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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.

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.

International audience; Carrying out toxicological investigations in biological samples (e.g. hair) collected from extensively decomposed bodies and even more interpretation of subsequently obtained results is challenging, even more in some particular circumstances of death. In order to illustrate these pitfalls, we report the case of the exhumation of a methamphetamine body-packer. Autopsy examination of a 41-year-old man, one year after his burial, revealed the presence of 44 green pellets (7 out of 44 were torn) along all the gastrointestinal tract. A 6-cm long dark hair strand and pellets were sampled for toxicological analyses. Large toxicological screenings were applied to hair and pellets using both LC-MS/MS and LC-HRMS. Intact pellets contained around 10 g of methamphetamine (MA) with a purity ranging from 29 to 35 %. Positive hair results were amiodarone (4.12 ng/mg), desethylamiodarone (5.29 ng/mg) and methamphetamine (7.63 ng/mg). Methamphetamine pellets in gastrointestinal tract were consistent with the autopsy conclusion, i.e. fatal intoxication due to in corpore pellet rupture in a body-packer (the victim was initially deemed to have died from heart failure). In the absence of available data in the literature, amiodarone and metabolite presence in hair could putatively be the consequence of a chronic treatment. Methamphetamine hair concentration was similar to those observed in regular consumers. However, interpreting this hair result is challenging due to (i) the possibility of contamination by sweat at the time of death, and (ii) the probable contamination by putrefaction fluids. This latter hypothesis (artifactual contamination during the post-mortem period) is highly supported by high concentration of methamphetamine in decontamination bath, and even more by the absence of the major methamphetamine metabolite (amphetamine) in hair. As a conclusion, in this particular situation, the hair analysis result (presence of MA and concomitant absence of amphetamine) is in agreement with the previously-established cause of death.

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.

Despite its well-known sedative properties, chloroform is rarely used for drug-facilitated sexual assault (DFSA) as its administration cannot be achieved without the victim's knowledge: we report an unusual case of DFSA using this solvent. A 26-year-old woman declared that her partner get her to sleep using chloroform the previous night. When she waked up at 3 am, her hands were tied. She immediately suspected violence and sexual penetration. Toxicological blood screening using a liquid chromatography-electrospray coupled tandem mass spectrometry method highlighted the presence of bamifylline and theophylline, two therapeutics of asthma. A screening method for volatile substances using a headspace-gas chromatography coupled with mass spectrometry method showed (i) the presence of chloroform in blood at a concentration subsequently estimated at 580 µg/L using an external calibration, and (ii) chloroform traces on a piece of a scarf brought by the patient and suspected to have been used to put her to sleep. These results were consistent with an exposure to chloroform by inhalation and demonstrate that there is no limit in the use of chemical weapons in DFSA.

Analyzing a new database that makes it possible to disaggregate trade flows across many countries according to unit values, we show that international specialization in terms of quality within industries and product categories plays an important role in the dynamics of North–South competition. The different specialization of countries at different levels of development within products and across varieties is mirrored in the recent shifts in world market shares, which are very different across quality segments: the South is not gaining market share in high-value portions of trade pattern. In this respect Europe's specialization pattern appears to be different from that of the US and Japan, and may allow it to better resist the competitive pressure of the South. — Lionel Fontagne, Guillaume Gaulier and Soledad Zignago

A liquid chromatography-electrospray-mass spectrometry technique for the screening and determination of five non-depolarizing neuromuscular blocking agents (NDBAs), atracurium and its product of degradation/metabolite laudanosine, rocuronium, pancuronium, vecuronium, and mivacurium has been developed using ambenonium as the internal standard (I.S.). Samples were acidified upon reception by adding 20 micro L 0.5M H(2)SO(4) to 500 micro L of biofluid. Sample preparation consisted of simple blood purification and/or protein precipitation using 1 mL I.S. in acetonitrile. Chromatographic separation was carried out on an X-TERRA trade mark column along with a gradient of acetonitrile in 2mM ammonium formate (pH 3). Detection was carried out in the positive selected ion monitoring mode, targeting one quantitation ion and one confirmation ion per compound. The limit of quantitation was 2.5 micro g/L for mivacurium and laudanosine, 5 micro g/L for rocuronium and pancuronium and 10 micro g/L for atracurium and vecuronium in serum (i.e., in the range of, or less than, therapeutic levels). The technique was found to be linear between the respective LOQs and 2000 micro g/L, with correlation coefficients higher than 0.999 in all matrices. Intra- and interday precision and accuracy in serum fulfilled the international criteria. This method was employed for the investigation of a case of suicide by infusion of drugs. Laudanosine, the metabolite or degradation product of both atracurium and cisatracurium, and rocuronium were found in urine and whole blood, at supratherapeutic concentrations in the latter (rocuronium: 1.53 and 2.18 mg/L, laudanosine: 8.86 and 0.31 mg/L, respectively), and even therapeutic concentrations would have been lethal in the absence of respiratory assistance.

Postmortem drug concentrations do not necessarily reflect concentrations at the time of death, as drug levels may vary according to the sampling site and the interval between death and specimen collection. These site- and time-dependent variations are called "postmortem redistribution" (PMR). The underlying mechanisms are complex and of different types. Passive drug release from drug reservoirs such as the gastrointestinal tract, liver, lungs, and myocardium may occur immediately after death and, later on, cell autolysis and the putrefactive process participate in redistribution. There is evidence that basic lipophilic drugs with a large distribution volume are particularly susceptible to PMR. Nevertheless, this cannot explain the actual PMR of some nonbasic, nonlipophilic drugs. In addition, the persistence of drug metabolism immediately after death must be considered. Consequently, it is of great importance to analyze specimens from different sampling sites in order to detect potential PMR and avoid misinterpretation of results.

SUMMARY The motion of the Somalia plate relative to the Nubia (Africa), Arabia and Antarctica platcs is re-evaluated using a new inversion method based on a Monte Carlo technique and a least absolute value misfit criterion. A subset of the NUVEL 1 data set, with additional data along the Levant Fault and in the Red Sea is used. The results confirm that the motion of Arabia with respect to Africa is significantly different from the motion relative to Somalia. It is further shown that the data along the SW Indian Ridge are compatible with a pole of relative motion between Africa and Somalia located close to the hypothetical diffuse triple junction between the ridge and thc East African Rift. The resulting Africa-Somalia motion is then compatible with the geological structures and seismological data along the East African Rift system. Assuming a separate Somalia plate thus solves kinematic and geological problems around the Afar triple junction and along the East African Rift.

Ivabradine is a drug used for the treatment of angina and chronic heart failure in cases of intolerance or insufficiency of response to beta-blocker treatment. A 47-year-old man was admitted to the emergency department of the hospital for a voluntary intoxication with 280 mg of ivabradine: he presented drowsiness and a mild sinusal bradycardia (50 bpm) associated with a well-tolerated low blood pressure at 100/50 mmHg. No complication was noted and he was discharged from the hospital on Day 3. A method for ivabradine assay in serum was obtained using liquid chromatography coupled with a mass spectrometry detection method. After a deproteinization step using QuECHERS salts and acetonitrile, a chromatographic separation was performed using a 5-µm 50 × 2.1 mm Xterra® column (Waters, France). Detection was performed using an LTQ linear ion-trap mass spectrometer equipped with an electrospray ionization source used in a positive ionization mode (ThermoFisher Scientific, San Jose CA, USA) and a detection in full MS(2) scan. The limit of quantification of ivabradine was 10 µg/L, and the method was linear up to 1000 µg/L. The ivabradine concentration in the patient's serum was 375 µg/L. This concentration value was >30 times those measured after therapeutic doses intakes. Nevertheless, the bradycardia was no more severe than the one observed with therapeutic dosage. In conclusion, this case tends to show an absence of correlation between blood concentration and severity of the troubles in cases of overdosage.

This study evaluated the acceptance of psychological and pharmacological therapies among chronic insomniacs and noncomplaining good sleepers. After reading a brief written description of two treatment methods commonly used for persistent insomnia (i.e. cognitive-behavior therapy and pharmacotherapy), the subjects rated in a counter-balanced order several dimensions of these two treatment modalities. The results showed that the psychological intervention was rated as more acceptable and more suitable than the pharmacological one among both insomniacs and their noncomplaining significant others. Behavior therapy was also expected to be more effective on a long-term basis and to produce fewer side effects as well as more benefits on daytime functioning. The clinical implications and relevance of treatment acceptance in the management of insomnia are discussed.

colonies were apparent even at 16 h in most strains that we tested. None of the Australian carbapenem-resistant A. baumannii strains tested had an MIC low enough to suggest clinical utility for tigecycline. This is particularly disappointing because the isolates tested were those for which antibiotic choices are extremely limited and for which tigecycline would have been an attractive option. The propensity of A. baumannii to colonize the nosocomial environment and invasive medical devices, and be thereby exposed to antibiotic concentration gradients, raises concerns about whether tigecycline-resistant A. baumannii is likely to arise in vivo. This has been described in the Enterobacteriaceae and in A. baumannii, and our data further suggest that this will be the case. The phenomenon was consistent in multiple isolates of strains RB02 and PW01 (Table 1) and is unlikely to be unique to these isolates, as we have previously shown that strains WM96 and WM98 are closely related to the widespread A. baumannii EU clone II. Tigecycline is clearly a valuable addition to the formulary, but it should not be used against Gram-negative bacteria without prior susceptibility testing. Tigecycline resistance in A. baumannii appears to be stable and readily selected, pre-dates the use of the drug in this country and may be much more important than has been previously recognized. This may be especially true in strains exhibiting high-level resistance to multiple antibiotics, in which efflux systems may already be highly active.

We report the observation of false-positive results obtained with the AxSYM® FPIA Amphetamine/Methamphetamine II assay (AbbottTM), which is widely used to detect commonly abused amphetamine compounds in human urine. Two hospitalized patients treated with heptaminol chlorhydrate (1905 and 2413 mg daily oral doses, respectively) were positive for urine amphetamine (571 and 777 μg/L, respectively), based on a cutoff concentration of 500 μg/L. Heptaminol chlorhydrate, a cardiac stimulant and vasodilator, is widely used for the treatment of orthostatic hypotension. Recommended daily oral therapeutic doses for adults are usually 500-1500 mg. After oral administration, heptaminol is rapidly and completely absorbed. Metabolism includes hydroxylation, and nonconjugated forms are found in …