Risk Of Toxicity Research Articles

IN SILICO TRIAL APPROACHES BETWEEN PHYTOCHEMICAL COMPOSITION OF VERBENA OFFICINALIS AND LIVER CANCER TARGETS

Objective: The abundance of bioactive metabolites in Verbena officinalis explains the biological benefits and folkloric use of the plant. Liver cancer is an extremely heterogeneous malignant disease compared to other defined tumors. To explore the potential therapeutic value of bioactive metabolites in Verbena officinalis, this study aimed to filter secondary metabolites, conduct ADME-Tox assessments, perform drug similarity tests, and analyze with molecular dynamic simulations. The objective was to evaluate how potential drug candidates derived from Verbena officinalis behave in biological systems and assess their potential toxicity risks. Material and Method: Ligands selected from the ADME assay were utilized in in silico molecular docking studies against Glucose-6-phosphate dehydrogenase enzyme in the oxidative part of the pentose phosphate pathway, which is crucial for liver diseases. These studies were conducted using Autodock Vina embedded in Chimera 1.16. Molecular dynamics simulations were performed with the AMBER16. Result and Discussion: When the ADME test results were evaluated, 88 secondary metabolites were identified as ligands. Among all the ligands evaluated against Glucose-6-phosphate dehydrogenase enzyme, which is the key enzyme of the pentose phosphate pathway, quercetin flavonoid was determined to be the most active ligand with a docking score of -8.1 kcal/mol and binding energy of -118.51 kcal/mol. A molecular dynamics simulation performed for 300 nanoseconds confirmed that quercetin can remain stable in its microenvironment. The activity of this metabolite is worthy of further testing in vitro and in vivo as it may highlight a therapeutic modality within the pentose phosphate pathway.

Machine learning exploring the chemical compositions characteristics and sources of PM2.5 from reduced on-road activity

Particulate nitrate pollution has emerged as a major contributor to haze events in urban environment, due to the rapid increase of vehicle emissions. However, a comprehensive formation mechanisms of PM2.5 responses to vehicle emissions control still remains high uncertainties. In our study, hourly criteria air pollutants, meteorological parameters and chemical compositions of PM2.5 were continuously measured with or without reduced on-road activity at the coastal city in southeast China. XG Boost-SHAP models analysis showed that increasing concentrations of NO3−, NH4+, and BC contribute to elevated PM2.5 levels, due to the influence of vehicle emissions. Based on PMF model results, there was a notable increase in the contributions of traffic-related emissions, industrial activities, and dust sources to PM2.5, with increments of 13%, 4%, and 7%, respectively. In addition, metal elements such as Mn emerged as the primary contributor to hazard quotient (HQ) values, originated from non-exhaust emissions of vehicles, which might cause the potential toxic risks on human health, particularly during haze events. Hence, this study improve the understanding of air quality and human health both direct and indirect responses to vehicle emissions control in future urban management.

Revisiting the Evidence Base Informing the Use of Adjunctive Therapy for Enterococcus faecalis Endocarditis: A Systematic Review and Meta-Analysis.

Current guidelines recommend adjunctive gentamicin for the treatment of Enterococcus faecalis infective endocarditis (EFIE) despite a risk of toxicity. We sought to revisit the evidence for adjunctive therapy in EFIE and to synthesize the comparative safety and effectiveness of adjunctive use of the aminoglycosides versus ceftriaxone by systematic review and meta-analysis. For historical context, we reviewed the seminal case series and in vitro studies informing the evolution from penicillin monotherapy to modern-day regimens for EFIE. Next, we searched MEDLINE and Embase from inception to January 16, 2024 for studies of EFIE comparing 1) adjunctive aminoglycosides versus ceftriaxone or 2) adjunctive therapy versus monotherapy. Where possible, clinical outcomes were compared between regimens by random-effects meta-analysis. Otherwise, data were narratively summarized. Results for the systematic review and meta-analysis were limited to 10 observational studies totaling 911 patients. All studies were at high risk of bias. Relative to adjunctive ceftriaxone, gentamicin had similar all-cause mortality (Risk Difference [RD]=-0.8%, 95% Confidence interval [95%CI]=-5.0, 3.5), relapse (RD=-0.1%, 95%CI=-2.4, 2.3), and treatment failure (RD=1.1%, 95%CI=-1.6, 3.7), but higher discontinuation due to toxicity (RD=26.3%, 95%CI=19.8, 32.7). The 3 studies comparing adjunctive therapy to monotherapy included only 30 monotherapy patients and heterogeneity precluded meta-analysis. Adjunctive therapy with ceftriaxone appeared to be equally effective and less toxic than gentamicin for the treatment of EFIE. The existing evidence does not clearly establish the superiority of either adjunctive therapy or monotherapy. Pending randomized evidence, if adjunctive therapy is to be used, ceftriaxone appears to be a reasonable option.

Screen-Printed Electrodes-A Promising Tool for Antineoplastic Drug Detection (Cisplatin and Bleomycin) in Biological Samples.

Cancer remains one of the leading causes for death worldwide. Palliative chemotherapy is vital for certain cancer patients, highlighting the critical need for treatment monitoring tools to prevent drug accumulation and mitigate the risk of high toxicity. Therefore, our aim was to evaluate the potential of screen-printed electrodes for the development of sensitive and accurate biosensors for the detection/quantification of antineoplastic drugs. To this purpose, we developed a cisplatin sensor. By functionalizing the gold electrode with human serum albumin and by collecting the electrochemical signal obtained in a H2O2 solution, through voltammetry measurements, we were able to correlate the current measured at 430 mV with the concentration of cisplatin present in human serum samples, with a correlation coefficient of R2 = 0.99. Also, a bleomycin biosensor was developed and proven functional, but further optimization steps were employed in order to improve the accuracy. The developed biosensors have a detection range of 0.0006-43.2 mg/mL for cisplatin and 0.23-7.56 μg/mL for bleomycin in the serum samples. Our preliminary results show that these biosensors can facilitate the real-time monitoring of cisplatin and bleomycin serum levels, allowing healthcare professionals to tailor treatment strategies based on individual patient responses.

Occurrence, removal and risk assessment of chemicals of emerging concern in selected rivers and wastewater treatment plants in western Kenya

Water resources play a crucial role in sustaining life on earth yet chemicals of emerging concern (CECs) arising from extensive human applications are an increasing threat towards their existence. In this study, we examined the occurrence, removal and potential risk of CECs found in rivers and wastewater treatment plants (WWTPs) in western Kenya. Samples were prepared by solid-phase extraction and analysed using high performance liquid chromatography-mass spectrometry with a target list of 785 compounds. Out of these, 333 and 352 (influent 322, effluent 265) compounds were quantified in rivers and wastewater respectively, with pharmaceuticals, industrial compounds, and pesticides being frequently detected in both rivers and WWTPs. Compounds with highest concentrations included saccharin (9.9 μg/L), metformin (7.5 μg/L), and oxypurinol (6.5 μg/L) in rivers whereas caffeine (280 μg/L), deoxycholic acid (179 μg/L), 2-oxindole (10.9 μg/L) and ibuprofen (8.1 μg/L) were found at high concentrations in WWTPs. Based on the types of crops grown, samples from maize growing regions recorded the highest number of pesticides (75) which coincided with the spraying season. The WWTP showed the capacity to eliminate some compounds although the removal efficiencies varied greatly with 204 compounds exhibiting an average removal efficiency exceeding 50 %. Based on the risk assessment, crustaceans had the highest potential risk for toxicity with toxic unit (TU) values up to 5.4 driven primarily by diazinon and dichlorvos followed by algae (TU up to 0.07) and fish (TU up to 0.01) in rivers. A similar trend was observed in WWTP with diazinon (TU up to 5.5), diuron (TU up to 0.07) and carbendazim (TU up to 0.006) driving the risk for crustaceans, algae and fish respectively. These findings highlight the significance of surface water and WWTPs as sources and sinks of CECs in the environment translating to potential risks on aquatic organisms and humans.

Shared Care Planning for a pregnant patient with uveal melanoma treated with interventional radiotherapy (brachytherapy)

Introduction: Uveal melanoma (UM) is the most prevalent primary intraocular tumor in adulthood, with an important risk of metastasis, notably to the liver, rendering standard chemotherapy ineffective. Cases of UM onset during pregnancy are rare but can exhibit accelerated tumor growth. For these cases the best conservative treatment is interventional radiotherapy (IRT) also known as brachytherapy (BT). It is a form of radiotherapy that demonstrates efficacy comparable to the more common enucleation, while mitigating any risks of intrauterine toxicity. Objective: We reported the case of M., a 39-year-old pregnant patient, diagnosed with UM and undergoing brachytherapy treatment. Our aim is to make pertinent ethical considerations about: a. The ethical and clinical approach favouring a treatment strategy that preserves the affected organ and its functionality, b. The advance care planning process conducted within a multidisciplinary team. Case discussion: With the objective of preserving the mother’s health and ensuring the protection of the foetus, the team unanimously agreed, through a collaborative decision-making process, to proceed with the viable brachytherapy intervention. This approach results in a lower burden and maximizes benefits for both the patient and the unborn child. Conclusions: Considering a holistic evaluation, especially considering the patient’s pregnancy, the multidisciplinary approach proves fundamental. Collaboration between bioethicists and health-care professionals facilitated the development of a shared document for healthcare ethics planning, expressing the team’s ethical-clinical considerations.

The Role of Oxidative Stress and DNA Hydroxymethylation in the Pathogenesis of Benzo[a]pyrene-Impaired Reproductive Function in Male Mice.

Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon, is known to cause teratogenesis. Environmental exposure of BaP has led to wide public concerns due to their potential risk of reproductive toxicity. However, the exact mechanism is still not clear. We aimed to explore the alterations of oxidative stress and DNA hydroxymethylation during BaP-impaired reproductive function. BALB/c mice were intragastrically administered with different doses of BaP (0.01, 0.1, and 1 mg/kg/day, once a day), while control mice were administered with corn coil. Then, the reproductive function, alterations of oxidative stress, DNA methylation, and DNA hydroxymethylation of testis tissues were evaluated. We found that BaP caused obvious histopathological damages of testis tissues. As for sperm parameters after BaP administration, testis weight and the rate of teratosperm were increased, as well as sperm count and motility were decreased. In mechanism, BaP upregulated HO-1 and MDA levels and downregulated SOD and CAT activity and GSH content in testis tissues, indicating that oxidative stress was induced by BaP. Furthermore, a significant induction of hydroxymethylation and inhibition of methylation were observed in testis tissues after BaP exposure. Collectively, BaP-induced oxidative stress and hydroxymethylation were involved in impairing reproductive function, which may be the mechanism of the male infertility.

Toxic elements, sources and health risk assessment of PM2.5 in an industrial area of Surabaya, Indonesia

ABSTRACT A comprehensive study on air quality in the industrial area of Indonesia, which significantly impacts respiratory health and poses breathing hazards, is still lacking. This study aims to uncover the contents of toxic elements, identify potential sources of fine particles, and evaluate their contributions to health risks in Surabaya’s industrial area. The study focuses on identifying chemical composition, sources, and assessing health risks for both children and adults. The PM2.5 concentration from 2021 to 2022 ranged from 3.29 to 27.05 µg m−3, with an average value of 13.63 ± 4.54 µg m−3, exceeding the WHO’s annual standard of 5 µg m−3. Black carbon (BC) accounted for 27% of PM2.5 composition. A seasonal variation was found; the highest PM2.5 and BC were observed during the dry season, with the highest peak in June. The highest concentration of elements in PM2.5 was observed for S, followed by Si, K, Zn, Fe, and Pb, with maximum values of 3.53, 1.16, 1.01, 1.86, 0.29, and 0.37 µg m−3, respectively. Source apportionment using positive matrix factorisation (PMF) revealed eight sources: galvanising industry, ammonium chloride, secondary sulphate, biomass burning emission, soil, steel industry, vehicle emissions, and lead smelting, with metal industries accounting for 37.3%. Investigation into their potential source locations was conducted using the conditional bivariate probability function (CBPF) method. Human health assessment for adults and children indicates carcinogenic risks with a total risk of 9.50 × 10−5 and 2.38 × 10−5, respectively. The results emphasise the significance of managing sources linked to industry and transportation-related sources, crucial in decreasing high PM2.5 levels and several elevated elements and mitigating the health impact in Surabaya’s industrial area, Indonesia.

Quantitative analysis of toxicity risks in the operation of ammonia-fueled tugboats

As efforts to conserve energy and reduce emissions in the global shipping industry intensify, people are constantly looking for new types of energy to replace traditional fuels. Ammonia is considered a novel energy source due to its potential for carbon-neutral shipping when produced from renewable energy sources and is extremely promising for the shipping industry. In this study, the fuel toxicity risk of ammonia-fueled ships under operating conditions was quantified for the first time. The assessment process adopts the traditional quantitative risk assessment (QRA) framework with accident probability calculations based on Bayesian theory, and the process of partial quantification of consequences also guides the delineation of safety zones. The results of the study suggest that ammonia-powered tugboats are at a higher risk of toxic accidents during operation than accidents at sea, but both are within the acceptable limits of current international maritime safety and environmental standards. Finally, safety measures and risk mitigation strategies are proposed based on the study results. This provides important support in safety risk analysis for the design, production and operation of subsequent ammonia fueled vessels and is of great theoretical and practical importance.

Pritelivir for the treatment of nucleoside analogue–resistant orolabial herpes simplex virus 2 in a person living with HIV

Background: Nucleoside analogue–resistant herpes simplex virus infections are increasingly observed especially in immunocompromised patients. Currently, other options for treatment such as foscarnet and cidofovir are limited by difficulty of administration and significant risk of toxicity. Our report describes use of pritelivir, a novel helicase-primase inhibitor, in the treatment of nucleoside analogue–refractory orolabial HSV-2 infection. Methods: In 2017, a 53-year-old male with HIV on therapy presented with swelling of the right upper lip and a solid lesion inferior to the right nostril. Biopsy revealed cytopathic effects and immunohistochemistry staining confirming herpes simplex virus infection. The patient received multiple treatment courses including nucleoside analogue therapy, topical and intravenous foscarnet and cidofovir, and topical imiquimod but these failed to establish a significant and durable therapeutic response. Results: A swab of the lesion tested positive for HSV-2 via PCR. Subsequent genotyping revealed a M183X mutation in UL23 expected to convey resistance to acyclovir and penciclovir. The patient was started on oral pritelivir 400 mg once followed by 100 mg daily for 27 days, obtained through Health Canada's Special Access Program, resulting in near complete resolution of the lesion. Conclusion: Pritelivir is a novel helicase-primase inhibitor that appears to be an attractive option for management of resistant herpes simplex infections due to its unique mechanism, excellent oral bioavailability, and minimal toxicity. To our knowledge, this is the first described case of treatment of nucleoside analogue–resistant orolabial herpes simplex 2 infection with pritelivir and the first documented use of pritelivir in Canada.

Perchlorate in foodstuffs from South China and its implication for human dietary exposure

Perchlorate, an aqueous-soluble compound resistant to degradation, is mainly used in the synthesis of pyrotechnics, herbicides, and other products. It serves as a pivotal component in the production of fireworks, rocket fuel, and explosives. Perchlorate was recognized as a pollutant owing to the potential toxic risk to thyroid function, which could pose a potential threat to the nervous system of infants and pregnant women. Some study had found that perchlorate existed in food, water and air. This study aimed to investigate the levels of perchlorate in six types of foods (n = 570) from South China, and evaluate potential exposure risks for residents. Vegetables were found to have the highest median levels of foods, attributed to elevated water content in leafy vegetables and facile solubility of perchlorate in water. The relatively low levels of perchlorate in food compared to other studies could attribute to the fact that the period of food we purchased in this study was during the wet season while the contaminants, such as perchlorate, were diluted. The maximum hazard quotient (HQ) values for all residents consuming different foods and water were all higher than 1 This suggested that there is a potential health risk of perchlorate to residents in South China. Those may be attributed to the high levels of perchlorate in some individual samples of meat and eggs. However, the 95th percentile of HQ values in all residents was less than 1, indicating that there is no potential health risk of perchlorate to most residents in South China.

Intestinal microbiota composition is predictive of radiotherapy-induced acute gastrointestinal toxicity in prostate cancer patients

The search for factors beyond the radiotherapy dose that could identify patients more at risk of developing radio-induced toxicity is essential to establish personalised treatment protocols for improving the quality-of-life of survivors. To investigate the role of the intestinal microbiota in the development of radiotherapy-induced gastrointestinal toxicity, the MicroLearner observational cohort study characterised the intestinal microbiota of 136 (discovery) and 79 (validation) consecutive prostate cancer patients at baseline radiotherapy. Gastrointestinal toxicity was assessed weekly during RT using CTCAE. An average grade >1.3 over time points was used to identify patients suffering from persistent acute toxicity (endpoint). The microbiota of patients was quantified from the baseline faecal samples using 16S rRNA gene sequencing technology and the Ion Reporter metagenomic pipeline. Statistical techniques and computational and machine learning tools were used to extract, functionally characterise, and predict core features of the bacterial communities of patients who developed acute gastrointestinal toxicity. Analysis of the core bacterial composition in the discovery cohort revealed a cluster of patients significantly enriched for toxicity, displaying a toxicity rate of 60%. Based on selected high-risk microbiota compositional features, we developed a clinical decision tree that could effectively predict the risk of toxicity based on the relative abundance of genera Faecalibacterium, Bacteroides, Parabacteroides, Alistipes, Prevotella and Phascolarctobacterium both in internal and external validation cohorts. We provide evidence showing that intestinal bacteria profiling from baseline faecal samples can be effectively used in the clinic to improve the pre-radiotherapy assessment of gastrointestinal toxicity risk in prostate cancer patients. Italian Ministry of Health (Promotion of Institutional Research INT-year 2016, 5 × 1000, Ricerca Corrente funds). Fondazione Regionale per la Ricerca Biomedica (ID 2721017). AIRC (IG 21479).

Studies on uranium concentration in groundwater samples and its associated health hazards to the residents of surrounding regions of Manchanabele reservoir, Bengaluru, Karnataka, India.

Uranium occurs naturally in groundwater and surface water. Being a radioactive element, high uranium concentration can cause impact on human health. The health effects associated with consumption of uranium through water includes increased cancer risk and kidney toxicity. In view of this, an attempt was made in the present study to establish the level of radiological and chemical toxicity of uranium. Radiological toxicity was evaluated in terms of lifetime cancer risk and chemical toxicity through hazard quotient. For the said purpose, groundwater samples from the selected villages of the surrounding region of the Manchanabele reservoir, southwest of Bengaluru, were collected. The collected groundwater samples were analysed for Uranium mass concentration using Light emitting diode (LED) fluorimeter and is found to range from 0.88 to 581.47ppb with a GM of 20.82ppb. The result reveals that ~ 66% of the samples show concentration of uranium within the safe limit of 30ppb as set by the World Health Organisation. The radiological risk estimated in terms of lifetime cancer risk is in the range of 0.0028 × 10-3 to 1.85 × 10-3 with a GM of 0.066 × 10-3. The chemical toxicity risk measured as lifetime annual daily dose is found to range from 0.03 to 21.65μg per kg per d with a GM of 0.77μg per kg per d.

Insight into enhancing the performance of sludge dewatering using a novel flocculant CS–TA prepared through free radical-mediated conjugation

ABSTRACT Flocculation is one of the most significant conditioning methods for sludge dewatering. In the study, a novel flocculant CS–TA, prepared through free radical-mediated conjugation of tannic acid (TA) and chitosan (CS), was proposed to improve sludge dewatering. The characterisation using Fourier transform infra-red spectroscopy and X-ray diffraction analysis shows that the CS chain was the backbone of CS–TA, and the presence of CS–TA aromatic rings confirmed the conjugation of CS with TA. Moreover, the conditioning of CS–TA yielded the best dewatering performance at 30 mg g TS−1 with the water content of sludge cake by press filtration (Wsc) of 59.78% ± 0.3% and capillary suction time (CST) of 11.8s ± 0.35 s, compared to 98.2% ± 0.15% and 56.2 s ± 0.16 in raw sludge. The results of different influencing factors (e.g. pH and temperature) on flocculation efficiency indicated that CS–TA possessed the capacity for enhancing sludge dewaterability over a wide range of pH, and the optimal temperature was observed to be 35 °C. Furthermore, the increase of particle size and zeta potential implied the addition of CS–TA favoured the formation of larger particles charge neutralisation and adsorption bridging effect. In addition, extracellular polymer substances (EPS) analysis indicated that the decrease in the polysaccharide and protein contents in EPS after CS–TA addition could increase the relative hydrophobicity of sludge. Moreover, the contents of heavy metals in sludge and their leaching toxicity and environmental risk were reduced. This study provides comprehensive insights into the exploration of CS–TA for sludge dewatering and the maintenance of ecological security in an eco-friendly.

Pharmacogenomic Assessment of Genes Implicated in Thiopurine Metabolism and Toxicity in a UK Cohort of Pediatric Patients With Inflammatory Bowel Disease.

Thiopurine drugs are effective treatment options in inflammatory bowel disease and other conditions but discontinued in some patients due to toxicity. We investigated thiopurine-induced toxicity in a pediatric inflammatory bowel disease cohort by utilizing exome sequencing data across a panel of 46 genes, including TPMT and NUDT15. The cohort included 487 patients with a median age of 13.1 years. Of the 396 patients exposed to thiopurines, myelosuppression was observed in 11%, gastroenterological intolerance in 11%, hepatotoxicity in 4.5%, pancreatitis in 1.8%, and "other" adverse effects in 2.8%. TPMT (thiopurine S-methyltransferase) enzyme activity was normal in 87.4%, intermediate 12.3%, and deficient in 0.2%; 26% of patients with intermediate activity developed toxicity to thiopurines. Routinely genotyped TPMT alleles associated with defective enzyme activity were identified in 28 (7%) patients: TPMT*3A in 4.5%, *3B in 1%, and *3C in 1.5%. Of these, only 6 (21%) patients developed toxic responses. Three rare TPMT alleles (*3D, *39, and *40) not assessed on routine genotyping were identified in 3 patients, who all developed toxic responses. The missense variant p.R139C (NUDT15*3 allele) was identified in 4 patients (azathioprine 1.6mg/kg/d), but only 1 developed toxicity. One patient with an in-frame deletion variant p.G13del in NUDT15 developed myelosuppression at low doses. Per-gene deleteriousness score GenePy identified a significant association for toxicity in the AOX1 and DHFR genes. A significant association for toxicity was observed in the AOX1 and DHFR genes in individuals negative for the TPMT and NUDT15 variants. Patients harboring the NUDT15*3 allele, which is associated with myelosuppression, did not show an increased risk of toxicity.

Comparison of Weight-Based Valproic Acid Dosing in Treatment of Mental Illness Among Obese and Nonobese Patients.

A weight-based dosing approach of 20-30 mg/kg per day of valproic acid (VPA) has been shown to achieve rapid attainment of mood symptom control. Due to interindividual pharmacokinetic variability, therapeutic drug monitoring may be a useful tool to avoid VPA toxicity. Limited research exists on the impact of patient body weight on VPA pharmacokinetic profiles. This analysis aims to explore the correlation between steady-state serum levels of VPA and weight-based dosing strategies, including total body weight (TBW), ideal body weight (IBW), and adjusted body weight (AdjBW), between obese and nonobese patients. This single-center, retrospective, observational cohort analysis evaluated weight-based dosing of VPA in obese and nonobese patients admitted to inpatient psychiatry at a large academic medical center between July 1, 2017, and July 1, 2022. This analysis included 93 obese and 93 nonobese patients. No significant difference in median VPA serum concentrations was observed between groups ( P = 0.82). However, the obese group received a lower median weight-based dose (15.6 mg/kg) compared with the nonobese group (19.5 mg/kg, P < 0.001). A stronger correlation was found between VPA dose and therapeutic serum levels in the obese group compared with the nonobese group regardless of weight-based dosing strategy. Dosing with AdjBW in obese patients most closely approximated dosing with TBW in nonobese patients. In obese patients, our analysis suggests dosing VPA using AdjBW may be considered as the preferred dosing strategy over IBW or TBW to minimize toxicity risk. Further research is needed with larger sample sizes and diverse patient populations to confirm these findings.

Impact of age on safety of Busulfan-Melphalan followed by autologous hematopoietic stem-cell transplantation versus standard chemotherapy in the patients of the EURO-E.W.I.N.G. 99 and Ewing 2008 clinical trials

IntroductionEwing sarcoma (ES), is a rare cancer affecting children, adolescents and adults. After VIDE (vincristine-ifosfamide-doxorobucin-etoposide) induction chemotherapy, Busulfan-Melphalan (BuMel) high-dose chemotherapy followed by autologous hematopoietic stem cells transplantation improved outcomes in unfavourable localized ES, but with more toxicities than conventional chemotherapy (VAI: Vincristine-dactinomycin-Ifosfamide). We evaluated whether the risk of acute toxicity associated with BuMel compared to VAI varied according to age in patients recruited in the R2Loc and R2Pulm randomised trials of the Euro-E.W.I.N.G.99 and Ewing-2008 trials. MethodsWe included patients with a localized high-risk disease, or pulmonary or pleural metastasis. We analysed the risk of severe toxicity according to randomised treatment group (VAI versus BuMel) and age group (<12 years, 12–17 years, 18–24 years, ≥25 years). We evaluated the heterogeneity of treatment effects by age group using interaction terms in logistic multivariable models. ResultsThe analysis included 243 patients treated with VAI and 205 with BuMel. Overall, BuMel was associated with a higher risk of severe acute toxicity than VAI particularly haematological, gastrointestinal, liver, sinusoidal occlusive syndrome, and infections. Severe haematological toxicity and lower general condition were significantly more frequent in younger patients, whatever treatment. We did not observe any significant heterogeneity in terms of the excess risk of severe toxicities associated with BuMel compared to VAI according to age group. ConclusionThe excess of acute toxicity associated with BuMel compared to VAI does not vary significantly with age, suggesting the feasibility of BuMel across all age groups.

Designing Microneedle Patch for Prophylaxis of Postoperative Atrial Fibrillation.

Postoperative atrial fibrillation (POAF) is a common complication following cardiac surgery, which often occurs within 30 postoperative days, especially peaking at 2-3 days. Antiarrhythmic medications such as amiodarone are recommended in clinical practice for the prophylaxis and treatment of POAF. However, conventional oral administration is hindered due to delayed drug action and high risks of systemic toxicity, and emerging localized delivery strategies suffer from a limited release duration (less than 30 days). Herein, we develop a microneedle (MN) patch for localized delivery of amiodarone to the atria in a "First Rapid and Then Sustained" dual-release mode. Specifically, this patch is composed of a needle array integrated with an amiodarone-loaded reservoir for a sustained and steady release for over 30 days; and an amiodarone-containing coating film deposited on the needle surface via the Langmuir-Blodgett technique for a rapid release at the first day. Upon this design, only one MN patch enables a higher drug accumulation in the atrial tissue at the first day than oral administration and simultaneously remains therapeutical levels for over 30 days, despite at a significantly reduced drug dosage (5.08 mg in total versus ∼10 mg per day), thereby achieving ideal preventive effects and safety in a rat model. Our findings indicate that this MN device provides a robust and efficient delivery platform for long-term prophylaxis of POAF.

Development and Validation of a Prediction Model for Thyroid Dysfunction in Patients During Immunotherapy

ObjectiveThis study was designed to develop and validate a predictive model for assessing the risk of thyroid toxicity following treatment with immune checkpoint inhibitors. MethodsA retrospective analysis was conducted on a cohort of 586 patients diagnosed with malignant tumors who received programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors. The patients were randomly divided into training and validation cohorts in a 7:3 ratio. Logistic regression analyses were performed on the training set to identify risk factors of thyroid dysfunction, and a nomogram was developed based on these findings. Internal validation was performed using K-fold cross-validation on the validation set. The performance of the nomogram was assessed in terms of discrimination and calibration. Additionally, decision curve analysis was utilized to demonstrate the decision efficiency of the model. ResultsOur clinical prediction model consisted of 4 independent predictors of thyroid immune-related adverse events, namely baseline thyrotropin (TSH, OR = 1.427, 95%CI:1.163-1.876), baseline thyroglobulin antibody (TgAb, OR = 1.105, 95%CI:1.035-1.180), baseline thyroid peroxidase antibody (TPOAb, OR = 1.172, 95%CI:1.110-1.237), and baseline platelet count (platelet, OR = 1.004, 95%CI:1.000-1.007). The developed nomogram achieved excellent discrimination with an area under the curve of 0.863 (95%CI: 0.817-0.909) and 0.885 (95%CI: 0.827-0.944) in the training and internal validation cohorts respectively. Calibration curves exhibited a good fit, and the decision curve indicated favorable clinical benefits. ConclusionThe proposed nomogram serves as an effective and intuitive tool for predicting the risk of thyroid immune-related adverse events, facilitating clinicians making individualized decisions based on patient-specific information.

Hydrogel encapsulation facilitates a low-concentration cryoprotectant for cryopreservation of mouse testicular tissue

Cryopreserved testicular tissue offers a promising method to restore fertility in male infertility patients. Current protocols rely on high concentrations of penetrating cryoprotectants (pCPAs), such as dimethyl sulfoxide (DMSO), which necessitating complex washing procedures and posing risks of toxicity. Hydrogel encapsulation presents a non-toxic alternative for cellular cryopreservation. This study investigates the effects of various types, concentrations, and thicknesses of hydrogel encapsulation on the cryopreservation of mouse testicular tissue. Testicular tissues loaded with varying concentrations of DMSO were encapsulated in alginate or gelatin-methacryloyl (GelMA) hydrogels. We evaluated hydrogels as potential CPAs to reduce pCPA concentrations and determine optimal combinations for cryopreservation. Post-cryopreservation, tissues were cultured using organ culture methods to assess spermatogenesis progression. Cryomicroscopy and differential scanning calorimetry (DSC) were used to examine ice crystal formation, melting enthalpy, and non-freezing water content in different hydrogels during cooling. Results indicate that 3 % alginate or 5 % GelMA hydrogel with thin encapsulation optimally preserves mouse testicular tissue. Using 20 % DMSO in 5 % GelMA thin encapsulation showed comparable apoptosis rates, improved morphology, higher mitochondrial activity, and enhanced antioxidant capacity compared to conventional 30 % DMSO without encapsulation. This suggests that hydrogel encapsulation reduces pCPA concentration by 10 %, thereby mitigating toxic damage. Hydrogel encapsulation can reduce basement membrane shrinkage of testicular tissue during cryopreservation. Moreover, frozen tissues remained viable with preserved germ cells after being cultured for one week on alginate methacryloyl (AlgMA) hydrogel using the gas-liquid interphase method. Cryomicroscopy and DSC studies confirmed the hydrogel's ability to inhibit ice crystal growth. In conclusion, this study introduces novel strategies for male fertility preservation and advances cryopreservation technology for clinical applications in assisted reproduction.