logs and biostratigraphy on cores), (b) decompacted lithologies (well-logs), and (c) palaeodepth/palaeoaltitude (sedimentology and well-logs). Application of these methods to the intracratonic Paris basin during the Lias (early Jurassic) suggests a tectonic origin for the 1–5 Myr stratigraphic cycles, with basin-scale flexure during transgressive half-cycles, and 10–100 km uplift of basement units, during regressive half-cycles. [ABSTRACT FROM AUTHOR]

Driving under the influence of drugs (DUID) is a worldwide problem with potentially major forensic and life-threatening consequences. Although it is obvious that new psychoactive substances (NPS) could lead to impaireddriving, the prevalence of NPS use in a DUID context is unknown as the applied roadside screening tests for drugs of abuse (DOA) are not adapted for NPS detection. This works aims to tested oral fluid (OF) specimens for NPS in French drivers circulating around two music festivals (Artsenik 2017 and Garorock 2017) in order to assess the prevalence of consumption and the kind of used NPS in this particular population. OF samples consisted in dried saliva spots obtained from used Drugwipe-5S® tests (after a positive or negative roadside screening test for DOA). These OF were analyzed using a liquid chromatography coupled with tandem mass spectrometry or high-resolution mass spectrometry method. NPS were detected in 17 out of the 229 OF collected specimens (7.4%). Eleven various NPS were identified (number of identification): 5F-AKB48 (2), MAM2201 (1), JWH122 (1), 4F-PVP (1), 3- or 4-MMC (2), fluoromethamphetamine (1), ketamine (3), MXE (3), methoxyketamine (1), 6-APB (2) and 25C-NBOMe (1). There is an apparent effect of the music festival proximity on the prevalence of NPS in OF from this controlled driver population compared to that of 140 controlled drivers from Northern France analyzed in the same period (7.4% versus 3%). The variety of used NPS appears to be increasing (e.g. large proportion of cyclohexanones). In addition, 5% of drivers initially roadside-tested negative for DOA were in fact driving after NPS use in this specific population. From a forensic perspective, these results confirm the reality of driving after NPS use in French drivers, notably in those driving to or from a music festival. [ABSTRACT FROM AUTHOR]

Background: Driving under the influence of drugs (DUID) is a worldwide problem with potentially major judiciary and life-threatening consequences. Up to now, only classical drugs of abuse (DOA) are tested for DUID detection. A challenging issue for drafting up-dated international drug policies is to take into account the recent and expanding new psychoactive substances (NPS) market. NPS consist in various narcotic or psychotropic drugs, most of them having a "legal" status, that replicate chemical structures and/or pharmacological effects of classical DOA. Although it is obvious that NPS can lead to impaired driving, the prevalence of NPS use in a DUID context is unknown since the applied roadside screening tests are not yet adapted for these compounds.Methods: Between January and December 2016, a total of 391 oral fluid specimens were obtained from used roadside immunochemical test devices for DOA (Drugwipe-5S® device). These specimens were analyzed using liquid chromatography coupled with tandem mass spectrometry and high resolution mass spectrometry.Results: NPS (mainly cathinone derivatives) were detected in 33 out of the 391 oral fluid samples. This NPS positivity rate of 8.4% in oral fluid of drivers who were submitted to a roadside drug testing in 2016 in France and in Belgium is comparable to the available blood data (NPS positivity rate of 7%) observed in 2015 in similar populations.Conclusion: Our results demonstrate the reality of driving after NPS use in French and Belgian drivers who were submitted to a roadside DOA test. As there is a lack of on-site detection methods to screen for NPS, the detection of NPS in a rapid and cost-effective DUID detection strategy is currently impossible. The expanding use of NPS, notably by drivers as reported here, and the inability of currently used drug detection tests, should be urgently addressed by road safety and law enforcement authorities. [ABSTRACT FROM AUTHOR]

Abstract: Leprosy is generally revealed by cutaneous lesions often associated to nerve impairment. Rarely, it may be revealed by polyarthritis. The diagnosis, often delayed in the cutaneous-nevritic form because of the low prevalence of the disease in metropolitan France, is very difficult in case of rheumatic presentation. We report the case of a 28 year-old woman from Mali, who was diagnosed with lepromatous borderline leprosy with reversal reaction occurring in the postpartum as she presented with polyarthritis and skin lesions. [Copyright &y& Elsevier]

Abstract: A collaborative study was conducted in France in order to determine the prevalence of cannabinoids, opiates, cocaine metabolites and amphetamines in blood samples from drivers killed in road accidents in 2003 and 2004 and to compare these values with those of a previous study performed during the period 2000–2001 involving 900 drivers. Blood samples were provided from 2003 under 30-year-old drivers, killed in a traffic accident. Drugs of abuse were determined by gas chromatography–mass spectrometry using the same analytical procedures in all the 12 laboratories. The most frequently observed compounds were by far cannabinoids, that tested positive in 39.6% of the total number of samples. Δ9 tetrahydrocannabinol (THC), the most active of the principle constituents in marijuana (cannabis sativa), was detected in the blood of 28.9% drivers and was the single drug of abuse in 80.2% of the positive cases. It was associated with amphetamines in 7.4% and with opiates and cocaine in 1.9 and 4.8%, respectively. Amphetamines were present in 3.1% of the total number of samples, cocaine metabolites in 3.0% and opiates in 3.5%. When comparing these results with those of a previous study performed 3 years before, a significant increase is observed for THC (28.9% versus 16.9%), cocaine metabolites (3.0% versus 0.2%) and amphetamines (3.1% versus 1.4%). This study demonstrates the critical necessity of implementing in France as soon as possible systematical roadside testing for drugs of abuse. [Copyright &y& Elsevier]

A collaborative case-control study was conducted in France in order to determine the prevalence of alcohol, cannabinoids, opiates, cocaine metabolites, amphetamines and therapeutic psychoactive drugs in blood samples from drivers injured in road accidents and to compare these values with those of a control population. Recruitment was performed in emergency departments of six university or general hospitals and comprised 900 drivers involved in a non-fatal accident and 900 patients (controls) who attended the same emergency units for a non-traumatic reason. Drivers and controls were matched by sex and age. Alcohol was determined by flame ionization–gas chromatography, drugs of abuse (DOA) by gas chromatography–mass spectrometry with the same analytical procedures in the six laboratories, and medicines by high performance liquid chromatography with diode array detection.Blood alcohol concentration exceeding 0.5 g/l (i.e. the legal French threshold) was found in 26% of drivers and 9% of controls. In the 18–27 years age range, alcohol was the only toxic found in blood samples of 17% drivers and 5% controls, leading to an odds-ratio (OR) of 3.8. A significant relationship was found between alcohol blood concentrations and OR values. All age groups confounded, the main active substance of cannabis, Δ9 tetrahydrocannabinol (THC), was found in 10% of drivers and 5% of controls. In the less than 27 years old, THC (>1 ng/ml) was detected alone in the blood of 15.3% drivers and of 6.7% controls, giving OR=2.5, whereas there was no link between THC blood concentrations and OR value. THC was found alone in 60% of cases and associated with alcohol in 32%, with OR=4.6 between drivers and controls for this association. The difference in morphine prevalence between drivers (2.7%) and controls (0.03%) was highly significant (P<0.001), with OR=8.2. The number of positive cases for amphetamines and cocaine metabolites was too low for reaching any interpretation. The most frequently observed psychoactive therapeutic drugs were by far benzodiazepines, that were found alone in 9.4% of drivers and 5.8% of controls, which led to OR=1.7 (P<0.01).This study demonstrates a higher prevalence of opiates, alcohol, cannabinoids and the combination of these last two compounds in blood samples from drivers involved in road accidents than in those from controls, which suggests a causal role for these compounds in road crashes. [Copyright &y& Elsevier]

During the Keuper, the Paris Basin was an intracratonic sedimentary basin filled by continental deposits. Using paleo-environmental, isopach and paleo-altitude maps, we estimate the variations of accommodation rate at the scale of stratigraphic minor hemi-cycle (1–3 Ma). An analysis of the short- and long-wavelength accommodation variations allows us to assess the relative influence of tectonics, eustasy and sediment supply on the stratigraphic record. Our data suggest a pattern of subsidence along three trends: E–W in the Carnian, E–W to NNE–SSW in the Norian and NE–SW in the Norian–Rhaetian. During the Keuper, the Paris Basin accurately records the different phases of the opening of the Tethys Ocean associated with a rotation of the extension direction. The Norian cycle could thus reflect the intraplate stresses in a transitional period between the Triassic and the Liassic. [Copyright &y& Elsevier]

Drug-facilitated crime (DFC) is defined as the concealed or forced administration of psychoactive substances (PAS) to victim for criminal purposes (sexual assault, robbery…). In this situation, the victim is under influence of PAS consumed unwittingly while, in cases of chemical vulnerability, PAS (mainly alcohol) are voluntarily consumed by victims, putting them in a more vulnerable and therefore dangerous position. Objectives to remind about the harmful effects of voluntarily alcohol and other PAS intake in chemical vulnerability studies. Method we report the results of French surveys on DFC carried out between 2003 and 2013. Data were collected mainly from forensic toxicological laboratories and forensic emergency units. Results we analyzed 646 cases files for victims of DFC. Users of non therapeutic PAS were more predominant (448 / 69%) and younger (mean age 23.7 years) than users of all kinds of PAS (198 / 31%, mean age 25.7 years). As most victims were female (88%), sexual assault was the predominant offence in 88% of cases, followed by robbery (10%). Alcohol and cannabis intake were noted in respectively 93.5% and 33% of the first group and 70% and 27% of the second one. Victims presented anterograde amnesia (60%) and vigilance disorders (17%), effects usually sought by assailants. Conclusion victims are often surprised to find that alcohol consumption, with or without cannabis, can have forensic consequences with serious traumatic stress. According to our study, it is important to increase awareness among the general public and to make this problem known to professionals concerned by DFC. [ABSTRACT FROM AUTHOR]