Aurélien Thomas

The illicit opioid market has undergone notable diversification, with 2-benzylbenzimidazoles (nitazenes) representing an increasingly prevalent class of non-fentanyl synthetic opioids. These compounds challenge forensic toxicology through marked µ-opioid receptor potency and rapid structural evolution, often undetected by routine immunoassay screening. We report two fatal polysubstance intoxications involving inhalation of nitazene analogues via vaping devices, identified in biological matrices. GC-MS-based identification was corroborated by untargeted LC-HRMS screening with in silico data mining and confirmed against certified reference standards. Case 1 involved a 40-year-old male found deceased after an estimated 2–3 days without contact. Fluetonitazepyne was quantified at 0.58 ng/mL in peripheral blood alongside ethanol (0.55 g/kg), supra-therapeutic citalopram (340 ng/mL), sub-therapeutic lithium, and cannabinoid metabolites, concordant with a recovered vaping vial containing the same nitazene. Death could not be established with certainty; based on toxicological findings, it was most likely acute fluetonitazepyne intoxication in the presence of central nervous system (CNS) depressants. Case 2 concerned a 22-year-old male with a witnessed cardiorespiratory arrest following inhalation from a vaping device confirmed to contain 5-methyl etodesnitazene. Despite bystander cardiopulmonary resuscitation (CPR), naloxone administration (1.6 mg), and intensive care, he died from acute anoxic encephalopathy approximately 24 h later. Ante mortem peripheral blood confirmed 5-methyl etodesnitazene at 3.3 ng/mL alongside barbital at toxic concentrations (39 mg/L). Concurrent CNS depressant exposure potentiated fatal respiratory depression, more clearly established in Case 2. These cases document the lethal potential of emerging nitazene analogues and the value of untargeted HRMS-based screening in the absence of certified reference standards.

Visceral white adipose tissue (vAT) is more susceptible than subcutaneous white adipose tissue (scAT) to obesity-associated metaflammation, but the metabolic pathways accompanying this depot-specific transition remain incompletely defined. We profiled vAT and scAT from mice fed a control diet or a 60%-kcal high-fat diet (HFD) for 1 or 8 weeks. Untargeted metabolomics was integrated with targeted endocannabinoid quantification, gene-expression and promoter-associated chromatin analyses, adipocyte and stromal vascular fraction (SVF) measurements, cross-omics correlation analysis, and cell-culture perturbations. After 1 week, HFD induced relatively few metabolic changes, although vAT showed early alterations associated with sphingomyelin metabolism. By week 8, both depots exhibited extensive but distinct metabolic remodeling. The KEGG retrograde endocannabinoid-signaling pathway was the highest-ranked enriched pathway in vAT, with 2-arachidonoylglycerol (2-AG) among the most strongly altered metabolites. Targeted analysis confirmed selective 2-AG accumulation in vAT, accompanied by coordinated changes in genes and promoter-associated chromatin marks related to endocannabinoid synthesis, degradation and receptor expression. Cellular fractionation localized excess 2-AG predominantly to vAT adipocytes, whereas Cnr2 was enriched in the SVF and induced by HFD specifically in vAT. Cross-omics integration further revealed a denser and predominantly inverse transcript–metabolite association network in vAT than in scAT. Using macrophage–adipocyte co-culture and secretome profiling, we demonstrated that cannabinoid stimulation shifts activated macrophage outputs away from pro-inflammatory cytokines ( Il1b , Ccl2 ) toward extracellular matrix (ECM) proteoglycan remodeling and intercellular signaling. Graphical Early lipid remodeling in visceral adipose tissue is followed by coordinated endocannabinoid-system stimulation during sustained high-fat-diet feeding inducing inflammation Metabolic alterations were detectable after 1 week of HFD feeding in VAT. Sustained HFD exposure preferentially remodels the visceral adipose ECS, producing extensive and predominantly coordination between ECS-related transcriptional and metabolic profiles. In presence of both macrophage and adipocytes THC dampens the pro-inflammatory effect of LPS in adipocytes

Although many organophosphate pesticides are now banned in European countries, they continue to be used in various parts of the world and can still be detected as pollutants of surface waters. Organophosphates are well characterized for their acute neurotoxic effects, while the long-term effects of sub-lethal concentrations, closer to the levels that can be found in the environment, remain poorly understood. In this study, we examined the multigenerational epigenetic effects of diazinon exposure in the freshwater keystone species Daphnia magna. Using chronic exposure to an environmentally relevant concentration (30 ng/L), combined with genome-wide DNA methylation profiling at nucleotideresolution, we found that diazinon induces distinct and context-dependent changes in DNA methylation, without significantly affecting global methylation levels. Methylation patterns varied across generations and exposure windows, with the strongest effects observed following indirect embryonic exposure. Despite such exposure-specific epigenetic signature, we identified a core set of twelve genes whose methylation levels were consistently altered in exposed parents (F0) and their direct offspring (F1). These genes are involved in key biological processes, including reproduction, regulation of gene expression and development, in line with previously reported phenotypic effects of diazinon. Together, our results show that low-dose diazinon exposure reshapes the epigenetic landscape of D. magna in a developmental stage–dependent manner and is consistent with a potential role for DNA methylation in mediating both adaptive and adverse responses to diazinon across multiple generations.

Background: Chronic kidney disease (CKD) is a global public health issue. Heavy metals and trace elements may influence kidney function. This study aimed to investigate the association between plasma concentrations of 24 heavy metals and trace elements and kidney function, including estimated glomerular filtration rate (eGFR) and CKD status in European adults. Methods: This study included adult participants from the Swiss Kidney Project on Genes in Hypertension cohort (2008–2013). Associations with eGFR and CKD were assessed using multivariable linear and logistic regression, and restricted cubic spline models for non-linear trends. Mixture effects were evaluated using least absolute shrinkage and selection operator for variable selection, followed by weighted quantile sum (WQS) regression. Multiple sensitivity analyses were conducted to assess robustness. Results: Of the 988 participants (mean age 47.0 years, 52.3% female), 72 (7.3%) had CKD. In multivariable linear models with continuous exposures, higher plasma tin, antimony and iodine were associated with lower eGFR, but none remained significant after false discovery rate (FDR) correction. In quartile analyses, lower eGFR was observed in the highest exposure quartile for zinc and thallium, with a borderline trend for iodine. Arsenic showed a significant non-linear relationship with eGFR, with a turning point at ≈11.7 μg/l and an estimated decline of 3.27 ml/min/1.73 m2 from the 25th percentile. For CKD, elevated levels of molybdenum, copper and iodine were linked to higher odds, whereas aluminum and silver were inversely associated. After FDR correction, only molybdenum remained significant. WQS regression indicated that tin, antimony, iodine, molybdenum and cadmium contributed most to lower eGFR, while iodine, arsenic, palladium, manganese and copper showed the strongest associations with CKD. Conclusions: After FDR adjustment across 24 elements, no individual element remained associated with eGFR, whereas molybdenum remained linked to CKD. Findings involving iodine were nominal and should be considered exploratory. Longitudinal and mechanistic studies are needed to validate these observations and clarify causality.

Background: Heart failure (HF) is a life‐threatening syndrome with significant morbidity and mortality. Although evidence‐based drug treatments have effectively reduced morbidity and mortality in HF with reduced ejection fraction (EF), few therapies have been demonstrated to improve outcomes in HF with preserved EF. This may be caused by the existence of several HF with preserved EF subtypes that each need different treatments. There is therefore an unmet need for a comprehensive approach to subtype patients with HF with preserved EF. This protocol details the approach employed in the HeartMagic (Heart Failure Studied With a Machine Learning, Genomics, and Imaging Combination) study to address this gap. Methods: This prospective multicenter observational cohort study will include 500 consecutive patients with HF with preserved EF at 2 Swiss university hospitals, along with 50 age‐matched patients with HF with reduced EF and 50 healthy controls. In addition to routine clinical workup, participants undergo genomic, transcriptomic, and metabolomic analyses, and the anatomy, composition, and function of the heart are quantified by comprehensive echocardiography and magnetic resonance imaging. Quantitative magnetic resonance imaging is also applied to characterize the kidney. The primary outcome is a composite of 1‐year cardiovascular mortality or rehospitalization. Machine learning–based multimodal clustering will be employed to identify distinct HF with preserved EF subtypes. Statistical analysis will include group comparisons, survival analysis, and integrative multimodal clustering combining clinical, imaging, ECG, genomic, transcriptomic, and metabolomic data to identify and validate HF with preserved EF subtypes. Conclusions: The integration of comprehensive magnetic resonance imaging with extensive genomic and metabolomic profiling in this study will result in an unprecedented panoramic view of HF with preserved EF and help distinguish functional subgroups, which may provide a basis for personalized therapies.

To assess iodine status and factors associated with iodine deficiency. Cross-sectional study conducted between 2003 and 2006 including 6,341 community dwellers, aged 35–75 years old, from a population-based sample from the city of Lausanne, Switzerland. Urinary iodine concentration (UIC) was used to assess iodine status. Iodine status was considered as adequate for UIC ≥ 100 mcg/L, mild deficiency if 50 ≤ UIC ≤ 99 mcg/L, moderate deficiency if 20 ≤ UIC ≤ 49 mcg/L, and severe deficiency if UIC < 20 mcg/L. A further categorization into adequate and deficient (UIC < 100 mcg/L) was performed. Overall, 70.5% of the participants presented with adequate iodine status, 23.0% with mild, 6.0% with moderate and 0.5% with severe iodine deficiency. After multivariable analysis, being a woman (odds ratio (95% confidence interval): 1.64 (1.45 ; 1.85)), hypertension 1.41 (1.24 ; 1.60) and increasing age (p for trend < 0.001) were associated with iodine deficiency. Conversely, increasing body mass index (p for trend < 0.001), current smoking 0.86 (0.75 ; 0.99) and thyroid hormone supplementation 0.48 (0.33 ; 0.70) were negatively associated with iodine deficiency. A positive correlation was found between UIC and urinary sodium concentration: 0.277, p < 0.001. In Lausanne, approximately one third of participants presented with iodine deficiency. Factors such as older age, being a woman or presenting with hypertension are associated with iodine deficiency, making those groups the main targets for further preventive interventions.

Background/Objectives: Due to its potent local anesthetic and vasoconstrictive properties, cocaine is sometimes used in otolaryngologic surgical interventions. However, cocaine topical administration is not always adequately documented by practitioners, which can lead to serious legal consequences, particularly in the context of drug-impaired driving (DUID) investigations. This study retrospectively analyzes five road accident cases where cocaine was detected in biological samples after medical interventions. Case descriptions: Following pedestrian–car, or car–car accidents, five distinct patients aged between 30 and 84 years underwent maxillofacial surgery due to significant injuries. Given the severity of the accident and the circumstances, the police requested blood toxicological analysis to determine whether the patients were under the influence of psychoactive substances at the moment of the accidents. Results: The five cases described in this manuscript had blood cocaine concentrations exceeding the Swiss legal limit for drivers (15 µg/L). Since no information was initially provided about the medical use of cocaine after the crash, recreational use of cocaine was suspected. However, subsequent investigations confirmed that the cases involved medical administration. Conclusions: After sinonasal procedures involving the topical application of cocaine, patients may yield positive results on urine and blood drug tests, potentially resulting in serious legal repercussions, including the withdrawal of their driving license. Therefore, practitioners should thoroughly document the medical use of topical cocaine, particularly in DUID cases. These results also raise questions about the benefit–risk ratio of such use, considering that alternatives exist.

Background: Recent evidence suggests that magnesium deficiency may play a role in the development and progression of chronic kidney disease (CKD). We assessed the association between genetic variations, serum magnesium levels, and CKD risk in the general population. Methods: In this population-based prospective study (n=4047; mean age 53 years; 54% female; mean follow-up 12.5 years). Cox regression models evaluated the effects of hypomagnesemia on CKD risk. Genetic risk scores and mediation analyses were used to assess the direct and indirect effects of single-nucleotide polymorphisms (SNPs) on CKD development through magnesium levels. One-sample and two-sample Mendelian randomization (MR) analyses were conducted to examine the causal relationship between genetically predicted serum magnesium levels and CKD risk. Results: Multivariable cox regression analyses identified that hypomagnesemia was significantly associated with an increased risk of CKD, with a hazard ratio of 1.73 (95% CI: 1.14-2.61, p=0.010). Analyses based on single SNPs and SNP scores did not reveal direct effects on CKD risk. Mediation analyses demonstrated that 4 SNPs exerted significant indirect effects on CKD risk through serum magnesium levels. However, the proportion of the total effect mediated by magnesium was low and not statistically significant. MR analyses did not provide strong evidence for a significant causal relationship between genetically predicted magnesium levels and CKD risk. Conclusions: Hypomagnesemia was significantly associated with an increased risk of long-term CKD. Genetic analysis suggests that serum magnesium levels may play an indirect role in CKD risk, but no clear causal relationship was found.