Development of the European Laparoscopic Intermediate Urological Skills LUSs2 Curriculum: A Delphi Consensus from the European School of Urology.

Background and objective: While programmes such as the European Basic Laparoscopic Urological Skills have made strides in foundational training, a significant gap exists for intermediate and advanced laparoscopy education. Our objective is to develop and validate the European laparoscopic intermediate urological skills (LUSs2) curriculum, which will establish uniformity in the training of urological laparoscopic procedures and facilitate proficiency among practitioners. Methods: The study combines a literature review, cognitive task analysis development by a steering group, and a two-round Delphi survey involving international experts in urological laparoscopy. Consensus was defined as agreement of ≥70% among experts. The survey included statements on various laparoscopic procedures, assessed on a Likert scale from 1 (strongly disagree) to 9 (strongly agree). Key findings and limitations: The Delphi process achieved consensus on 85% (235/275) of statements, indicating a strong agreement on the curriculum's content. Areas covered include renal hilum dissection, major vessel injury management, enucleation and renorrhaphy, vesicourethral anastomosis, and pyeloplasty. Limitations include the nonsystematic nature of the literature review and potential biases inherent in expert-based consensus methods. Conclusions and clinical implications: The LUSs2 curriculum significantly advances the standardised training of laparoscopic urological skills. It offers a detailed, consensus-validated framework that addresses the need for uniformity in surgical education and aims to enhance surgical proficiency and patient care. Patient summary: This study presents the development of a new standardised training curriculum for urological laparoscopic surgery. We intend this curriculum to improve the quality of surgical training and ensure high-quality patient care.

Exploring Corymbia torelliana hydrochar combustion kinetics through thermogravimetric analysis, peak deconvolution and reaction profile modelling.

This study aims to conduct an applied and innovative investigation to enhance the energy quality of wood residues through hydrothermal carbonization pretreatment. For this purpose, the treatment was carried out at three different temperatures: 180, 220, and 240 °C under autogenous pressure. The in natura material and the hydrochars were characterized, and thermogravimetric analyses were performed in an O2 atmosphere with heating rates of 2.5, 5, 10, and 20 °C min-1. The global activation energy for natura biomass combustion was determined to be 112.49 kJ.mol-1. On the other hand, the hydrothermal carbonization process promoted a reduction in this value for the 94.85 kJ.mol-1. The conversion function for the in natura biomass was characterized as 1 - α , order 1, while the hydrochars was 2(1-α) [-ln(1-α)] (1/2), Avrami-Erofe'ev I. Triple kinetic parameters were ascertained, and the conversion curves along with their respective derivatives were modeled, exhibiting minimal deviations between theoretical and experimental data. This facilitated the mathematical representation of the reaction processes and allowed for a comprehensive comparison of the results.

Microextraction of steroidal hormones from urine samples using natural deep eutectic solvents: insights into chemical interactions using molecular dynamics simulations.

Natural deep eutectic solvents (NADES) are gaining significant attention in analytical chemistry due to attractive physico-chemical properties associated with sustainable aspects. They have been successfully evaluated in different fields, and applications in sample preparation have increased in the last years. However, there is a limited knowledge related to chemical interactions and mechanism of intermolecular action with specific analytes. In this regard, for the first time, this study exploited a computational investigation using molecular dynamics (MD) predictions combined with experimental data for the extraction/determination of steroidal hormones (estriol, ß-estradiol, and estrone) in urine samples using NADES. The ultrasound-assisted liquid-liquid microextraction (UALLME) approach followed by high-performance liquid chromatography with diode array detection (HPLC-DAD) was employed using menthol:decanoic acid as extraction solvent. Experimental parameters were optimized through multivariate strategies, with the best conditions consisting of 3 min of extraction, 150 µL of NADES, and 3 mL of sample (tenfold diluted). According to molecular dynamics predictions confirmed by experimental data, a molar ratio that permitted the highest efficiency consisted of menthol:decanoic acid 2:1 v/v. Importantly, computational simulations revealed that van der Waals interactions were the most significant contributor to the interaction energy of analytes-NADES. Using the optimized conditions, limits of detection (LOD) ranged from 3 and 8 µg L-1, and precision (n = 3) varied from 8 to 19%. Intraday precision was evaluated at 3 concentrations: low (LOQ according to each analyte), medium (100 µg L-1), and high (750 µg L-1). Accuracy was successfully assessed through recoveries that ranged from 82 to 98%. In this case, molecular dynamics simulations proved to be an important tool for in-depth investigations of interaction mechanisms of DES with different analytes.

Ferulic Acid-Loaded Nanostructure Maintains Brain Levels of ACh, Glutamate, and GABA and Ameliorates Anxiety and Memory Impairments Induced by the D-Galactose Aging Process in Rats.

Population aging is a global reality driven by increased life expectancy. This demographic phenomenon is intrinsically linked to the epidemic of cognitive disorders such as dementia and Alzheimer's disease, posing challenges for elderly and their families. In this context, the search for new therapeutic strategies to prevent or minimize cognitive impairments becomes urgent, as these deficits are primarily associated with oxidative damage and increased neuroinflammation. Ferulic acid (FA), a natural and potent antioxidant compound, is proposed to be nanoencapsulated to target the central nervous system effectively with lower doses and an extended duration of action. Here, we evaluated the effects of the nanoencapsulated FA on d-galactose (d-Gal)- induced memory impairments. Male Wistar adult rats were treated with ferulic acid-loaded nanocapsules (FA-Nc) or non-encapsulated ferulic acid (D-FA) for 8 weeks concurrently with d-Gal (150 mg/kg s.c.) injection. As expected, our findings showed that d-Gal injection impaired memory processes and increased anxiety behavior, whereas FA-Nc treatment ameliorated these behavioral impairments associated with the aging process induced by d-Gal. At the molecular level, nanoencapsulated ferulic acid (FA-Nc) ameliorated the decrease in ACh and glutamate induced by d-galactose (d-Gal), and also increased GABA levels in the dorsal hippocampus, indicating its therapeutic superiority. Additional studies are needed to elucidate the mechanisms underlying our current promising outcomes. Nanoscience applied to pharmacology can reduce drug dosage, thereby minimizing adverse effects while enhancing therapeutic response, particularly in neurodegenerative diseases associated with aging. Therefore, the strategy of brain-targeted drug delivery through nanoencapsulation can be effective in mitigating aging-related factors that may lead to cognitive deficits.

KRASG 12C-inhibitor-based combination therapies for pancreatic cancer: insights from drug screening.

Pancreatic ductal adenocarcinoma (PDAC) has limited treatment options, emphasizing the urgent need for effective therapies. The predominant driver in PDAC is mutated KRAS proto-oncogene, KRA, present in 90% of patients. The emergence of direct KRAS inhibitors presents a promising avenue for treatment, particularly those targeting the KRASG12C mutated allele, which show encouraging results in clinical trials. However, the development of resistance necessitates exploring potent combination therapies. Our objective was to identify effective KRASG12C-inhibitor combination therapies through unbiased drug screening. Results revealed synergistic effects with son of sevenless homolog 1 (SOS1) inhibitors, tyrosine-protein phosphatase non-receptor type 11 (PTPN11)/Src homology region 2 domain-containing phosphatase-2 (SHP2) inhibitors, and broad-spectrum multi-kinase inhibitors. Validation in a novel and unique KRASG12C-mutated patient-derived organoid model confirmed the described hits from the screening experiment. Our findings propose strategies to enhance KRASG12C-inhibitor efficacy, guiding clinical trial design and molecular tumor boards.

Development of a User-Friendly Self-Screening Tool for Assessing Metabolic Syndrome Risk in Youths from Economically Challenged Regions.

BACKGROUND: Metabolic syndrome increases the risk of heart disease and diabetes. Early identification and management are crucial, especially in economically challenged regions with limited healthcare access. AIMS: To develop nomograms for individualized risk estimation for metabolic syndrome in young people from low-income regions. METHODS: We assessed 496 college students from two Brazilian cities with Gini indices ≤0.56. Of these, 69.9% were female, 65.1% were younger than 20 years, 71.8% were non-white, and 64.3% were enrolled in health-related courses. For external validity, we assessed metabolic syndrome in a subset of 375 students. RESULTS: We found 10 variables associated with abdominal obesity by logistic regression: age, biological sex, physical education facilities, enrollment in sports competitions during elementary school, grade retention, physical education as the preferred subject, physical education classes per week, and enrollment in sports training in secondary school (score A); adherence to 24 h movement behaviors (B score); and body weight (score C). We designed three nomograms (for scores A, B, and C), all of which showed acceptable performance according to the area under the receiver operating characteristic curve (≥0.70) and calibration (Hosmer-Lemeshow test, p > 0.05). In the external validation, we observed higher predictive capability for the A and B scores, while the C score had lower but still acceptable predictive ability. CONCLUSIONS: User-friendly self-reported data accurately predict metabolic syndrome among youths from economically challenging areas.

High CIB1 expression in colorectal cancer liver metastases correlates with worse survival and the replacement histopathological growth pattern.

To date, nearly one-quarter of colorectal cancer (CRC) patients develop liver metastases (CRCLM), and its aggressiveness can be correlated to defined histopathological growth patterns (HGP). From the three main HGPs within CRCLM, the replacement HGP emerges as particularly aggressive, characterized by heightened tumor cell motility and vessel co-option. Here, we investigated the correlation between the expression of calcium- and integrin-binding protein 1 (CIB1), a ubiquitously expressed gene involved in various cellular processes including migration and adhesion, and disease-free (DFS) and overall survival (OS) in primary CRC patients. Additionally, we explored the correlation between CIB1 expression and different HGPs of CRCLM. Proteomic analysis was used to evaluate CIB1 expression in a cohort of 697 primary CRC patients. Additionally, single-cell and spatial RNA-sequencing datasets, along with publicly available bulk sequencing data were used to evaluate CIB1 expression in CRCLM. In silico data were further validated by formalin-fixed paraffin-embedded immunohistochemical stainings. We observed that high CIB1 expression is independently associated with worse DFS and OS, regardless of Union Internationale Contre le Cancer stage, gender, or age. Furthermore, the aggressive replacement CRCLM HGP is significantly associated with high CIB1 expression. Our findings show a correlation between CIB1 levels and the clinical aggressiveness of CRC. Moreover, CIB1 may be a novel marker to stratify HGP CRCLM.

Tumor Vessel Normalization via PFKFB3 Inhibition Alleviates Hypoxia and Increases Tumor Necrosis in Rectal Cancer upon Radiotherapy.

Treatment of patients with locally advanced rectal cancer (RC) is based on neoadjuvant chemoradiotherapy followed by surgery. In order to reduce the development of therapy resistance, it is necessary to further improve previous treatment approaches. Recent in vivo experimental studies suggested that the reduction of tumor hypoxia by tumor vessel normalization (TVN), through the inhibition of the glycolytic activator PFKFB3, could significantly improve tumor response to therapy. We have evaluated in vitro and in vivo the effects of the PFKFB3 inhibitor 2E-3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) on cell survival, clonogenicity, migration, invasion, and metabolism using colorectal cancer cells, patient-derived tumor organoid (PDO), and xenograft (PDX). 3PO treatment of colorectal cancer cells increased radiation-induced cell death and reduced cancer cell invasion. Moreover, gene set enrichment analysis shows that 3PO is able to alter the metabolic status of PDOs toward oxidative phosphorylation. Additionally, in vivo neoadjuvant treatment with 3PO induced TVN, alleviated tumor hypoxia, and increased tumor necrosis. Our results support PFKFB3 inhibition as a possible future neoadjuvant addition for patients with RC. SIGNIFICANCE: Novel therapies to better treat colorectal cancer are necessary to improve patient outcomes. Therefore, in this study, we evaluated the combination of a metabolic inhibitor (3PO) and standard radiotherapy in different experimental settings. We have observed that the addition of 3PO increased radiation effects, ultimately improving tumor cell response to therapy.

A single and short exposure to heated tobacco vapor or cigarette smoke affects macrophage activation and polarization.

The toxicity of heated tobacco products (HTP) on the immune cells remains unclear. Here, U937-differentiated macrophages were exposed to a single and short-term exposure (30 minutes) of HTP vapor or cigarette smoke (CS) in an air-liquid interface (ALI) system to evaluate the effects on macrophages' early activation and polarization. In our system, HTP released lower amounts of polycyclic aromatic hydrocarbons (PAHs), but higher nicotine levels than CS into the cell culture supernatant. Both tobacco products triggered the expression of the α-7 nicotinic receptor (α7 nAChR) and reactive oxygen species (ROS) production. When challenged with a bacterial product, lipopolysaccharide (LPS), cells exposed to HTP or CS failed to respond properly and enhance ROS production upon LPS stimuli. Furthermore, both tobacco products also impaired bacterial phagocytosis and the exposures triggered higher IL-1ß secretion. The α7 nAChR antagonist treatment rescued the effects caused only by HTP exposure. The CS-exposed group switched macrophage to the pro-inflammatory M1, while HTP polarized to the suppressive M2 profile. Associated, data highlight that HTP and CS exposures similarly activate macrophages; nonetheless, the α7 nAChR pathway is only involved in HTP actions, and the distinct subsequent polarization caused by HTP or CS may influence the outcome of host defense.

In vitro antimicrobial, antibiofilm photodynamic activity, and molecular dynamic simulations of tetra-cationic porphyrinmembrane interactions against foodborne microorganisms.

This manuscript presents a new report on the in vitro antimicrobial photo-inactivation of foodborne microorganisms (Salmonella spp. and Listeria monocytogenes) using tetra-cationic porphyrins. Isomeric tetra-cationic porphyrins (3MeTPyP, 4MeTPyP, 3PtTPyP, and 4PtTPyP) were tested, and antimicrobial activity assays were performed at specific photosensitizer concentrations under dark and white-light LED irradiation conditions. Among the tested bacterial strains, 4MeTPyP exhibited the highest efficiency, inhibiting bacterial growth within just 60 min at low concentrations (17.5 µM). The minimal inhibitory concentration of 4MeTPyP increased when reactive oxygen species scavengers were present, indicating the significant involvement of singlet oxygen species in the photooxidation mechanism. Furthermore, the checkerboard assay testing the association of 4MeTPyP showed an indifferent effect. Atomic force microscopy analyses and dynamic simulations were conducted to enhance our understanding of the interaction between this porphyrin and the strain's membrane.

Interaction of Statherin-Derived Peptide with the Surface of Hydroxyapatite: Perspectives Based on Molecular Dynamics Simulations.

INTRODUCTION: Statherin-derived peptide (StatpSpS) has shown promise against erosive tooth wear. To elucidate its interaction with the hydroxyapatite (HAP) surface, the mechanism related to adsorption of this peptide with HAP was investigated through nanosecond-long all-atom molecular dynamics simulations. METHODS: StatpSpS was positioned parallel to the HAP surface in 2 orientations: 1 - neutral and negative residues facing the surface and 2 - positive residues facing the surface. A system containing StatpSpS without HAP was also simulated as control. In the case of systems with HAP, both partially restrained surface and unrestrained surface were constructed. Structural analysis, interaction pattern, and binding-free energy were calculated. RESULTS: In the peptide system without the HAP, there were some conformational changes during the simulation. In the presence of the surface, only moderate changes were observed. Many residues exhibited short and stable distances to the surface, indicating strong interaction. Specially, the residues ASP1 and SER2 have an important role to anchor the peptide to the surface, with positively charged residues, mainly arginine, playing a major role in the further stabilization of the peptide in an extended conformation, with close contacts to the HAP surface. CONCLUSION: The interaction between StatpSpS and HAP is strong, and the negative charged residues are important to the anchoring of the peptide in the surface, but after the initial placement the peptide rearranges itself to maximize the interactions between positive charged residues.

Analysis of omarigliptin forced degradation products by ultra-fast liquid chromatography, mass spectrometry, and in vitro toxicity assay.

Omarigliptin (OMG) is an antidiabetic drug indicated for the treatment of type 2 diabetes mellitus. Forced degradation studies are practical experiments to evaluate the stability of drugs and to establish degradation profiles. Herein, we present the investigation of the degradation products (DPs) of OMG formed under various stress conditions. OMG was subjected to hydrolytic (alkaline and acidic), oxidative, thermal, and photolytic forced degradation. A stability-indicating ultra-fast liquid chromatography method was applied to separate and quantify OMG and its DPs. Five DPs were adequately separated and detected in less than 6 min, while other published methods detected four DPs. MS was applied to identify and obtain information on the structural elucidation of the DPs. Three m/z DPs confirmed previously published research, and two novel DPs were described in this paper. The toxicity of OMG and its DPs were investigated for the first time using in vitro cytotoxicity assays, and the sample under oxidative conditions presented significant cytotoxicity. Based on the results from forced degradation studies, OMG was found to be labile to hydrolysis, oxidation, photolytic, and thermal stress conditions. The results of this study contribute to the quality control and stability profile of OMG.

Development of an innovative analytical method for forensic detection of cocaine, antidepressants, and metabolites in postmortem blood using magnetic nanoparticles.

Cocaine and antidepressants rank high globally in substance consumption, emphasizing their impact on public health. The determination of these compounds and related substances in biological samples is crucial for forensic toxicology. This study focused on developing an innovative analytical method for the determination of cocaine, antidepressants, and their related metabolites in postmortem blood samples, using unmodified commercial Fe3O4 nanoparticles as a sorbent for dispersive magnetic solid-phase extraction (m-d-SPE), coupled with liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis. An aliquot of 100 µL of whole blood and 5 µL of the internal standard pool were added to 30 mg of nanoparticles. The nanoparticles were separated from the sample using a neodymium magnet inserted into a 3D-printed microtube rack. The liquid was then discarded, followed by desorption with 300 µL of 1/1/1 acetonitrile/methanol/ethyl acetate. The sample was vortexed and separated, and 1.5 µL of the organic supernatant was injected into the LC-MS/MS. The method was acceptably validated and successfully applied to 263 postmortem blood samples. All samples evaluated in this study were positive for at least one substance. The most frequent analyte was benzoylecgonine, followed by cocaine and cocaethylene. The most common antidepressants encountered in the analyzed samples were citalopram and fluoxetine, followed by fluoxetine's metabolite norfluoxetine. This study describes the first report of this sorbent in postmortem blood analysis, demonstrating satisfactory results for linearity, precision, accuracy, and selectivity for all compounds. The method's applicability was confirmed, establishing it as an efficient and sustainable alternative to traditional techniques for forensic casework.

Enhancement of colorectal cancer therapy through interruption of the HSF1-HSP90 axis by p53 activation or cell cycle inhibition.

The stress-associated molecular chaperone system is an actionable target in cancer therapies. It is ubiquitously upregulated in cancer tissues and enables tumorigenicity by stabilizing hundreds of oncoproteins and disturbing the stoichiometry of protein complexes. Most inhibitors target the key component heat-shock protein 90 (HSP90). However, although classical HSP90 inhibitors are highly tumor-selective, they fail in phase 3 clinical oncology trials. These failures are at least partly due to an interference with a negative feedback loop by HSP90 inhibition, known as heat-shock response (HSR): in response to HSP90 inhibition there is compensatory synthesis of stress-inducible chaperones, mediated by the transcription factor heat-shock factor 1 (HSF1). We recently identified that wildtype p53 (p53) actively reduces the HSR by repressing HSF1 via a p21-CDK4/6-MAPK-HSF1 axis. Here we test the hypothesis that in HSP90-based therapies simultaneous p53 activation or direct cell cycle inhibition interrupts the deleterious HSF1-HSR axis and improves the efficiency of HSP90 inhibitors. Indeed, we find that the clinically relevant p53 activator Idasanutlin suppresses the HSF1-HSR activity in HSP90 inhibitor-based therapies. This combination synergistically reduces cell viability and accelerates cell death in p53-proficient colorectal cancer (CRC) cells, murine tumor-derived organoids and patient-derived organoids (PDOs). Mechanistically, upon combination therapy human CRC cells strongly upregulate p53-associated pathways, apoptosis, and inflammatory immune pathways. Likewise, in the chemical AOM/DSS CRC model in mice, dual HSF1-HSP90 inhibition strongly represses tumor growth and remodels immune cell composition, yet displays only minor toxicities in mice and normal mucosa-derived organoids. Importantly, inhibition of the cyclin dependent kinases 4 and 6 (CDK4/6) under HSP90 inhibition phenocopies synergistic repression of the HSR in p53-proficient CRC cells. Even more important, in p53-deficient (mutp53-harboring) CRC cells, an HSP90 inhibition in combination with CDK4/6 inhibitors similarly suppresses the HSF1-HSR system and reduces cancer growth. Likewise, p53-mutated PDOs strongly respond to dual HSF1-HSP90 pathway inhibition and thus, providing a strategy to target CRC independent of the p53 status. In sum, activating p53 (in p53-proficient cancer cells) or inhibiting CDK4/6 (independent of the p53 status) provide new options to improve the clinical outcome of HSP90-based therapies and to enhance colorectal cancer therapy.

A validated dilute-and-shoot LC-MS-MS urine screening for the analysis of 95 illicit drugs and medicines: Insights from clinical and forensic Brazilian cases.

Urine toxicological analysis is a relevant tool in both clinical and forensic scenarios, enabling the diagnosis of acute poisonings, elucidation of deaths, verification of substance use in the workplace and identification of drug-facilitated crimes. For these analyses, the dilute-and-shoot technique associated with liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS) is a promising alternative since it has demonstrated satisfactory results and broad applicability. This study developed and validated a comprehensive LC-MS-MS screening method to analyze 95 illicit drugs and medicines in urine samples and application to clinical and forensic Brazilian cases. The dilute-and-shoot protocol was defined through multivariate optimization studies and was set using 100 µL of sample and 300 µL of solvent. The total chromatographic run time was 7.5 min. The method was validated following the recommendations of the ANSI/ASB Standard 036 Guideline. The lower limits of quantification varied from 20 to 100 ng/mL. Within-run and between-run precision coefficient of variations% were <20%, and bias was within ± 20%. Only 4 of the 95 analytes presented significant ionization suppression or enhancement (>25%). As proof of applicability, 839 urine samples from in vivo and postmortem cases were analyzed. In total, 90.9% of the analyzed samples were positive for at least one substance, and 78 of the 95 analytes were detected. The most prevalent substances were lidocaine (40.2%), acetaminophen (38.0%) and benzoylecgonine (31.5%). The developed method proved to be an efficient and simplified alternative for analyzing 95 therapeutic and illicit drugs in urine samples. Additionally, the results obtained from sample analysis are essential for understanding the profile of Brazilian substance use, serving as a valuable database for the promotion of health and safety public policies.

A partial agonist of PPARγ prevents paclitaxel-induced peripheral neuropathy in mice, by inhibiting neuroinflammation.

BACKGROUND AND PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of paclitaxel, affecting 30-50% of patients. Increased survival and concern with patients' quality of life have encouraged the search for new tools to prevent paclitaxel-induced neuropathy. This study presents the glitazone 4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-N-phenylbenzene-sulfonamide (TZD-A1) as a partial agonist of peroxisome proliferator-activated receptor γ (PPARγ), its toxicological profile and effects on paclitaxel-induced CIPN in mice. EXPERIMENTAL APPROACH: Interactions of TZD-A1 with PPARγ were analysed using in silico docking and in vitro reporter gene assays. Pharmacokinetics and toxicity were evaluated using in silico, in vitro and in vivo (C57Bl/6 mice) analyses. Effects of TZD-A1 on CIPN were investigated in paclitaxel-injected mice. Axonal and dorsal root ganglion damage, mitochondrial complex activity and cytokine levels, brain-derived neurotrophic factor (BDNF), nuclear factor erythroid 2-related factor 2 (Nrf2) and PPARγ, were also measured. KEY RESULTS: Docking analysis predicted TZD-A1 interactions with PPARγ compatible with partial agonism, which were corroborated by in vitro reporter gene assays. Good oral bioavailability and safety profile of TZD-A1 were shown in silico, in vitro and in vivo. Paclitaxel-injected mice, concomitantly treated with TZD-A1 by i.p. or oral administration, exhibited decreased mechanical and thermal hypersensitivity, effects apparently mediated by inhibition of neuroinflammation and mitochondrial damage, through increasing Nrf2 and PPARγ levels, and up-regulating BDNF. CONCLUSION AND IMPLICATIONS: TZD-A1, a partial agonist of PPARγ, provided neuroprotection and reduced hypersensitivity induced by paclitaxel. Allied to its safety profile and good bioavailability, TZD-A1 is a promising drug candidate to prevent and treat CIPN in cancer patients.

Realistic assessment of tire and road wear particle emissions and their influencing factors on different types of roads.

This study aims to examine tire and road wear particle (TRWP) emissions under realistic conditions in order to provide some valuable insights into understanding their sources and fate in the environment. TRWP emissions were evaluated with a fully instrumented vehicle driving on five representative road types: urban, ring road, suburban, highway, and rural. Multiple vehicle dynamic variables were recorded to assess the factors influencing these emissions. For the first time, emitted particles were collected on filters and analyzed by means of pyrolysis coupled with gas chromatography-mass spectrometry to determine the polymeric content of tires, in specifically quantifying styrene-butadiene rubber (SBR) and butadiene rubber (BR) pyrolytic markers. The measurements obtained from the five road types revealed similar size distributions for SBR + BR emissions, with maxima found in the (ultra)fine fraction (< 0.39 µm). Upon applying an SBR + BR-to-TRWP conversion factor, (ultra)fine fraction TRWP emissions proved to be the highest for suburban (64 ± 5 µg/km), followed by highway, urban, ring road and rural routes. The output represents up to 480 tons of TRWP per year emitted in the EU27, thus suggesting a widely impregnated atmospheric compartment capable of threatening human health. Furthermore, an analysis of variables revealed that acceleration, tire constraints, and constant sustained driving factors had specific impacts on TRWP emissions.

Insulin infusion sets associated with adverse events: strategies for improved diabetes education.

Introduction: Insulin Infusion Sets (IIS) play a crucial role in ensuring the safe delivery of insulin through a Continuous Subcutaneous Insulin Infusion (CSII) for individuals with Type 1 Diabetes (T1D). Recent advancements in therapy have highlighted the need to address issues such as unexplained hyperglycemia and IIS occlusion. Objective: To investigate the adverse events (AEs) associated with IIS that impact the treatment of T1D, with a specific focus on promoting effective educational practices. Methods: One hundred and eighteen patients under treatment at the Diabetes Center Insulin Pump Ambulatory, Federal University of São Paulo responded to a semi-structured questionnaire. Over 6 months, a nurse researcher interviewed them via video calls. Results: Catheter-related adverse events (AEs) included catheter knots, folding, and accidental traction. AEs associated with cannula use were mainly related to cannula fixation adhesive, insulin leakage, bleeding episodes, and skin problems. The cannula patch tends to detach easily in hot conditions or when used for more than 3 days, leading to local itching. Adhesive glue can cause redness and pain. Insulin leakage typically occurs after the catheter disconnects from the cannula, accidental cannula traction, or beneath the cannula patch. Bleeding has been reported inside the cannula or at the insertion site, resulting in local pain and, in some cases, obstruction of insulin flow. When accidental cannula traction occurs, it is recommended to replace the entire IIS system. In situations involving bleeding, leakage, insulin odor, or unsuccessful attempts to correct hyperglycemic episodes with a "bolus" of insulin, it is advisable to change the IIS system and evaluate appropriate techniques for handling and infusing the device. Moreover, regular inspections of the device and reservoir/cartridge are essential. Conclusion: Serious AEs can occur even in cases where the occlusion alarm is not activated, leading to interruptions in insulin flow. Conversely, in less severe situations, alarm activation can occur even in the absence of insulin flow interruption. Accidental catheter traction and catheter bending are commonly encountered in everyday situations, while issues related to the cannula directly affect blood glucose levels. AEs related to the IIS cannula often involve insulin leakage into the skin, bleeding, and skin events attributed to adhesive issues with the cannula.

Development of Potential Multi-Target Inhibitors for Human Cholinesterases and Beta-Secretase 1: A Computational Approach.

Alzheimer's disease causes chronic neurodegeneration and is the leading cause of dementia in the world. The causes of this disease are not fully understood but seem to involve two essential cerebral pathways: cholinergic and amyloid. The simultaneous inhibition of AChE, BuChE, and BACE-1, essential enzymes involved in those pathways, is a promising therapeutic approach to treat the symptoms and, hopefully, also halt the disease progression. This study sought to identify triple enzymatic inhibitors based on stereo-electronic requirements deduced from molecular modeling of AChE, BuChE, and BACE-1 active sites. A pharmacophore model was built, displaying four hydrophobic centers, three hydrogen bond acceptors, and one positively charged nitrogen, and used to prioritize molecules found in virtual libraries. Compounds showing adequate overlapping rates with the pharmacophore were subjected to molecular docking against the three enzymes and those with an adequate docking score (n = 12) were evaluated for physicochemical and toxicological parameters and commercial availability. The structure exhibiting the greatest inhibitory potential against all three enzymes was subjected to molecular dynamics simulations (100 ns) to assess the stability of the inhibitor-enzyme systems. The results of this in silico approach indicate ZINC1733 can be a potential multi-target inhibitor of AChE, BuChE, and BACE-1, and future enzymatic assays are planned to validate those results.