Search

Abstract Background and Objectives Esmethadone (dextromethadone; d-methadone; S-methadone (+)-methadone; REL-1017) is a low potency N-methyl-D-aspartate (NMDA) receptor channel blocker that showed a rapid and sustained adjunctive antidepressant effects in patients with major depressive disorder with inadequate response to ongoing serotonergic antidepressant treatment. Previous studies indicated that esmethadone is partially excreted by the kidney (53.9% of the dose) and by the liver (39.1% of the dose). Methods Here we studied the pharmacokinetics and safety of esmethadone after a single oral dose of 25 mg in subjects with different stages of kidney and liver impairment. Results In subjects with a mild and moderate decrease in glomerular fraction rate (GFR), esmethadone C max and AUC0–inf values did not differ compared with healthy subjects. In patients with severe renal impairment, the ratios of C max and AUC0–inf values compared with healthy subjects were above 100% (138.22–176.85%) and, while modest, these increases reached statistical significance. In subjects with end stage renal disease (ESRD) undergoing intermittent hemodialysis (IHD), C max and AUC0–inf values were not statistically different compared with healthy subjects. IHD did not modified plasma total esmethadone concentrations in blood exiting versus entering the dialyzer. Dose adjustment is not warranted in subjects with mild-to-moderate impaired renal function. Dose reduction may be considered for select patients with severe renal disfunction. In subjects with mild-or-moderate hepatic impairment, C max and AUC0–inf were approximately 20–30% lower compared with healthy controls. The drug free fraction increased with the severity of hepatic impairment, from 5.4% in healthy controls to 8.3% in subjects with moderate hepatic impairment. Conclusion Mild and moderate hepatic impairment has a minimal to modest impact on exposure to total or unbound esmethadone and dose adjustments are not warranted in subjects with mild and moderate hepatic impairment. Administration of esmethadone was well tolerated in healthy adult subjects, in subjects with mild or moderate hepatic impairment, and in subjects with mild moderate or severe renal impairment, including patients with ESRF undergoing dialysis.

Malignant pleural mesothelioma (MPM) represents a significant clinical challenge due to limited therapeutic options and poor prognosis. Beyond mere survivorship, setting up an effective framework to improve functioning and quality of life is an urgent need in the comprehensive management of MPM patients. Therefore, this study aims to review the current understanding of MPM sequelae and the effectiveness of rehabilitative interventions in the holistic approach to MPM. A narrative review was conducted to summarize MPM sequelae and their impact on functioning, disability, and quality of life, focusing on rehabilitation interventions in MPM management and highlighting gaps in knowledge and areas for further investigation. Our findings showed that MPM patients experience debilitating symptoms, including fatigue, dyspnea, pain, and reduced exercise tolerance, decreasing quality of life. Supportive and rehabilitative interventions, including pulmonary rehabilitation, physical exercise improvement, psychological support, pain management, and nutritional supplementation, seem promising approaches in relieving symptoms and improving quality of life but require further research. These programs emphasize the pivotal synergy among patient-tailored plans, multidisciplinary team involvement, and disease-specific focus. Despite advancements in therapeutic management, MPM remains a challenging disease with limited effective interventions that should be adapted to disease progressions. Rehabilitative strategies are essential to mitigate symptoms and improve the quality of life in MPM patients. Further research is needed to establish evidence-based guidelines for rehabilitative interventions tailored to the unique needs of MPM patients.

Abstract Photocatalyst‐assisted charge transfer at the interface between two immiscible electrolyte solutions (ITIES) has been previously proven. However, its practical application requires information on its performance under solar irradiation. We investigated photocatalyst‐assisted oxidation of water at ITIES under solar irradiation using TCNQ 7,7,8,8‐Tetracyanoquinodimethane (TCNQ) as electron scavenger and bis(triphenylphosphoranylidene) ammonium tetrakis(4‐chlorophenyl)borate (BTPPA‐TPBCl) as organic phase electrolyte. No enhancement of water oxidation after assembling photocatalyst nanoparticles at the ITIES was observed. Photocurrents with photocatalyst were similar to those without but in the presence of TCNQ. Photocurrents observed both with and without photocatalyst are shown to be due to photogeneration of TCNQ⋅−, either by reaction with the organic electrolyte or by interfacial oxidation of water. The former dominates at positive potentials and results in a positive photocurrent due to transfer of TCNQ⋅− across the ITIES. The latter dominates at negative potentials and results in a negative photocurrent. Electron paramagnetic resonance (EPR) detected TCNQ⋅− and revealed its stabilisation by formation of an adduct with BTPPA+, which must contribute to making the photoactivity of TCNQ the dominant process even with photocatalyst. These findings highlight the necessity of research on alternative suitable electron scavenger‐supporting electrolyte combinations for implementing ITIES in the photoelectrocatalytic conversion of solar energy.

Background: Despite the well-known efficacy of anti-COVID-19 vaccines in preventing morbidity and mortality, several vaccinated individuals are diagnosed with SARS-CoV-2 breakthrough infection, which might require hospitalisation. This multicentre, observational, and retrospective study aimed to investigate the clinical characteristics and outcomes of vaccinated vs. non-vaccinated patients, both hospitalised with SARS-CoV-2 infection in 3 major hospitals in Northern Italy. Methods: Data collection was retrospective, and paper and electronic medical records of adult patients with a diagnosed SARS-CoV-2 infection were pseudo-anonymised and analysed. Vaccinated and non-vaccinated individuals were manually paired, using a predetermined matching criterion (similar age, gender, and date of hospitalisation). Demographic, clinical, treatment, and outcome data were compared between groups differing by vaccination status using Pearson’s Chi-square and Mann-Whitney tests. Moreover, multiple logistic regression analyses were performed to assess the impact of vaccination status on ICU admission or intra-hospital mortality. Results: Data from 360 patients were collected. Vaccinated patients presented with a higher prevalence of relevant comorbidities, like kidney replacement therapy or haematological malignancy, despite a milder clinical presentation at the first evaluation. Non-vaccinated patients required intensive care more often than their vaccinated counterparts (8.8% vs. 1.7%, p = 0.002). Contrariwise, no difference in intra-hospital mortality was observed between the two groups (19% vs. 20%, p = 0.853). These results were confirmed by multivariable logistic regressions, which showed that vaccination was significantly associated with decreased risk of ICU admission (aOR=0.172, 95%CI: 0.039–0.542, p = 0.007), but not of intra-hospital mortality (aOR=0.996, 95%CI: 0.582–1.703, p = 0.987). Conclusions: This study provides real-world data on vaccinated patients hospitalised with COVID-19 in Northern Italy. Our results suggest that COVID-19 vaccination has a protective role in individuals with higher risk profiles, especially regarding the need for ICU admission. These findings contribute to our understanding of SARS-CoV-2 infection outcomes among vaccinated individuals and emphasise the importance of vaccination in preventing severe disease, particularly in those countries with lower first-booster uptake rates.

The article aims to address the use of the theoretical-methodological teaching strategy, Problematized Experimental Activity (PEA), to introduce a method employed in chemometrics, called Principal Component Analysis, through digital images linked to a smartphone app (REDGIM®). The application of a didactic workshop occurred in the pandemic context of SARS-CoV2, in remote teaching, with students of the undergraduate course in Chemistry of a public University of Espírito Santo. The students were divided into two groups and developed solutions to a proposed problem, working with the themes: differentiation of false and true banknotes, and recognition of patterns in vegetable oils. The groups presented promising results in terms of learning in the development of their experimental methodologies and were able to have contact with analysis of chemical problems that are still little explored in the undergraduate course.

In this article, we present a novel analysis of infinitive fronting in Old and Middle French (9th-16th century). We find that in sentences with modal verbs and clitic climbing, the infinitive may either follow the main verb or precede it. When the subject of the main verb is overt and the infinitive is fronted, the order is Subj-Vinf-Vfin. Moreover, we find that the object of the fronted infinitive either cliticises onto the main verb (i.e. clitic climbing) or moves as a full DP with the infinitive, in which case the order is Subj-Obj-Vinf-Vfin. We compare our data to Stylistic Fronting, and we show that infinitive fronting in Old and Middle French is a different mechanism. Our analysis takes infinitive fronting to be vP-movement to Spec,TP, an operation which patterns alongside other Transparency Effects. Therefore, infinitive fronting provides further evidence for monoclausal restructuring in earlier French.

Abstract Background and Objective Esmethadone (dextromethadone; d-methadone; S-methadone (+)-methadone; REL-1017) is the opioid inactive dextro-isomer of racemic methadone. Esmethadone is a low potency N-methyl-D-aspartate (NMDA) receptor channel blocker with higher affinity for GluN2D subtypes. Esmethadone showed robust, rapid, and sustained antidepressant effects in patients with major depressive disorder (MDD) with inadequate response to ongoing serotonergic antidepressant treatment. Methods Here we described the results of in vitro and phase 1 clinical trials aimed at investigating the esmethadone metabolism and possible drug-drug interactions. Results Esmethadone is primarily metabolized to EDDP (2-ethylene-1,5-dimethyl-3,3-diphenylpyrrolidine) by multiple enzymes, including CYP3A4/5 and CYP2B6. In vitro studies showed that esmethadone inhibits CYP2D6 with IC50 of 9.6 μM and is an inducer of CYP3A4/5. The clinical relevance of the inhibition of CYP2D6 and the induction of CYP3A4 were investigated by co-administering esmethadone and dextromethorphan (a substrate for CYP2D6) or midazolam (a substrate for CYP3A4) in healthy volunteers. The administration of esmethadone at the dosage of 75 mg (which is the loading dose administered to patients in MDD clinical trials) significantly increased the exposure (AUC) of both dextromethorphan and its metabolite dextrorphan by 2.71 and 3.11-fold, respectively. Esmethadone did not modify the pharmacokinetic profile of midazolam, while it increased C max and AUC of its metabolite 1′-hydroxymidazolam by 2.4- and 3.8-fold, respectively. A second study evaluated the effect of the CYP3A4 inhibitor cobicistat on the pharmacokinetics of esmethadone. Cobicistat slightly increase (+32%) the total exposure (AUC0–inf) of esmethadone. Conclusions In summary, esmethadone demonstrated a negligible effect on CYP3A4 induction and its metabolism was not meaningfully affected by strong CYP3A4 inhibitors while it increased exposure of CYP2D6-metabolized drugs.

Herein, we investigated the toxicity and membrane-permeabilizing capabilities of Lpt and Lpt-like peptides, belonging to type I toxin–antitoxin systems carried by plasmid DNA of Lacticaseibacillus strains. These 29 amino acid peptides are predicted to form α-helical structures with a conserved central hydrophobic sequence and differently charged hydrophilic termini. Like Lpt, the expression of Lpt-like in E. coli induced growth arrest, nucleoid condensation, and cell membrane damage, suggesting membrane interaction as the mode of action. The membrane permeabilization activity of both peptides was evaluated by using liposome leakage assays, dynamic light scattering, and CD spectroscopy. Lpt and Lpt-like showed liposome leakage activity, which did not lead to liposome disruption but depended on peptide concentration. Lpt was generally more effective than Lpt-like, probably due to different physical chemical properties. Leakage was significantly reduced in larger liposomes and increased with negatively charged PCPS liposomes, indicating that electrostatic interactions and membrane curvature influence peptide activity. Contrary to most membrane-active peptides, Lpt an Lpt-like progressively lost their α-helical structure upon interaction with liposomes. Our data are inconsistent with the formation of membrane-spanning peptide pores but support a mechanism relying on the transient failure of the membrane permeability barrier possibly through the formation of “lipid pores”.

An impacted third molar is one of the most common abnormalities of the tooth position, impacting patients and their quality of life. Based on the impact and the invasive removal procedure, this study aimed to evaluate the characteristics of impacted third molars based on their radiographic features as well as their association with demographic characteristics. Outpatient dental records of the oral and maxillofacial surgery department of Hasan Sadikin Hospital, Bandung, Indonesia, from 1 January 2018 to 31 December 2019, were sorted, and relevant clinical and demographic data and panoramic radiographic examination results were extracted from these records. All data were then tabulated and analyzed by using SPSS version 29. As many as 3019 impacted third molars were identified. Our findings suggested the association between age to the occurrence of impacted third molars where patients aged between 17 and 29 years old showed high occurrences of impacted third molars. Male patients with impacted third molars are more likely to have multiple impacted third molars, while this risk decreases in females. Radiographic examination showed that the mesioangular position is the most common position for mandibular third molars. The variation in high occurrences of the impacted third molar is associated with several demographic factors.

Abstract Esmethadone (REL-1017) is the opioid-inactive dextro-isomer of methadone and a low-affinity, low-potency uncompetitive NMDA receptor antagonist. In a Phase 2, randomized, double-blind, placebo-controlled trial, esmethadone showed rapid, robust, and sustained antidepressant effects. Two studies were conducted to evaluate the abuse potential of esmethadone. Each study utilized a randomized, double-blind, active-, and placebo-controlled crossover design to assess esmethadone compared with oxycodone (Oxycodone Study) or ketamine (Ketamine Study) in healthy recreational drug users. Esmethadone 25 mg (proposed therapeutic daily dose), 75 mg (loading dose), and 150 mg (Maximum Tolerated Dose) were evaluated in each study. Positive controls were oral oxycodone 40 mg and intravenous ketamine 0.5 mg/kg infused over 40 min. The Ketamine study included oral dextromethorphan 300 mg as an exploratory comparator. The primary endpoint was maximum effect (Emax) for Drug Liking, assessed using a bipolar 100-point visual analog scale (VAS). A total of 47 and 51 participants completed the Oxycodone Study and the Ketamine Study, respectively (Completer Population). In both studies, esmethadone doses ranging from therapeutic (25 mg) to 6 times therapeutic (150 mg) had a meaningful and statistically significantly (p

The nematode Caenorhabditis elegans is a widely used model organism for neuroscience. Although its nervous system has been fully reconstructed, the physiological bases of single-neuron functioning are still poorly explored. Recently, many efforts have been dedicated to measuring signals from C. elegans neurons, revealing a rich repertoire of dynamics, including bistable responses, graded responses, and action potentials. Still, biophysical models able to reproduce such a broad range of electrical responses lack. Realistic electrophysiological descriptions started to be developed only recently, merging gene expression data with electrophysiological recordings, but with a large variety of cells yet to be modeled. In this work, we contribute to filling this gap by providing biophysically accurate models of six classes of C. elegans neurons, the AIY, RIM, and AVA interneurons, and the VA, VB, and VD motor neurons. We test our models by comparing computational and experimental time series and simulate knockout neurons, to identify the biophysical mechanisms at the basis of inter and motor neuron functioning. Our models represent a step forward toward the modeling of C. elegans neuronal networks and virtual experiments on the nematode nervous system.

In the emerging field of whole-brain imaging at single-cell resolution, which represents one of the new frontiers to investigate the link between brain activity and behavior, the nematode Caenorhabditis elegans offers one of the most characterized models for systems neuroscience. Whole-brain recordings consist of 3D time series of volumes that need to be processed to obtain neuronal traces. Current solutions for this task are either computationally demanding or limited to specific acquisition setups. Here, we propose See Elegans, a direct programming algorithm that combines different techniques for automatic neuron segmentation and tracking without the need for the RFP channel, and we compare it with other available algorithms. While outperforming them in most cases, our solution offers a novel method to guide the identification of a subset of head neurons based on position and activity. The built-in interface allows the user to follow and manually curate each of the processing steps. See Elegans is thus a simple-to-use interface aimed at speeding up the post-processing of volumetric calcium imaging recordings while maintaining a high level of accuracy and low computational demands. (Contact: enrico.lanza@iit.it).

Dapagliflozin, a sodium-glucose co-transporter-2 inhibitor and semaglutide, a glucagon-like peptide 1 receptor agonist, have both demonstrated efficacy in glycemic control, reducing blood pressure, body weight, risk of renal and heart failure in type 2 diabetes mellitus. In this observational, real-world, study we aimed to investigate the efficacy of the combination therapy with those two agents over glycemic control. We thus obtained the data of 1335 patients with type 2 diabetes followed by 11 Diabetes centers in Lombardia, Italy. A group of 443 patients was treated with dapagliflozin alone, the other group of 892 patients was treated with the combination therapy of dapagliflozin plus oral semaglutide. We analyzed changes in glycated hemoglobin from baseline to 6 months of follow-up, as well as changes in fasting glycemia, body weight, body mass index, systolic and diastolic pressure, heart rate, creatinine, estimated glomerular filtration rate and albuminuria. Both groups of patients showed an improvement of glycometabolic control after 6 months of treatment; indeed, the treatment with dapagliflozin plus oral semaglutide showed a reduction of glycated hemoglobin of 1.2% as compared to the 0.5% reduction observed in the dapagliflozin alone group. Significant changes were observed in body mass index, fasting plasmatic glucose, blood pressure, total cholesterol, LDL and albumin to creatinine ratio, with a high rate (55%) of near-normalization of glycated hemoglobin. Our real world data confirmed the potential of the oral combination therapy dapagliflozin with semaglutide in inducing pharmacological remission of type 2 diabetes mellitus.

Abstract Background Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown cardiovascular benefits in cardiovascular outcome trials in type 2 diabetes mellitus. However, the most convincing evidence was obtained in subjects with established cardiovascular (CV) disease. We analyzed the determinants of GLP-1 RA-mediated CV protection in a real-world population of persons with type 2 diabetes with and without a history of CV events with long-term follow-up. Methods Retrospective cohort study of 550 individuals with type 2 diabetes (395 in primary CV prevention, 155 in secondary CV prevention), followed at a single center after the first prescription of a GLP-1 RA between 2009 and 2019. CV and metabolic outcomes were assessed. Results Median duration of follow-up was 5.0 years (0.25–10.8) in primary prevention and 3.6 years (0–10.3) in secondary prevention, with a median duration of treatment of 3.2 years (0–10.8) and 2.5 years (0–10.3) respectively. In the multivariable Cox regression model considering GLP-1 RA treatment as a time-dependent covariate, in the primary prevention group, changes in BMI and glycated hemoglobin did not have an impact on MACE risk, while age at the time of GLP-1 initiation (HR 1.08, 95% CI 1.03–1.14, p = 0.001) and GLP-1 RA cessation by time (HR 3.40, 95% CI 1.82–6.32, p