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We present our results on the synthesis and preliminary in silico and in vitro studies of the toxicology and antioxidant properties of selenylated analogs of Tacrine. Initially, we synthesized 2-aminobenzonitriles containing an organic selenium moiety, resulting in sixteen compounds with various substituents linked to the portion derived from diorganyl diselenide. These compounds were then used as substrates in reactions with cyclic ketones, in the presence of 1.4 equivalents of trifluoroboroetherate as a Lewis acid, to synthesize selenylated analogs of Tacrine with yields ranging from 20 % to 87 %. In silico studies explored computational parameters related to antioxidant activity and hepatotoxicity. In vitro studies elucidated the antioxidant effects of Tacrine and its selenium hybrid (TSe) in neutralizing ABTS radicals, scavenging DPPH radicals, and reducing iron ions. Additionally, the acute oral toxicity of one synthesized compound was evaluated.

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The risk of the use of toxic chemicals for unlawful acts has been a matter of concern for different governments and multilateral agencies. The Organisation for the Prohibition of Chemical Weapons (OPCW), which oversees the implementation of the Chemical Weapons Convention (CWC), considering recent events employing chemical warfare agents as means of assassination, has recently included in the CWC "Annex on Chemicals" some organophosphorus compounds that are regarded as acting in a similar fashion to the classical G- and V-series of nerve agents, inhibiting the pivotal enzyme acetylcholinesterase. Therefore, knowledge of the activity of the pyridinium oximes, the sole class of clinically available acetylcholinesterase reactivators to date, is plainly justified. In this paper, continuing our research efforts in medicinal chemistry on this class of toxic chemicals, we synthesized an A-230 nerve agent surrogate and applied a modified Ellman's assay to evaluate its ability to inhibit our enzymatic model, acetylcholinesterase from Electrophorus eel, and if the clinically available antidotes are able to rescue the enzyme activity for the purpose of relating the findings to the previously disclosed in silico data for the authentic nerve agent and other studies with similar A-series surrogates. Our experimental data indicates that pralidoxime is the most efficient compound for reactivating acetylcholinesterase inhibited by A-230 surrogate, which is the opposite of the in silico data previously disclosed.

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BACKGROUND: The Covid-19 pandemic has affected patients with end-stage kidney disease (ESKD). Whether dialysis parameters have a prognostic value in ESKD patients with Covid-19 remains unclear. MATERIALS AND METHODS: We retrospectively evaluated clinical characteristics, blood pressure (BP) and dialysis parameters in ESKD patients undergoing maintenance outpatient hemodialysis, with (Covid-ESKD) and without (No-Covid-ESKD) Covid-19, at four Brazilian hemodialysis facilities. The Covid-ESKD (n = 107; 54% females; 60.8 ± 17.7 years) and No-Covid-ESKD (n = 107; 62% females; 58.4 ± 14.6 years) groups were matched by calendar time. The average BP and dialysis parameters were calculated during the pre-infection, acute infection, and post-infection periods. The main outcomes were Covid-19 hospitalization and all-cause mortality. RESULTS: Covid-ESKD patients had greater intradialytic and postdialysis systolic BP and lower predialysis weight, postdialysis weight, ultrafiltration rate, and interdialytic weight gain during acute-illness compared to 1-week-before-illness, while these changes were not observed in No-Covid-ESKD patients. After 286 days of follow-up (range, 276-591), there were 18 Covid-19-related hospitalizations and 28 deaths among Covid-ESKD patients. Multivariable logistic regression analysis showed that increases in predialysis systolic BP from 1-week-before-illness to acute-illness (OR, 95%CI = 1.06, 1.02-1.10; p = .004) and Covid-19 vaccination (OR, 95%CI = 0.16, 0.04-0.69; p = .014) were associated with hospitalization in Covid-ESKD patients. Multivariable Cox-regression analysis showed that Covid-19-related hospitalization (HR, 95%CI = 5.17, 2.07-12.96; p < .001) and age (HR, 95%CI = 1.05, 1.01-1.08; p = .008) were independent predictors of all-cause mortality in Covid-ESKD patients. CONCLUSION: Acute Covid-19 illness is associated with variations in dialysis parameters of volume status in patients with ESKD. Furthermore, increases in predialysis BP during acute Covid-19 illness are associated with an adverse prognosis in Covid-ESKD patients.

Dialysis parameters were influenced by SARS-CoV-2 infection and may have prognostic value in patients with Covid-19.Increases in blood pressure during acute Covid-19 illness and the lack of vaccination for Covid-19 were predictors of hospitalization for Covid-19.Hospitalization for Covid-19 and age were independent risk factors for all-cause death.

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With the global concerns on antibiotic resistance (AR) as a public health issue, it is pivotal to have data exchange platforms for studies on antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs) in the environment. For this purpose, the NORMAN Association is hosting the NORMAN ARB&ARG database, which was developed within the European project ANSWER. The present article provides an overview on the database functionalities, the extraction and the contribution of data to the database. In this study, AR data from three studies from China and Nepal were extracted and imported into the NORMAN ARB&ARG in addition to the existing AR data from 11 studies (mainly European studies) on the database. This feasibility study demonstrates how the scientific community can share their data on AR to generate an international evidence base to inform AR mitigation strategies. The open and FAIR data are of high potential relevance for regulatory applications, including the development of emission limit values / environmental quality standards in relation to AR. The growth in sharing of data and analytical methods will foster collaboration on risk management of AR worldwide, and facilitate the harmonization in the effort for identification and surveillance of critical hotspots of AR. The NORMAN ARB&ARG database is publicly available at: https://www.norman-network.com/nds/bacteria/.

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Microvasculature failure is expected in sepsis and at higher amine concentrations. Therefore, special attention focused individually on microcirculation is needed. Here, we present that methylene blue can prevent leukocytes from adhering to the endothelium in a rat model of lipopolysaccharide-induced endotoxemia. As hypothesis evidence, an intravital microscopy image is presented.

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The recent advisory issued by the United States Food and Drug Administration, cautioning against the routine administration of probiotics in preterm neonates, has sparked a lively debate within the scientific community. This commentary presents a perspective from members of the Special Interest Group on Gut Microbiota and Modifications within the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and other authors who contributed to the ESPGHAN position paper on probiotics for preterm infants, as well as representatives from the European Foundation for the Care of Newborn Infants. We advocate for a more nuanced and supportive approach to the use of certain probiotics in this vulnerable population, balancing the demonstrated benefits and risks.

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Genetic testing for germline RET pathogenic variants, which cause the Multiple Endocrine Neoplasia Type 2 (MEN2) syndrome, has become crucial in managing patients with medullary thyroid carcinoma (MTC). Classically, RET heterozygous missense pathogenic variants are transmitted in a Mendelian autosomal dominant pattern, of which germline/gonadal mosaicism has never been reported. We report the novel occurrence of a MEN2A patient's family in which the siblings inherited three different RET 634 genotypes: wild type (p.Cys634), p.Cys634Gly or p.Cys634Arg heterozygous pathogenic variants. We hypothesized that germline/gonadal mosaicism, derived from an inherited + early somatic mutation in the mother or a double de novo mutation during maternal embryogenesis, led to this rare event in the RET gene. Exome analysis of the proband's deceased mother's paraffin-embedded thyroid tissue confirmed the three nucleotides in the same 634 codon position. For the first time, we describe germline/gonadal mosaicism in RET, generating a second pathogenic amino acid change in the same codon causing MEN2A. Our finding shows that RET parental mosaicism, confirmed by somatic exome sequencing, might explain discrepant genotype cases in siblings with inherited cancers.

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BACKGROUND: The proportion of Canadian youth seeking mental health support from an emergency department (ED) has risen in recent years. As EDs typically address urgent mental health crises, revisiting an ED may represent unmet mental health needs. Accurate ED revisit prediction could aid early intervention and ensure efficient healthcare resource allocation. We examine the potential increased accuracy and performance of graph neural network (GNN) machine learning models compared to recurrent neural network (RNN), and baseline conventional machine learning and regression models for predicting ED revisit in electronic health record (EHR) data. METHODS: This study used EHR data for children and youth aged 4-17 seeking services at McMaster Children's Hospital's Child and Youth Mental Health Program outpatient service to develop and evaluate GNN and RNN models to predict whether a child/youth with an ED visit had an ED revisit within 30 days. GNN and RNN models were developed and compared against conventional baseline models. Model performance for GNN, RNN, XGBoost, decision tree and logistic regression models was evaluated using F1 scores. RESULTS: The GNN model outperformed the RNN model by an F1-score increase of 0.0511 and the best performing conventional machine learning model by an F1-score increase of 0.0470. Precision, recall, receiver operating characteristic (ROC) curves, and positive and negative predictive values showed that the GNN model performed the best, and the RNN model performed similarly to the XGBoost model. Performance increases were most noticeable for recall and negative predictive value than for precision and positive predictive value. CONCLUSIONS: This study demonstrates the improved accuracy and potential utility of GNN models in predicting ED revisits among children and youth, although model performance may not be sufficient for clinical implementation. Given the improvements in recall and negative predictive value, GNN models should be further explored to develop algorithms that can inform clinical decision-making in ways that facilitate targeted interventions, optimize resource allocation, and improve outcomes for children and youth.

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An organocatalytic [3+2] cycloaddition reaction between thiazolidine-containing ß-ketoester 1 and aryl azides 2 was employed to synthesize new 1,2,3-triazolyl-thiazolidine hybrids 3. In this metal-free approach, twelve compounds were isolated in yields ranging from 23 % to 96 % by using diethylamine (10 mol%) and DMSO at 75 °C for 24 hours. DNA-binding assays were conducted through absorption, emission spectroscopy and viscosimetry analysis, to evaluate the interaction capacity of the studied derivatives with nucleic acids. All the synthesized compounds were evaluated for their interactions with a specific group of compounds containing the pharmacophoric groups triazole and thiazolidine through a molecular docking speculative study, aimed at identifying the interaction profile of these compounds with DNA. The obtained results suggest that 1,2,3-triazolyl-thiazolidine hybrids could be a promising approach in the development of novel therapeutic agents targeting DNA-related processes.

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Bloodstream infection (BSI) caused by carbapenem-resistant Klebsiella pneumoniae (KP) poses significant challenges, particularly when the infecting isolate carries multiple antimicrobial resistance (AMR) genes/determinants. This study, employing short- and long-read whole-genome sequencing, characterizes six New Delhi metallo-ß-lactamase (NDM) 1 and KP carbapenemase (KPC) 3 co-producing KP isolates, the largest cohort investigated in Europe to date. Five [sequence type (ST) 512] and one (ST11) isolates were recovered from patients who developed BSI from February to August 2022 or February 2023 at two different hospitals in Rome, Italy. Phylogenetic analysis revealed two distinct clusters among ST512 isolates and a separate cluster for the ST11 isolate. Beyond blaNDM-1 and blaKPC-3, various AMR genes, indicative of a multidrug resistance phenotype, including colistin resistance, were found. Each cluster-representative ST512 isolate harbored a blaNDM-1 plasmid (IncC) and a blaKPC-3 plasmid [IncFIB(pQil)/IncFII(K)], while the ST11 isolate harbored a blaNDM-1 plasmid [IncFII(pKPX1)] and a blaKPC-3 plasmid [IncFIB(K)/IncFII(K)]. The blaNDM-1 plasmids carried genes conferring resistance to clinically relevant antimicrobial agents, and the aminoglycoside resistance gene aac(6')-Ib was found on different plasmids. Colistin resistance-associated mgrB/pmrB gene mutations were present in all isolates, and the yersiniabactin-encoding ybt gene was unique to the ST11 isolate. In conclusion, our findings provide insights into the genomic context of blaNDM-1/blaKPC-3 carbapenemase-producing KP isolates.IMPORTANCEThis study underscores the critical role of genomic surveillance as a proactive measure to restrict the spread of carbapenemase-producing KP isolates, especially when key antimicrobial resistance genes, such as blaNDM-1/blaKPC-3, are plasmid borne. In-depth characterization of these isolates may help identify plasmid similarities contributing to their intra-hospital/inter-hospital adaptation and transmission. Despite the lack of data on patient movements, it is possible that carbapenem-resistant isolates were selected to co-produce KP carbapenemase and New Delhi metallo-ß-lactamase via plasmid acquisition. Studies employing long-read whole-genome sequencing should be encouraged to address the emergence of KP clones with converging phenotypes of virulence and resistance to last-resort antimicrobial agents.

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ABSTRACT Microvasculature failure is expected in sepsis and at higher amine concentrations. Therefore, special attention focused individually on microcirculation is needed. Here, we present that methylene blue can prevent leukocytes from adhering to the endothelium in a rat model of lipopolysaccharide-induced endotoxemia. As hypothesis evidence, an intravital microscopy image is presented.

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Resumen Introducción: La disección carotídea consiste en el desgarro de la pared del vaso. Es una patología infrecuente, pero es la causa más común de enfermedad vascular cerebral (EVC) isquémica en personas menores de 45 años. Las manifestaciones clínicas son muy variables. Método: Utilizamos las recomendaciones CARE para el reporte de casos clínicos. Caso clínico: Hombre de 45 años previamente sano, con debilidad aguda de la extremidad torácica derecha sin causa aparente. La tomografía simple de cráneo no evidenció alteraciones. La resonancia magnética mostró una oclusión completa de la arteria carótida interna en todos sus segmentos y disminución del flujo de la arteria cerebral media izquierda. La evolución clínica fue desfavorable. Conclusión: La disección carotídea debe sospecharse en personas con EVC sin factores de riesgo cardiovascular.

Abstract Introduction: Carotid dissection consists of a tear in the vessel wall. It is a rare pathology, but it is the most common cause of ischemic cerebral vascular disease (CVD) in people under 45 years of age. The clinical manifestations are very variable. Method: We used CARE recommendations for reporting clinical cases. Clinical case: Previously, a healthy 45-year-old man with acute weakness of the right thoracic extremity without apparent cause. The simple skull tomography did not show any alterations. MRI showed complete occlusion of the internal carotid artery in all its segments and decreased flow of the left middle cerebral artery. The clinical evolution was unfavorable. Conclusion: Carotid dissection should be suspected in people with CVD without cardiovascular risk factors.

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Schistosomiasis, a parasitic disease affecting nearly 250 million individuals globally, poses a significant health challenge. With praziquantel being the sole available treatment and its limited efficacy in early stage infections, the identification of novel bioactive compounds becomes imperative. This study examines the potential of dehydrodieugenol B (1) and its methyl ether (2), derived from the leaves of the Brazilian Nectandra leucantha plant (Lauraceae), in combatting Schistosoma mansoni infections through a preclinical approach. Initially, compound 1 displayed noteworthy in vitro antiparasitic activity with an EC50 of 31.9 µM, showcasing low toxicity in mammalian cells and an in vivo animal model (Caenorhabditis elegans). Conversely, compound 2 exhibited no activity. In silico predictions pointed to favorable oral bioavailability and the absence of PAINS similarities. Subsequently, a single oral dose of 400 mg/kg of compound 1 or praziquantel was administered to mice infected with adult (patent infection) or immature parasites (prepatent infection). Remarkably, in prepatent infections, 1 resulted in a significant reduction (approximately 50%) in both worm and egg burden, while praziquantel reduced worm and egg numbers by 30%. The superior efficacy of dehydrodieugenol B (1) compared to praziquantel in premature infections holds the potential to advance the development of new molecular prototypes for schistosomiasis treatment.

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Insulin (INS) resistance is often found in cancer-bearing, but its correlation with cachexia development is not completely established. This study investigated the temporal sequence of the development of INS resistance and cachexia to establish the relationship between these factors in Walker-256 tumor-bearing rats (TB rats). INS hepatic sensitivity and INS resistance-inducing factors, such as free fatty acids (FFA) and tumor necrosis factor-α (TNF-α), were also evaluated. Studies were carried out on Days 2, 5, 8, and/or 12 after inoculation of tumor cells in rats. The peripheral INS sensitivity was assessed by the INS tolerance test and the INS hepatic sensitivity in in situ liver perfusion. TB rats with 5, 8, and 12 days of tumor, but not 2 days, showed decreased peripheral INS sensitivity (INS resistance), retroperitoneal fat, and body weight, compared to healthy rats, which were more pronounced on Day 12. Gastrocnemius muscle wasting was observed only on Day 12 of tumor. The peripheral INS resistance was significantly correlated (r = -.81) with weight loss. Liver INS sensitivity of TB rats with 2 and 5 days of tumor was unchanged, compared to healthy rats. TB rats with 12 days of tumor showed increased plasma FFA and increased TNF-α in retroperitoneal fat and liver, but not in the gastrocnemius, compared to healthy rats. In conclusion, peripheral INS resistance is early, starts along with fat and weight loss and before muscle wasting, progressive, and correlated with cachexia, suggesting that it may play an important role in the pathogenesis of the cachectic process in TB rats. Therefore, early correction of INS resistance may be a therapeutic approach to prevent and treat cancer cachexia.

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Background: Schizophrenia (SCZ) is marked by working memory (WM) deficits, which predict poor functional outcome. While most functional magnetic resonance imaging studies of WM in SCZ have focused on the dorsolateral prefrontal cortex (PFC), some recent work suggests that the medial PFC (mPFC) may play a role. We investigated whether task-evoked mPFC deactivation is associated with WM performance and whether it mediates deficits in SCZ. In addition, we investigated associations between mPFC deactivation and cortical dopamine release. Methods: Patients with SCZ (n = 41) and healthy control participants (HCs) (n = 40) performed a visual object n-back task during functional magnetic resonance imaging. Dopamine release capacity in mPFC was quantified with [11C]FLB457 in a subset of participants (9 SCZ, 14 HCs) using an amphetamine challenge. Correlations between task-evoked deactivation and performance were assessed in mPFC and dorsolateral PFC masks and were further examined for relationships with diagnosis and dopamine release. Results: mPFC deactivation was associated with WM task performance, but dorsolateral PFC activation was not. Deactivation in the mPFC was reduced in patients with SCZ relative to HCs and mediated the relationship between diagnosis and WM performance. In addition, mPFC deactivation was significantly and inversely associated with dopamine release capacity across groups and in HCs alone, but not in patients. Conclusions: Reduced WM task-evoked mPFC deactivation is a mediator of, and potential substrate for, WM impairment in SCZ, although our study design does not rule out the possibility that these findings could relate to cognition in general rather than WM specifically. We further present preliminary evidence of an inverse association between deactivation during WM tasks and dopamine release capacity in the mPFC.

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In utero, the developing brain is highly susceptible to the environment. For example, adverse maternal experiences during the prenatal period are associated with outcomes such as altered neurodevelopment and emotion dysregulation. Yet, the underlying biological mechanisms remain unclear. Here, we investigate whether the function of a network of genes co-expressed with the serotonin transporter in the amygdala moderates the impact of prenatal maternal adversity on the structure of the orbitofrontal cortex (OFC) in middle childhood and/or the degree of temperamental inhibition exhibited in toddlerhood. T1-weighted structural MRI scans were acquired from children aged 6-12 years. A cumulative maternal adversity score was used to conceptualize prenatal adversity and a co-expression based polygenic risk score (ePRS) was generated. Behavioural inhibition at 18 months was assessed using the Early Childhood Behaviour Questionnaire (ECBQ). Our results indicate that in the presence of a low functioning serotonin transporter gene network in the amygdala, higher levels of prenatal adversity are associated with greater right OFC thickness at 6-12 years old. The interaction also predicts temperamental inhibition at 18 months. Ultimately, we identified important biological processes and structural modifications that may underlie the link between early adversity and future deviations in cognitive, behavioural, and emotional development.

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BACKGROUND: Peripheral nerve injury caused by leprosy can lead to foot drop, resulting in an altered gait pattern that has not been previously described using 3D gait analysis. METHODS: Gait kinematics and dynamics were analyzed in 12 patients with unilateral foot drop caused by leprosy and in 15 healthy controls. Biomechanical data from patients' affected and unaffected limbs were compared with controls using inferential statistics and a standard distance, based on principal components analysis (PCA). FINDINGS: Patients walked slower than controls (0.8 ± 0.2 vs. 1.1 ± 0.2 m/s, p = 0.003), with a reduced stance and increased swing percentage. The affected limb increased (p < 0.05) plantar flexion at the initial contact (-16.8o ± 8.3), terminal stance (-29.1o ± 11.5), and swing (-12.4o ± 6.2) in the affected limb compared to unaffected (-6.6o ± 10.3; -14.6o ± 11.6; 2.4o ± 7.6) and controls (-5.4o ± 2.5; -18.8o ± 5.8; -1.4o ± 3.9). Increased pelvic tilt and knee adduction/abduction range, with lower hip adduction, were observed. The second peak of ground reaction force (98.6 ± 5.2 %BW), ankle torque (0.99 ± 0.33 Nm/kg), and net ankle work in stance (-0.03 ± 5.4 J/Kg) decreased in the affected limb compared to controls (104.1 ± 5.5 %BW; 1.24 ± 0.4 Nm/kg; -4.58 ± 5.19 J/kg; p < 0.05). There were decreasing multivariate standard distances in the affected limb compared with the unaffected and controls. PCA loading factors highlighted the major differences between groups. INTERPRETATION: Leprosy patients with foot drop presented altered gait patterns in affected and unaffected limbs. There were remarkable differences in ankle kinematics and dynamics. Rehabilitation devices, such as ankle foot orthosis or tendon transfer surgeries to increase ankle dorsiflexion, could benefit these patients and reduce deviations from normal gait.

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