Risk Of Toxicity Research Articles

Genetic ancestry proportion influences risk of adverse events from tuberculosis treatment in Brazil.

Tuberculosis (TB) treatment is highly effective, but response to therapy can vary by geography, race, and ethnicity. We assessed for differences in TB treatment response in a representative and heterogeneous Brazilian population. We estimated genetic ancestry proportion according to major ancestry groups (African, European, and Amerindian ancestry) in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort. RePORT-Brazil is an observational prospective cohort study of individuals with newly-diagnosed, culture-confirmed, pulmonary TB. TB treatment outcomes that were attributed to TB treatment included Grade 2 or higher adverse drug reaction (ADR), Grade 3 or higher ADR, hepatic ADR, and failure/recurrence. Ancestry proportion was the main predictor in logistic regression for each outcome, with adjustments for candidate confounders. There were 941 pulmonary TB patients included in this study. We observed a decreased risk of Grade 2+ ADR when African ancestry proportion increased by 10% (Odds Ratio [OR] 0.41, 95% Confidence Interval [CI] 0.20 -0.85) and an increased risk for Grade 2+ ADR with increasing European ancestry (OR 2.84, 95% CI 1.47 - 5.48). We then performed the same analysis adding HIV status as an interaction term. The decreased risk for Grade 2+ ADR seen for African ancestry proportion did not hold for persons living with HIV; we observed increased risk for Grade 2+ ADR with increasing African ancestry proportion. There were no associations with Amerindian ancestry or for other treatment outcomes. In this Brazilian TB cohort, toxicity risk was associated with African and European ancestry, divergent, and affected by HIV. #RePORT-Brazil Consortium members include: Aline Benjamin and Flavia M. Sant'Anna Instituto Nacional de Infectologia Evandro Chagas, Fiocruz, Rio de Janeiro, Brazil Jamile Garcia de Oliveira and João Marine Clínica de Saúde Rinaldo Delmare, Rio de Janeiro, Brazil Adriana Rezende and Anna Cristina Carvalho Secretaria de Saúde de Duque de Caxias, Rio de Janeiro, Brazil Michael Rocha and Betânia Nogueira Instituto Brasileiro para Investigação da Tuberculose, Fundação José Silveira, Salvador, Brazil Alexandra Brito and Renata Spener Fundação Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil Megan Turner Vanderbilt University Medical Center, Nashville, USA.

Stereotactic body radiotherapy in ultracentrally located lung tumors

Stereotactic body radiotherapy (SBRT) is a highly conformal radiotherapy technique that delivers high doses of radiation per fraction, typically in 1 – 5 fractions. It is a standard treatment option for patients with early-stage non-small cell lung cancer that is peripherally located, for those who are medically inoperable, or for patients who do not opt for surgery. Similarly, SBRT is considered an effective treatment option for oligometastatic lung tumors. However, in the case of ultracentrally located lung tumors—tumors situated close to the central airway and mediastinal region—there is an increased risk of severe toxicities (grade 4 – 5) due to the dose tolerances of the surrounding organs at risk. The definition of ultracentrally located lung tumors remains unclear. Some studies define an ultracentral lung tumor as one in which the gross tumor volume directly involves the proximal bronchial tree or trachea, while others define it as the planning target volume (PTV) that includes the trachea or main bronchial system. In addition, some studies consider tumors whose PTV touches or overlaps with the central bronchial tree, esophagus, pulmonary vein, or pulmonary artery as ultracentral. In addition, the optimal SBRT regime and organ-at-risk dose limitations for ultracentral tumors have yet to be clearly established. The aim of this review is to explore and discuss the role of SBRT in the treatment of ultracentrally located lung tumors.

Ecotoxicological study of seven pharmaceutically active compounds: Mixture effects and environmental risk assessment

Pharmaceutically active compounds (PhACs) have been detected in several aquatic compartments, which has been of environmental concern since PhACs can cause adverse effects on the aquatic ecosystem at low concentrations. Despite the variety of PhACs detected in surface water, ecotoxicological studies are non-existent for many of them, mainly regarding their mixture. In addition, water bodies can continuously receive the discharge of raw or treated wastewater with micropollutants. Thus, PhACs are subject to mixture and interactions, potentiating or reducing their toxicity. Therefore, the present study evaluated the toxicity on Aliivibrio fischeri of seven PhACs, which still needs to be explored in the literature. The effects were evaluated for the PhACs individually and for their binary and tertiary mixture. Also, the experimental effects were compared with the concentration addition (CA) and independent action (IA) models. Finally, an environmental risk assessment was carried out. Fenofibrate (FEN), loratadine (LOR), and ketoprofen (KET) were the most toxic, with EC50 of 0.32 mg L-1, 6.15 mg L-1 and 36.8 mg L-1, respectively. Synergistic effects were observed for FEN + LOR, KET + LOR, and KET + FEN + LOR, showing that the CA and IA may underestimate the toxicity. Environmental risks for KET concerning algae, and LOR e 17α-ethynylestradiol (EE2) for crustaceans and fish were high for several locations. Besides, high removals by wastewater treatment technologies are required to achieve the concentrations necessary for reducing KET and LOR risk quotients. Thus, this study contributed to a better understanding of the toxic interactions and environmental risks of PhACs.

Degradation of the novel herbicide tiafenacil in aqueous solution: Kinetics, various influencing factors, hydrolysis products identification, and toxicity assessment

As new pesticides are continually introduced into agricultural systems, understanding their environmental behavior and potential toxicity effects is crucial for effective risk assessment. This study utilized QuEChERS and UPLC-QTOF-MS/MS techniques to analyze Tiafenacil (TFA) and its six hydrolysis products (HP1 to HP6) in water, marking the first comprehensive report on these degradation products. Calibration curves demonstrated strong linearity (R2 ≥ 0.9903) across concentrations ranging from 0.02 to 3.50 mg L−1. TFA's hydrolysis followed single first-order kinetic (SFOK) model, with rapid degradation observed under alkaline and high-temperature conditions, resulting in half-lives ranging from 0.22 to 84.82 days. The ECOSAR model predicts that TFA's hydrolysis products exhibit acute and chronic toxicity to fish, Daphnia, and green algae. Additionally, hydrolysis products HP1, HP5, and HP6 were detected in irrigation water from citrus orchards, posing higher predicted toxicity risks to fish and green algae. This highlights the necessity for further risk assessments considering transformation products. Overall, this study enhances our understanding of TFA's environmental fate and supports its safe agricultural application and monitoring practices.

Effects of cadmium stress on the growth, physiology, mineral uptake, cadmium accumulation and fruit quality of 'Sharpblue' blueberry

Cadmium (Cd) contamination is becoming a widespread environmental problem, and Cd toxicity risk is increasing in blueberries, typical acidophilous plants. However, studies on the physiological mechanisms of Cd toxicity affecting the growth of blueberry plants and fruits remain limited. Herein, a pot experiment involving four treatments, CK (0 mg·kg−1), Cd1 (2.5 mg·kg−1), Cd2 (15 mg·kg−1) and Cd3 (50 mg·kg−1), was conducted to investigate the effects of Cd stress on the growth, fruit quality, physiological characteristics, mineral composition and Cd uptake of 'Sharpblue' blueberry cuttings, and relationships between physicochemical indices and phenotypic data under Cd stress were analyzed via principal component analysis and Mantel's test. Compared with CK, Cd treatment led to chlorosis (decrease in SPAD and N content) in 'Sharpblue' leaves and inhibited increases in plant height, basal stem, crown width and biomass (dry weight), with the most significant changes in the 50 mg·kg−1 Cd treatment. The size and thickness of the upper epidermal cells, as well as the thickness of the palisade mesophyll and spongy tissues of 'Sharpblue' were significantly reduced at Cd > 15 mg·kg−1, while the density of stomata was significantly increased. Moreover, Cd stress reduced the yield (decrease in size and single-fruit weight) and quality (decrease in anthocyanin, flavonoid and total phenol content and increase in titratable acid content) of 'Sharpblue' fruits, and Cd content in fruit exceeded the Chinese food safety threshold of 0.05 mg·kg−1 when Cd > 15 mg·kg−1. The Cd enrichment capacity of different organs of 'Sharpblue' plants was in the following order: root > shoot > leaf > fruit, and the 50 mg·kg−1 Cd treatment significantly inhibited the uptake of Fe, Mn, Cu, and Zn. Additionally, 'Sharpblue' plants responded to H2O2 and malondialdehyde accumulation in different organs under Cd stress by regulating levels of osmoregulatory substances (soluble protein (SP), soluble sugar, and proline) and altering the activities of catalase, superoxide dismutase, ascorbic acid, and glutathione in the antioxidant system. Finally, correlation analysis revealed that Mg, Fe, Mn, Cu, Cd, H2O2, SP, SPAD, N, anthocyanin, titratable acid, flavonoids, and total phenols were strongly correlated with 'Sharpblue' growth, leaf and fruit phenotype under Cd stress. These findings provide theoretical information for soil safety management and the breeding of Cd-tolerant cultivars during blueberry cultivation, as well as for the study of Cd stress response mechanisms in acidophilous plants.

UK national observational cohort study investigating Tolerance of Anti-cancer Systemic Therapy in the Elderly: the TOASTIE study

ObjectiveThe Cancer and Aging Research Group (CARG) score was developed to predict severe chemotherapy-induced toxicity risk in older adults; validation study results have varied. The Tolerance of Anti-cancer Systemic Therapy...

GSK-3β and Non-Small Cell Lung Cancer: A Review of Its Role in Disease Mechanisms and Treatment Strategies

Introduction Recent molecular docking studies have identified potential inhibitors targeting GSK-3β, offering promising avenues for therapeutic intervention. These inhibitors could potentially disrupt the oncogenic signaling pathways mediated by GSK-3β, thereby halting or reversing tumor progression. This literature review seeks to deliver a thorough examination of the current knowledge regarding GSK-3β influence on NSCLC. Methods The author carried out an extensive literature review utilizing various electronic databases such as PubMed, Scopus, and Europe PMC. The search keywords included "GSK-3β," "glycogen synthase kinase-3 beta," "non-small cell lung cancer," "NSCLC," "prognosis," "apoptosis," "cell proliferation," "autophagy," "radiosensitivity," "tumor differentiation," and "molecular docking." The findings from the included studies were integrated into a narrative review, emphasizing GSK-3β role in NSCLC pathogenesis, its potential as a therapeutic target, and its utility as a prognostic biomarker. Results GSK-3β is a multifunctional serine/threonine kinase involved in various cellular processes, including proliferation, differentiation, motility, and survival. Its expression is associated with NSCLC differentiation, with GSK-3β-negative tumors showing better prognosis. Preclinical studies have identified potential GSK-3β inhibitors with favorable docking scores and ADME profiles for NSCLC treatment. However, targeting GSK-3β for NSCLC treatment faces several significant challenges. One major issue is the broad role of GSK-3β in various cellular processes, including metabolism and cell survival, which increases the risk of off-target effects and toxicity. Conclusions GSK-3β has emerged as a critical biomarker in NSCLC, exerting a significant impact on disease progression, treatment response, and prognosis.

Pediatric Neem powder poisoning: a report of two cases and a review of toxicity mechanisms

Neem (Azadirachta indica) is a plant known for its wide array of therapeutic properties, derived from its diverse phytochemical makeup. Despite its medicinal benefits, neem can pose significant toxicity risks, especially in children. This report presents two pediatric cases of neem powder poisoning. The first case involves a two-year-old boy who ingested neem powder with milk, resulting in seizures and fatal cardiac arrest. The second case describes a six-year-old boy who experienced vomiting after consuming neem powder with milk. Prompt medical intervention, including gastric lavage and supportive care, led to his stabilization and discharge. Neem’s toxicity is attributed to compounds like azadirachtin, which disrupt mitochondrial function, leading to symptoms such as seizures, vomiting, and hepatic stress. These cases highlight the importance of recognizing the potential dangers of neem and underscore the need for public health education and regulatory oversight to prevent such adverse outcomes in pediatric populations.

Distribution, source apportionment and ecological risk assessment of heavy metals in Limbe River sediments, Atlantic Coast, Cameroon Volcanic Line

The objective of this research was to assess sediments contamination, provenance and metal pollution using single and complex pollution indicators. Limbe River sediment samples were analysed using Inductively Coupled Plasma—Mass Spectrometry. The Limbe River sediments exhibit high content in Fe2O3 sourced from haematization of basaltic rocks. The concentration of Cd, Co, Cr, Mn, Ni, Pb, Sn, Sr, V and Zn exceed upper continental crust and local baseline values for heavy metals. Correlation matrix analysis indicates the presence of common input sources and similar geochemical characteristics of heavy metals. Contamination factor (CF: 0.01–10.34), contamination degree (Cdeg: 14.91–36.57), pollution load index (PLI: 0.84–1.77), and nemerow integrated pollution index (NIPI: 0.2–1.7) indicates significant to high levels of contamination. The enrichment factor (EF: 0–5.67) and geo-accumulation index (Igeo: -7.55–2.59), suggests moderate to significant metal pollution of the Limbe River ecosystem, suggesting potential ecological effects. Modified hazard quotient (mHQ: 0.082–6.35) and toxic risk index (TRI: 10.49–27.43), indicates low to extreme pollution severity and high toxicity risks of heavy metals to the aquatic ecosystem fauna and flora. Primarily anthropogenic activities and secondary lithogenic provenance is attributed to sediments contamination and metals pollution. This study suggests that a greater emphasis should be placed on monitoring various provenances of metals entering the aquatic ecosystem from anthropogenic practices. The study emphasizes the significance of continual protection of aquatic ecosystem and biological resources and adaptive management. The development of reasonable goals for monitoring and remedial programmes can be aided by this data.

Exploring the Prospects and Challenges of Fluorine-Free Firefighting Foams (F3) as Alternatives to Aqueous Film-Forming Foams (AFFF): A Review.

This review provides a comparative analysis of the performance, toxicity, environmental impact, and health risks associated with fluorotelomer-based/short-chain AFFF and F3. Despite notable progress in F3 development, achieving comparable performance remains challenging in some cases. F3 formulations, while promising, are yet to be considered a direct replacement for AFFF in all Class B fire suppression scenarios due to variations in their performance across different fuel types and test conditions. Available studies indicate that commercially available F3 exhibit greater biodegradability and reduced environmental persistence compared to AFFF. However, some alternatives may still pose similar environmental impacts. Limited ecotoxicity studies suggest that some F3 may exhibit equal or even higher toxicity to aquatic species than short-chain (C6) AFFF. Toxicological assessments and risk evaluations of F3 should consider factors beyond environmental persistence, including acute and chronic ecotoxicity, potential endocrine disruption, and the full toxicological profile of foam formulations and their individual components. Further research is necessary to understand the fate, transport, bioaccumulation, and toxicity of F3 degradation products. Addressing these knowledge gaps is crucial to ensure the safe and sustainable implementation of F3 as an alternative fire suppression solution.

Next-generation pediatric care: nanotechnology-based and AI-driven solutions for cardiovascular, respiratory, and gastrointestinal disorders.

Global pediatric healthcare reveals significant morbidity and mortality rates linked to respiratory, cardiac, and gastrointestinal disorders in children and newborns, mostly due to the complexity of therapeutic management in pediatrics and neonatology, owing to the lack of suitable dosage forms for these patients, often rendering them "therapeutic orphans". The development and application of pediatric drug formulations encounter numerous challenges, including physiological heterogeneity within age groups, limited profitability for the pharmaceutical industry, and ethical and clinical constraints. Many drugs are used unlicensed or off-label, posing a high risk of toxicity and reduced efficacy. Despite these circumstances, some regulatory changes are being performed, thus thrusting research innovation in this field. Up-to-date peer-reviewed journal articles, books, government and institutional reports, data repositories and databases were used as main data sources. Among the main strategies proposed to address the current pediatric care situation, nanotechnology is specially promising for pediatric respiratory diseases since they offer a non-invasive, versatile, tunable, site-specific drug release. Tissue engineering is in the spotlight as strategy to address pediatric cardiac diseases, together with theragnostic systems. The integration of nanotechnology and theragnostic stands poised to refine and propel nanomedicine approaches, ushering in an era of innovative and personalized drug delivery for pediatric patients. Finally, the intersection of drug repurposing and artificial intelligence tools in pediatric healthcare holds great potential. This promises not only to enhance efficiency in drug development in general, but also in the pediatric field, hopefully boosting clinical trials for this population. Despite the long road ahead, the deepening of nanotechnology, the evolution of tissue engineering, and the combination of traditional techniques with artificial intelligence are the most recently reported strategies in the specific field of pediatric therapeutics.

Pear Wood Pyrolysis Influences Quality and Levels of Polycyclic Aromatic Hydrocarbons in Liquid Smoke

Limu smoked chicken is a traditional Chinese delicacy; however, polycyclic aromatic hydrocarbons (PAHs) are generated during the smoking process. We developed a pyrolysis process for pear wood liquid smoke with minimal PAH generation. Pear wood liquid smoke products were prepared under different pyrolysis conditions in a self-made pyrolysis reactor, and the total phenol, carbonyl compound, total acid, and PAH contents and PAH toxicity risk were evaluated. With increasing temperatures, the toxicity equivalent ΣPAH of the smoke liquid reached 3.004 μg/kg. With increasing particle sizes, the total phenol content reached 1.6 mg/mL; the phenol content was 5.95 mg/mL. With increasing particle sizes, the toxicity equivalent ΣPAHs of the smoke liquor reached 2.441 μg/kg. The optimal parameters for treating pear wood smoke liquid in the thermal reaction device were a pyrolysis temperature of pear wood of >350 °C, particle size of S2, and sucrose content of 8%.

Importance of glycoalkaloids analysis (α-solanine and α-chaconine) derived from potato consumption in pre-Hispanic inhabitants of the Americas

In the pre-Columbian societies of the Americas, a wide range of food practices was observed. However, several countries shared certain staple foods, such as the potato, which has held a significant place in the diet since ancient times. It is important to note that potatoes contain glycoalkaloids, a class of alkaloids with potential toxicity risks when consumed in high concentrations by both humans and animals. This study aims to offer guidance on the presence of glycoalkaloids in potatoes and proposes further research into these compounds in archaeological remains that were utilized as food across all American countries. This recommendation stems from the dearth of studies on this subject, particularly in cases where archaeological discoveries include potato starch granules. In this study, various databases were examined to discover historical insights into the potato and to elucidate the primary aspects of glycoalkaloid chemistry associated with this tuber. The findings underscore the crucial role played by the potato in pre-Columbian cultures of the Americas, particularly in the regions situated along the Andes mountain range. Furthermore, the analysis of its nutritional composition unveiled the prevalence of two key glycoalkaloids in the tuber: α-solanine and α-chaconine. In this research, a comprehensive review of the chemical properties, botanical functions, human metabolism, potential health effects, toxicity thresholds, and available analytical techniques for the detection and quantification of toxic compounds was conducted. The significance of identifying these molecules in archaeological contexts was highlighted, as their presence may prompt investigations into prevalent diseases among historical populations.

In vivo toxicity of upconversion nanoparticles (NaYF4:Yb, Er) in zebrafish during early life stages: Developmental toxicity, gut-microbiome disruption, and proinflammatory effects

Lanthanide-doped upconversion nanoparticles (Ln-UCNPs) have been considered promising materials for various fields, such as biomedical and industrial applications. However, data and reports regarding its toxicity and environmental risks are scarce. Under these circumstances, data must be obtained to fully understand potential toxicity and adverse outcome pathways. In the present study, the toxicity of uncoated Ln-UCNP cores (NaYF4:Yb, Er) was systematically assessed in zebrafish embryos during early developmental stages. Ln-UCNPs were found to have multiple toxic effects, such as effects on survival rates, delayed hatching times, shorter body lengths, altered heart rates and blood circulation (significantly reduced), and neurobehavioral impairments in response to photoperiod stimulation. Bioimaging showed that Ln-UCNPs were distributed on the chorion, eyes, and skin at 72 hpf. However, it accumulates in the pharynx, esophagus, and intestine after oral administration. Ln-UCNPs disrupt the diversity and abundance of host-associated microorganisms (gut microbiota) leading to an increase in the prevalence of harmful bacteria in zebrafish. Transcriptomic and Ingenuity Pathway Analysis (IPA) predicted Interleukin-8 (IL-8) signaling, neuroinflammation, cardiac hypertrophy signaling pathways, immune and inflammation-related response interferon-gamma (ifnγ), and miR-155 as key mediators in regulatory effects. Based on this, a causal network was built showing the strong links between the induced gene expression of differentially expressed genes (DEGs), such as nitric oxide synthase 2 (nos2) and tumor necrosis factor (tnf) upon Ln-UCNPs treatment, and with the downstream adverse outcomes, in particular, the promotion of apoptosis, liver damage, and inflammatory response. Finally, RT-qPCR analysis confirmed the up-regulated expression of nos2 and tnf in the exposed larvae, consistent with the observation of an increased number of fluorescence-labelled neutrophils and macrophages in lyz: DsRed transgenic zebrafish until 120 hpf exposure, which together demonstrated the proinflammatory effects of Ln-UCNPs on organisms. In conclusion, we illustrated the developmental toxicity, disruption of gut-microbiome, and proinflammatory effects of Ln-UCNP cores on zebrafish, and the causal network from IPA analysis may help further elucidate the adverse outcome pathway of Ln-UCNPs.

Long-term Results of Hypofractionated Radiotherapy With Intra-prostatic Boosts in Men With Intermediate- and High-risk Prostate Cancer: A Phase II Trial

AimsIn the conventionally fractionated phase III FLAME prostate trial, focal boosts improved local control and biochemical disease-free survival (bDFS). We explored the toxicity and effectiveness of a moderately hypofractionated schedule with focal boosts. Material and methodsBIOPROP20 is a phase II single-arm non-randomised trial for intermediate- to very high-risk localised prostate cancer patients with bulky tumour volumes. Multi-parametric magnetic resonance imaging (MRI) and 18F-choline positron emission tomography-computed tomography (PET-CT) scans were used for staging and boost volume definition. Patients were treated with 60Gy in 20 fractions with a boost dose up to 68Gy. Five patients with positive lymph nodes on the PET-CT scan received radiotherapy to pelvic lymph nodes (45Gy to elective nodes, boosted up to 50Gy to involved nodes). Primary outcomes were acute (≤18 weeks) and late urinary and gastrointestinal toxicity, prospectively recorded up to 5 years with Common Terminology Criteria for Adverse Events v4 (CTCAE). Secondary outcomes were biochemical or clinical progression, metastasis-free survival (MFS), and overall survival (OS). Results61 patients completed radiotherapy with hormone therapy (range: 6–36 months). Cumulative acute and late gastrointestinal toxicity was low at 6.6% and 5.0%, respectively. Cumulative acute and late urinary toxicity was 49.2% and 30.1%, respectively; the prevalence reduced to 5.9% at 5 years. At 5 years: 6 patients had biochemical progression (bDFS: 88.5%; 95% CI: 80.2–97.6%), the MFS was 82.4% (95% CI: 73.0–92.9%), 5 patients died (OS: 91.2%; 95% CI: 84.1–98.9%), one with prostate cancer. The prostate, boost, nodal planning volumes, and the organs at risk (rectum, bowel, urethra, and bladder) met the optimal protocol dose constraints. There was a trend to increased urinary toxicity with increasing urethral (RR: 1.95, 95% CI: 0.73–5.22, p = 0.18), but not bladder dose. ConclusionFocal boosts with a 20 fraction hypofractionated prostate radiotherapy schedule are associated with an acceptable risk of gastrointestinal and urinary toxicity and achieve good cancer control. ClinicalTrials.gov identifierNCT02125175.

Modes of administration of nitric oxide devices and ventilators flow-by impact the delivery of pre-determined concentrations

BackgroundNitric oxide (NO) is a strong vasodilator, selectively directed on pulmonary circulation through inhaled administration. In adult intensive care units (ICU), it is mainly used for refractory hypoxemia in mechanically ventilated patients. Several medical delivery devices have been developed to deliver inhaled nitric oxide (iNO). The main purpose of those devices is to guarantee an accurate inspiratory NO concentration, whatever the ventilator used, with NO2 concentrations lower than 0.3 ppm. We hypothesized that the performances of the different available iNO delivery systems could depend on their working principle and could be influenced by the ventilator settings. The objective of this study was to assess the accuracy of seven different iNO-devices combined with different ICU ventilators’ flow-by to reach inspiratory NO concentration targets and to evaluate their potential risk of toxicity.MethodsWe tested seven iNO-devices on a test-lung connected to distinct ICU ventilators offering four different levels of flow-by. We measured the flow in the inspiratory limb of the patient circuit and the airway pressure. The nitric oxide/nitrogen (NO/N2) flow was measured on the administration line of the iNO-devices. NO and NO2 concentrations were measured in the test-lung using an electrochemical analyzer.ResultsWe identified three iNO-device generations based on the way they deliver NO flow: “Continuous”, “Sequential to inspiratory phase” (I-Sequential) and “Proportional to inspiratory and expiratory ventilator flow” (Proportional). Median accuracy of iNO concentration measured in the test lung was 2% (interquartile range, IQR -19; 36), -23% (IQR -29; -17) and 0% (IQR -2; 0) with Continuous, I-Sequential and Proportional devices, respectively. Increased ventilator flow-by resulted in decreased iNO concentration in the test-lung with Continuous and I-Sequential devices, but not with Proportional ones. NO2 formation measured to assess potential risks of toxicity never exceeded the predefined safety target of 0.5 ppm. However, NO2 concentrations higher than or equal to 0.3 ppm, a concentration that can cause bronchoconstriction, were observed in 19% of the different configurations.ConclusionWe identified three different generations of iNO-devices, based on their gas administration modalities, that were associated with highly variable iNO concentrations’ accuracy. Ventilator’s flow by significantly impacted iNO concentration. Only the Proportional devices permitted to accurately deliver iNO whatever the conditions and the ventilators tested.

Semi-supervised abdominal multi-organ segmentation by object-redrawing.

Multi-organ segmentation is a critical task in medical imaging, with wide-ranging applications in both clinical practice and research. Accurate delineation of organs from high-resolution 3D medical images, such as CT scans, is essential for radiation therapy planning, enhancing treatment outcomes, and minimizing radiation toxicity risks. Additionally, it plays a pivotal role in quantitative image analysis, supporting various medical research studies. Despite its significance, manual segmentation of multiple organs from 3D images is labor-intensive and prone to low reproducibility due to high interoperator variability. Recent advancements in deep learning have led to several automated segmentation methods, yet many rely heavily on labeled data and human anatomy expertise. In this study, our primary objective is to address the limitations of existing semi-supervised learning (SSL) methods for abdominal multi-organ segmentation. We aim to introduce a novel SSL approach that leverages unlabeled data to enhance the performance of deep neural networks in segmenting abdominal organs. Specifically, we propose a method that incorporates a redrawing network into the segmentation process to correct errors and improve accuracy. Our proposed method comprises three interconnected neural networks: a segmentation network for image segmentation, a teacher network for consistency regularization, and a redrawing network for object redrawing. During training, the segmentation network undergoes two rounds of optimization: basic training and readjustment. We adopt the Mean-Teacher model as our baseline SSL approach, utilizing labeled and unlabeled data. However, recognizing significant errors in abdominal multi-organ segmentation using this method alone, we introduce the redrawing network to generate redrawn images based on CT scans, preserving original anatomical information. Our approach is grounded in the generative process hypothesis, encompassing segmentation, drawing, and assembling stages. Correct segmentation is crucial for generating accurate images. In the basic training phase, the segmentation network is trained using both labeled and unlabeled data, incorporating consistency learning to ensure consistent predictions before and after perturbations. The readjustment phase focuses on reducing segmentation errors by optimizing the segmentation network parameters based on the differences between redrawn and original CT images. We evaluated our method using two publicly available datasets: the beyond the cranial vault (BTCV) segmentation dataset (training: 44, validation: 6) and the abdominal multi-organ segmentation (AMOS) challenge 2022 dataset (training:138, validation:16). Our results were compared with state-of-the-art SSL methods, including MT and dual-task consistency (DTC), using the Dice similarity coefficient (DSC) as an accuracy metric. On both datasets, our proposed SSL method consistently outperformed other methods, including supervised learning, achieving superior segmentation performance for various abdominal organs. These findings demonstrate the effectiveness of our approach, even with a limited number of labeled data. Our novel semi-supervised learning approach for abdominal multi-organ segmentation addresses the challenges associated with this task. By integrating a redrawing network and leveraging unlabeled data, we achieve remarkable improvements in accuracy. Our method demonstrates superior performance compared to existing SSL and supervised learning methods. This approach holds great promise in enhancing the precision and efficiency of multi-organ segmentation in medical imaging applications.

Ocular adverse events associated with antibody-drug conjugates in oncology: a pharmacovigilance study based on FDA adverse event reporting system (FAERS).

Antibody-drug conjugates (ADCs) have emerged as the focus and hotspots in the cancer field, yet the accompanying ocular toxicity has often been underestimated. We aimed to comprehensively and comparatively analyze the risk of ocular toxicity associated with various ADCs using the FDA Adverse Event Reporting System (FAERS) database. Data were extracted from the FAERS database from Q3 2011 to Q3 2023. We analyzed the clinical characteristics of ADCs-related ocular adverse events (AEs). These data were further mined by proportional analysis and Bayesian approach to detect signals of ADCs-induced ocular AEs. Moreover, the time to onset of ocular toxicity was also evaluated. A total of 1,246 cases of ocular AEs were attributed to ADCs. Ocular toxicity signals were observed in patients treated with belantamab mafodotin, brentuximab vedotin, enfortumab vedotin, mirvetuximab soravtansine, sacituzumab govitecan, trastuzumab deruxtecan, and trastuzumab emtansine. Of these, belantamab mafodotin, trastuzumab emtansine, and mirvetuximab soravtansine, whose payloads are microtubule polymerization inhibitors, were more susceptible to ocular toxicity. The ten most common ADCs-related ocular AEs signals are keratopathy [ROR = 1,273.52, 95% CI (1,129.26-1,436.21)], visual acuity reduced [ROR = 22.83, 95% CI (21.2-24.58)], dry eye [ROR = 9.69, 95% CI (8.81-10.66)], night blindness [ROR = 259.87, 95% CI (228.23-295.89)], vision blurred [ROR = 1.78, 95% CI (1.57-2.02)], photophobia [ROR = 10.45, 95% CI (9.07-12.05)], foreign body sensation in eyes [ROR = 23.35, 95% CI (19.88-27.42)], ocular toxicity [ROR = 144.62, 95% CI (117.3-178.32)], punctate keratitis [ROR = 126.21, 95% CI (101.66-156.69)], eye disorder [ROR = 2.71, 95% CI (2.21-3.32)]. In terms of onset time, sacituzumab govitecan displayed an earlier onset of 21days, while trastuzumab deruxtecan exhibited the latest onset of 223days. ADCs may increase the risk of ocular toxicity in cancer patients, leading to serious mortality. With the widespread application of newly launched ADCs, combining the FAERS data with other data sources is crucial for monitoring the ocular toxicity of ADCs. In addition, novel ocular toxicity signals not documented in product labeling were detected. Further research will be necessary to validate our findings in the future.

Saliva Lipids May Determine Alprazolam Toxicity: An FTIR Study

Background: Alprazolam, a commonly prescribed benzodiazepine, poses risks of toxicity and severe withdrawal symptoms. There is an urgent need for a rapid and sensitive diagnostic method for detecting alprazolam poisoning. Objectives: This study aimed to detect alprazolam poisoning through Fourier-transform infrared (FTIR) analysis of saliva, addressing the need for a quick, cost-effective, and sensitive diagnostic method for poison control and differential diagnosis. Methods: Saliva samples were collected from 45 individuals with benzodiazepine toxicity, therapeutic consumption, and normal health status, as well as from a control group. The samples were analyzed using FTIR spectroscopy. The resulting spectra were processed with OriginPro software, and statistical analyses were performed using receiver operating characteristic (ROC) and analysis of variance (ANOVA). Results: The average age of the studied population was approximately 45 years, with women being the most affected by poisoning. Fourier-transform infrared analysis revealed significant differences in the structure of lipids between poisoned individuals, therapeutic receivers, and healthy individuals (P < 0.0001). Conclusions: Fourier-transform infrared analysis of saliva is a fast and accurate method for diagnosing alprazolam poisoning within minutes, enabling prompt and appropriate treatment during critical life-threatening situations. This non-invasive technique has the potential to guide treatment staff toward effective treatment options.

Expanding Beyond Genetic Subtypes in B-Cell Acute Lymphoblastic Leukemia: A Pathway-Based Stratification of Patients for Precision Oncology.

Precision oncology promises individually tailored drugs and clinical care for patients with cancer: That is, "the right drug, for the right patient, at the right dose, and at the right time." Although stratification of the risk for treatment resistance and toxicity is key to precision oncology, there are multiple ways in which such stratification can be achieved, for example, genetic, functional pathway based, among others. Moving toward precision oncology is sorely needed in the case of acute lymphoblastic leukemia (ALL) wherein adult patients display survival rates ranging from 30% to 70%. The present study reports on the pathway activity signature of adult B-ALL, with an eye to precision oncology. Transcriptome profiles from three different expression datasets, comprising 346 patients who were adolescents or adults with B-ALL, were harnessed to determine the activity of signaling pathways commonly disrupted in B-ALL. Pathway activity analyses revealed that Ph-like ALL closely resembles Ph-positive ALL. Although this was the case at the average pathway activity level, the pathway activity patterns in B-ALL differ from genetic subtypes. Importantly, clustering analysis revealed that five distinct clusters exist in B-ALL patients based on pathway activity, with each cluster displaying a unique pattern of pathway activation. Identifying pathway-based subtypes thus appears to be crucial, considering the inherent heterogeneity among patients with the same genetic subtype. In conclusion, a pathway-based stratification of the B-ALL could potentially allow for simultaneously targeting highly active pathways within each ALL subtype, and thus might open up new avenues of innovation for personalized/precision medicine in this cancer that continues to have poor prognosis in adult patients compared with the children.