Beyond black-box models: explainable AI for embryo ploidy prediction and patient-centric consultation.

PURPOSE: To determine if an explainable artificial intelligence (XAI) model enhances the accuracy and transparency of predicting embryo ploidy status based on embryonic characteristics and clinical data. METHODS: This retrospective study utilized a dataset of 1908 blastocyst embryos. The dataset includes ploidy status, morphokinetic features, morphology grades, and 11 clinical variables. Six machine learning (ML) models including Random Forest (RF), Linear Discriminant Analysis (LDA), Logistic Regression (LR), Support Vector Machine (SVM), AdaBoost (ADA), and Light Gradient-Boosting Machine (LGBM) were trained to predict ploidy status probabilities across three distinct datasets: high-grade embryos (HGE, n = 1107), low-grade embryos (LGE, n = 364), and all-grade embryos (AGE, n = 1471). The model's performance was interpreted using XAI, including SHapley Additive exPlanations (SHAP) and Local Interpretable Model-agnostic Explanations (LIME) techniques. RESULTS: The mean maternal age was 38.5 ± 3.85 years. The Random Forest (RF) model exhibited superior performance compared to the other five ML models, achieving an accuracy of 0.749 and an AUC of 0.808 for AGE. In the external test set, the RF model achieved an accuracy of 0.714 and an AUC of 0.750 (95% CI, 0.702-0.796). SHAP's feature impact analysis highlighted that maternal age, paternal age, time to blastocyst (tB), and day 5 morphology grade significantly impacted the predictive model. In addition, LIME offered specific case-ploidy prediction probabilities, revealing the model's assigned values for each variable within a finite range. CONCLUSION: The model highlights the potential of using XAI algorithms to enhance ploidy prediction, optimize embryo selection as patient-centric consultation, and provides reliability and transparent insights into the decision-making process.

The nematode-trapping fungus Arthrobotrys oligospora detects prey pheromones via G protein-coupled receptors.

The ability to sense prey-derived cues is essential for predatory lifestyles. Under low-nutrient conditions, Arthrobotrys oligospora and other nematode-trapping fungi develop dedicated structures for nematode capture when exposed to nematode-derived cues, including a conserved family of pheromones, the ascarosides. A. oligospora senses ascarosides via conserved MAPK and cAMP-PKA pathways; however, the upstream receptors remain unknown. Here, using genomic, transcriptomic and functional analyses, we identified two families of G protein-coupled receptors (GPCRs) involved in sensing distinct nematode-derived cues. GPCRs homologous to yeast glucose receptors are required for ascaroside sensing, whereas Pth11-like GPCRs contribute to ascaroside-independent nematode sensing. Both GPCR classes activate conserved cAMP-PKA signalling to trigger trap development. This work demonstrates that predatory fungi use multiple GPCRs to sense several distinct nematode-derived cues for prey recognition and to enable a switch to a predatory lifestyle. Identification of these receptors reveals the molecular mechanisms of cross-kingdom communication via conserved pheromones also sensed by plants and animals.

Multivariate analysis of carcinogenic equivalence (CEQ) to characterize carcinogenic VOC emissions in a typical petrochemical industrial park in Taiwan.

Large industrial emissions of volatile organic compounds (VOCs) from the petrochemical industry are a critical concern due to their potential carcinogenicity. VOC emissions vary in composition depending on the source and occur in mixtures containing compounds with varying degrees of toxicity. We proposed the use of carcinogenic equivalence (CEQ) and multivariate analysis to identify the major contributors to the carcinogenicity of VOC emissions. This method weights the carcinogenicity of each VOC by using a ratio of its cancer slope factor to that of benzene, providing a carcinogenic equivalence factor (CEF) for each VOC. We strategically selected a petrochemical industrial park in southern Taiwan that embodies the industry's comprehensive nature and serves as a representative example. The CEQs of different emission sources in three years were analyzed and assessed using principal component analysis (PCA) to characterize the major contributing sectors, vendors, sources, and species for the carcinogenicity of VOC emissions. Results showed that while the study site exhibited a 20.7 % (259.8 t) decrease in total VOC emissions in three years, the total CEQ emission only decreased by 4.5 % (15.9 t), highlighting a potential shift in the emitted VOC composition towards more carcinogenic compounds. By calculating CEQ followed by PCA, the important carcinogenic VOC emission sources and key compounds were identified. More importantly, the study compared three approaches: CEQ followed by PCA, PCA followed by CEQ, and PCA only. While the latter two methods prioritized sources based on emission quantities, potentially overlooking less abundant but highly carcinogenic compounds, the CEQ-first approach effectively identified vendors and sources with the most concerning cancer risks. This distinction underscores the importance of selecting the appropriate analysis method based on the desired focus. Our study highlighted how prioritizing CEQ within the analysis framework empowered the development of precise control measures that address the most carcinogenic VOC sources.

Effectiveness of health education and counseling on stages of change, decisional balance, and smoking cessation self-efficacy: A prospective self-control study.

OBJECTIVE: To examine the effectiveness of health education and counseling on the stages of change, decisional balance, and smoking cessations elf-efficacy in smokers with no intention of quitting. METHODS: A prospective self-controlled design was conducted between December 2020 and December 2022. The research period was divided into a control stage (first to fourth weeks) and an experimental stage (fifth to eighth weeks). Patients with coronary artery disease (CAD) and habitually smoked were recruited. Pearson correlation and a one-factor repeated-measurement analysis were performed to assess the effectiveness of the intervention. RESULTS: In total, 108 male CAD patients with a mean age of 58.1 years were recruited. After 4 weeks of the intervention, 55 (51%) exhibited behavior change (X 2 = 18.03, p = .001). The decisional balance and smoking cessation self-efficacy scores significantly improved in the experimental stage. No significant differences were observed in the control stage. CONCLUSIONS: Four weeks of health education and counseling could effectively improve participants' stage of change, decisional balance, and smoking cessation self-efficacy. PRACTICE IMPLICATION: Healthcare professionals can play key roles in helping CAD patients successfully quit smoking through individual education and counseling.

Hepatotoxicity evaluations of different surface charged carbon quantum dots in vivo and in vitro.

Recently, carbon quantum dots (CQDs) have become popular because of their simple synthesis and potential applications. Although CQDs have high biocompatibility, their biotoxicity must be verified to reduce the possible risks associated with large-scale application. In this study, the hepatotoxicity of three CQD types, namely diammonium citrate (AC)-based (CQDs-AC), spermidine trihydrochloride (Spd)-based (CQDs-Spd), and AC- and Spd-based CQDs (CQDs-AC/Spd), were evaluated in vivo and in vitro. It was observed in vivo that CQDs-Spd and CQDs-AC/Spd, but not CQDs-AC, caused histopathological damage, including liver steatosis and mild mixed inflammatory cell infiltration; however, reduced liver function was only observed in CQD-Spd-treated mice. The in vitro results revealed that only CQDs-Spd significantly decreased the number of viable HepG2 cells (NADH depletion) and induced oxidative stress (heme oxygenase-1 activation) after 24 h of exposure, which promoted inflammatory factor secretion (NF-κB activation). Additionally, decreasing zonula occludens-2 and α1-antitrypsin protein expression in HepG2 cells suggested that CQD-Spd exposure increases the risk of liver diseases. Our results revealed that CQDs-Spd had greater hepatotoxic potential than CQDs-AC and CQDs-AC/Spd, which might be attributable to their high positive surface charge. Overall, the risk of CQD-induced hepatotoxic risk must be considered when applying positively charged CQDs.

Transient Elastography Is the Best-Performing Non-Invasive Test of Liver Fibrosis in Obese Asian Patients with Non-Alcoholic Fatty Liver Disease: A Pilot, Cross-Sectional Study.

Background and Objectives: The prevalence of NAFLD (non-alcoholic fatty liver disease) is increasing, and up to 64% of Asian patients with NAFLD are obese. Non-invasive tests (NITs) for the assessment of liver fibrosis are increasingly being used, but data on their performance in obese Asian patients are lacking. In this pilot cross-sectional study, we aim to compare the distribution of serum and radiological markers of fibrosis between obese Asian biopsy-proven NAFLD patients with and without fibrosis and estimate the diagnostic accuracies of these indices. Materials and Methods: Obese Asian patients with NAFLD and who had undergone a liver biopsy showing histological evidence of NAFLD were invited to participate. Liver fibrosis was assessed using laboratory (APRI, AAR, BARD, FIB4, NFS, and Asia-Pacific NAFLD advanced fibrosis score) and imaging modalities (TE: transient elastography, MRE: magnetic resonance elastography, and SWU: shear wave ultrasonography). Results: A total of 16 patients were included in the final analysis. On liver biopsy, nine patients (56.3%) had significant fibrosis (F2 or higher), and six of these patients had advanced fibrosis (F3 or higher). F4 fibrosis was present in one patient (6.3%). For the laboratory markers, we found that the BARD score correctly identified five out of six patients with advanced fibrosis (83.4%, p value 0.045). Among all the NITs studied, liver stiffness measured by TE had the highest accuracy of 87.5% in its established threshold of 8.5 kPa for the detection of advanced fibrosis. MRE also performed well (81.2% in 3.64 kPa). Conclusions: In conclusion, TE has performed well in the detection of advanced fibrosis in obese Asian patients with biopsy-proven NAFLD in our pilot study. Further large-scale definitive studies are needed to validate the results of our findings.

Seasonal Disparities of Human Health Risk and Particle-Bound Metal Characteristics Associated with Atmospheric Particles in a Fishery Harbor.

The effects of atmospheric pollution from ship emissions have been considered for several harbors worldwide. The health risk assessment and source apportionment of particle-bound metals in a fishery harbor were investigated in this study. The most abundant metal elements in particulate matter (PM) on all sampling days in three seasons were Fe (280.94 ± 136.93 ng/m3), Al (116.40 ± 71.25 ng/m3), and Zn (110.55 ± 26.70 ng/m3). The ratios of V/Ni were 1.44 ± 0.31, 1.48 ± 0.09 and 1.87 ± 0.06 in PM10, PM2.5, and PM1, respectively. Meanwhile, the ratios higher than 1 indicated that fuel oil combustion from ship emission in fishery harbor. The highest deposits of total particle-bound metals in the human respiratory tract were in the head airway (HA), accounting for 76.77 ± 2.29% of the total particle-bound metal concentration, followed by 5.32 ± 0.13% and 2.53 ± 0.15% in the alveolar region (AR) and tracheobronchial (TB) region, respectively. The total cancer risk (CR) of inhalation exposure to local residents exceeded 10-6. Mean total CR values followed the sequence: autumn (1.24 × 10-4) > winter (8.53 × 10-5) > spring (2.77 × 10-6). Source apportionment of related metal emissions was mobile pollution emissions (vehicle/boat) (37.10-48.92%), metal fumes of arc welding exhaust (19.68-34.42%), spray-painting process (12.34-16.24%), combustion emissions (6.32-13.12%), and metal machining processes (9.04-16.31%) in Singda fishing harbor. These results suggest that proper control of heavy metals from each potential source in fishing harbor areas should be carried out to reduce the carcinogenic risk of adverse health effects.

Key processes required for the different stages of fungal carnivory by a nematode-trapping fungus.

Nutritional deprivation triggers a switch from a saprotrophic to predatory lifestyle in soil-dwelling nematode-trapping fungi (NTF). In particular, the NTF Arthrobotrys oligospora secretes food and sex cues to lure nematodes to its mycelium and is triggered to develop specialized trapping devices. Captured nematodes are then invaded and digested by the fungus, thus serving as a food source. In this study, we examined the transcriptomic response of A. oligospora across the stages of sensing, trap development, and digestion upon exposure to the model nematode Caenorhabditis elegans. A. oligospora enacts a dynamic transcriptomic response, especially of protein secretion-related genes, in the presence of prey. Two-thirds of the predicted secretome of A. oligospora was up-regulated in the presence of C. elegans at all time points examined, and among these secreted proteins, 38.5% are predicted to be effector proteins. Furthermore, functional studies disrupting the t-SNARE protein Sso2 resulted in impaired ability to capture nematodes. Additionally, genes of the DUF3129 family, which are expanded in the genomes of several NTF, were highly up-regulated upon nematode exposure. We observed the accumulation of highly expressed DUF3129 proteins in trap cells, leading us to name members of this gene family as Trap Enriched Proteins (TEPs). Gene deletion of the most highly expressed TEP gene, TEP1, impairs the function of traps and prevents the fungus from capturing prey efficiently. In late stages of predation, we observed up-regulation of a variety of proteases, including metalloproteases. Following penetration of nematodes, these metalloproteases facilitate hyphal growth required for colonization of prey. These findings provide insights into the biology of the predatory lifestyle switch in a carnivorous fungus and provide frameworks for other fungal-nematode predator-prey systems.

Acidosis promotes the metastatic colonization of lung cancer via remodeling of the extracellular matrix and vasculogenic mimicry.

Acidosis is a hallmark of the tumor microenvironment caused by the metabolic switch from glucose oxidative phosphorylation to glycolysis. It has been associated with tumor growth and progression; however, the precise mechanism governing how acidosis promotes metastatic dissemination has yet to be elucidated. In the present study, a long­term acidosis model was established using patient­derived lung cancer cells, to identify critical components of metastatic colonization via transcriptome profiling combined with both in vitro and in vivo functional assays, and association analysis using clinical samples. Xenograft inoculates of 1 or 10 acidotic cells mimicking circulating tumor cell clusters were shown to exhibit increased tumor incidence compared with their physiological pH counterparts. Transcriptomics revealed that profound remodeling of the extracellular matrix (ECM) occurred in the acidotic cells, including upregulation of the integrin subunit α­4 (ITGA4) gene. In clinical lung cancer, ITGA4 expression was found to be upregulated in primary tumors with metastatic capability, and this trait was retained in the corresponding secondary tumors. Expression of ITGA4 was markedly upregulated around the vasculogenic mimicry structures of the acidotic tumors, while acidotic cells exhibited a higher ability of vasculogenic mimicry in vitro. Acidosis was also found to induce the enrichment of side population cells, suggesting an enhanced resistance to noxious attacks of the tumor microenvironment. Taken together, these results demonstrated that acidosis actively contributed to tumor metastatic colonization, and novel mechanistic insights into the therapeutic management and prognosis of lung cancer were discussed.

Complete coding sequence of Tembusu virus isolated from geese in Taiwan in 2020.

We reported the complete coding sequence of a Tembusu virus (TMUV) isolated from sick geese in Taiwan in 2020. The nucleotide sequence of the 20120008 isolate was most closely related to the strain TP1906 isolated from mosquitoes in Taiwan and clustered within a subgroup of Cluster 4 of the Tembusu virus.

DoSurvive: A webtool for investigating the prognostic power of a single or combined cancer biomarker.

We present DoSurvive, a user-friendly survival analysis web tool and a cancer prognostic biomarker centered database. DoSurvive is the first database that allows users to perform multivariant survival analysis for cancers with customized gene/patient list. DoSurvive offers three survival analysis methods, Log rank test, Cox regression and accelerated failure time model (AFT), for users to analyze five types of quantitative features (mRNA, miRNA, lncRNA, protein and methylation of CpG islands) with four survival types, i.e. overall survival, disease-specific survival, disease-free interval, and progression-free interval, in 33 cancer types. Notably, the implemented AFT model provides an alternative method for genes/features which failed the proportional hazard assumption in Cox regression. With the unprecedented number of survival models implemented and high flexibility in analysis, DoSurvive is a unique platform for the identification of clinically relevant targets for cancer researcher and practitioners. DoSurvive is freely available at http://dosurvive.lab.nycu.edu.tw/.

Metastasis and immunosuppression promoted by mtDNA and PD-L1 in extracellular vesicles are reversed by WGP ß-glucan in oral squamous cell carcinoma.

The suppressive regulatory T cells (Treg) are frequently upregulated in cancer patients. This study aims to demonstrate the hypothesis that arecoline could induce the secretion of mitochondrial (mt) DNA D-loop and programmed cell death-ligand 1 (PD-L1) in extracellular vesicles (EVs), and attenuate T-cell immunity by upregulated Treg cell numbers. However, the immunosuppression could be reversed by whole glucan particle (WGP) ß-glucan in oral squamous cell (OSCC) patients. Arecoline-induced reactive oxygen specimen (ROS) production and cytosolic mtDNA D-loop were analyzed in OSCC cell lines. mtDNA D-loop, PD-L1, IFN-γ, and Treg cells were also identified for the surgical specimens and sera of 60 OSCC patients. We demonstrated that higher mtDNA D-loop, PD-L1, and Treg cell numbers were significantly correlated with larger tumor size, nodal metastasis, advanced clinical stage, and areca quid chewing. Furthermore, multivariate analysis confirmed that higher mtDNA D-loop levels and Treg cell numbers were unfavorable independent factors for survival. Arecoline significantly induced cytosolic mtDNA D-loop leakage and PD-L1 expression, which were packaged by EVs to promote immunosuppressive Treg cell numbers. However, WGP ß-glucan could elevate CD4+ and CD8+ T-cell numbers, mitigate Treg cell numbers, and promote oral cancer cell apoptosis. To sum up, arecoline induces EV production carrying mtDNA D-loop and PD-L1, and in turn elicits immune suppression. However, WGP ß-glucan potentially enhances dual effects on T-cell immunity and cell apoptosis and we highly recommend its integration with targeted and immune therapies against OSCC.

Key factors for residency interview selection from the National Resident Matching Program: analysis of residency Program Director surveys, 2016-2020.

CONTEXT: As the number of medical school graduates continues to outpace the available residency training positions, applying for residency in the United States has become a highly competitive process, often associated with a low rate of selection and invitation for interview. The National Resident Matching Program (NRMP) Program Director survey provides data assessing factors considered by Program Directors (PD) in selecting and inviting candidates for interview. Assessing the evolution of these factors over time is efficacious to inform and guide prospective applicants toward improving preparation for residency application. OBJECTIVES: We aim to synthesize NRMP data showing factors that PDs reported and rated as important in their decision to select and invite applicants for interview. METHODS: Data from residency PD surveys from 2008 to 2021 were accessed, but after applying inclusion/exclusion criteria, only the data from 2016 to 2020 were reviewed and analyzed. The NRMP survey reports provided two metrics that characterized PDs' evaluation of the residency factors for interview, namely, "percent citing factor" and "average rating" on a 0 to 5 Likert-type scale. These two metrics were combined into an aggregate measure of importance (AI), and another measure of relative importance (RI) was constructed from normalizing the AI of each individual factor to the sum of the AI within each survey year. RESULTS: The top ranked factors were United States Medical Licensing Examination (USMLE) Step 1/Comprehensive Osteopathic Medical Licensing Examination (COMLEX) Level 1, Letter of Recommendation (LOR) in the specialty, Medical Student Performance Evaluation (MSPE/Dean's Letter), and USMLE Step 2 Clinical Knowledge (CK)/COMLEX Level 2 Cognitive Exam (CE) score, any failed attempt in USMLE/COMLEX, and perceived commitment to specialty. Factors rising in importance were Audition Elective/Rotation Within Your Department, Personal Statement (PS), Perceived Commitment to Specialty, Perceived Interest in Program, LOR in the Specialty, Other Life Experience, and Personal Prior Knowledge of the Applicant. Factors with declining importance were Interest in Academic Career, Awards or Special Honors in Basic Sciences, Graduate of Highly Regarded US Medical School, Awards or Special Honors in Clinical Clerkships, Lack of Gaps in Medical Education, Awards or Special Honors in Clerkship in Desired Specialty, and Consistency of Grades. Compared to the 2021 PD survey, our findings show continued predictive consistency, particularly related to specialty and program commitment. CONCLUSIONS: The factors identified for the selection of medical school graduates for interview into a residency program reveal that PDs move toward a more integrated approach. Specifically, PDs are placing increasing emphasis on factors that border on subjective qualities more so than the more traditional, quantitative, and objective metrics. Medical students and educators need to continually apprise themselves of the NRMP data to inform students' preparation endeavors throughout medical school to strengthen their application portfolios and enhance their competitiveness for the matching process.

The Influences of Pore Blockage by Natural Organic Matter and Pore Dimension Tuning on Pharmaceutical Adsorption onto GO-Fe3O4.

The ubiquitous presence of pharmaceutical pollution in the environment and its adverse impacts on public health and aquatic ecosystems have recently attracted increasing attention. Graphene oxide coated with magnetite (GO-Fe3O4) is effective at removing pharmaceuticals in water by adsorption. However, the myriad compositions in real water are known to adversely impact the adsorption performance. One objective of this study was to investigate the influence of pore blockage by natural organic matter (NOM) with different sizes on pharmaceutical adsorption onto GO-Fe3O4. Meanwhile, the feasibility of pore dimension tuning of GO-Fe3O4 for selective adsorption of pharmaceuticals with different structural characteristics was explored. It was shown in the batch experiments that the adsorbed pharmaceutical concentrations onto GO-Fe3O4 were significantly affected (dropped by 2-86%) by NOM that had size ranges similar to the pore dimensions of GO-Fe3O4, as the impact was enhanced when the adsorption occurred at acidic pHs (e.g., pH 3). Specific surface areas, zeta potentials, pore volumes, and pore-size distributions of GO-Fe3O4 were influenced by the Fe content forming different-sized Fe3O4 between GO layers. Low Fe contents in GO-Fe3O4 increased the formation of nano-sized pores (2.0-12.5 nm) that were efficient in the adsorption of pharmaceuticals with low molecular weights (e.g., 129 kDa) or planar structures via size discrimination or inter-planar π-π interaction, respectively. As excess larger-sized pores (e.g., >50 nm) were formed on the surface of GO-Fe3O4 due to higher Fe contents, pharmaceuticals with larger molecular weights (e.g., 296 kDa) or those removed by electrostatic attraction between the adsorbate and adsorbent dominated on the GO-Fe3O4 surface. Given these observations, the surface characteristics of GO-Fe3O4 were alterable to selectively remove different pharmaceuticals in water by adsorption, and the critical factors determining the adsorption performance were discussed. These findings provide useful views on the feasibility of treating pharmaceutical wastewater, recycling valuable pharmaceuticals, or removing those with risks to public health and ecosystems.

Lysyl oxidase-like 2 promotes stemness and enhances antitumor effects of gefitinib in head and neck cancer via IFIT1 and IFIT3.

Lysyl oxidase-like 2 (LOXL2) is a matrix-remodeling enzyme that has recently been identified as an important regulator of tumor progression and metastasis. This study discovered that LOXL2 expression in oral squamous cell carcinoma (OSCC) tissues was significantly associated with tumor clinical stage, lymph node metastasis and patients' overall survival time. LOXL2-overexpressing human buccal SCC TW2.6 (TW2.6/LOXL2) and hypopharyngeal SCC FaDu (FaDu/LOXL2) cells exhibited enhanced migration, invasion, epithelial-mesenchymal transition (EMT), and cancer stem cell (CSC) phenotypes, independently of its enzymatic activity. Moreover, TW2.6/LOXL2 significantly increased tumor-initiating frequency in SCID mice. We further demonstrated that LOXL2 increased the levels of interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) and IFIT3 in TW2.6/LOXL2 and FaDu/LOXL2 cells. We also identified IFIT1 and IFIT3 as key downstream components of LOXL2 action in migration, invasion, EMT, and CSC phenotypes in TW2.6 and FaDu cells. Furthermore, a significant positive correlation between LOXL2 expression and IFIT1 and IFIT3 overexpression in human OSCC tissues was observed. In addition, TW2.6/LOXL2 and FaDu/LOXL2 cells were 3.3- to 3.6-fold more susceptible to the epidermal growth factor receptor (EGFR) inhibitor gefitinib than were their respective control cells. The antitumor effect of gefitinib on orthotopic TW2.6/LOXL2 xenograft tumor was fourfold higher than that on controls. Our results indicate that LOXL2 expression is a strong prognostic factor for OSCC and may be used as a marker to identify patients most likely to respond to EGFR-targeted therapy.

Investigation of New Psychoactive Substances (NPS), Other Illicit Drugs, and Drug-Related Compounds in a Taiwanese Wastewater Sample Using High-Resolution Mass-Spectrometry-Based Targeted and Suspect Screening.

The proliferation of new psychoactive substances (NPSs) in recent years has posed a significant challenge to public health. Traditional monitoring methods have proven insufficient in tracking these constantly evolving substances, leading to the development of alternative approaches such as wastewater-based epidemiology (WBE). The present study aims to utilize high-resolution mass spectrometry (HRMS)-based targeted and suspect screening to profile NPS, other illicit drugs, and drug-related compounds in a Taiwanese wastewater sample. For the targeted analysis, 8 out 18 standards of illicit drugs have been identified. The suspect screening approach based on approximately 3600 substances in the SWGDRUG library can further identify 92 compounds, including opiate analgesics, synthetic cathinones, phenylalkylamines derivatives, phenethylamine derivatives, tryptamine derivatives, steroids, and ephedrine-related compounds. Additionally, the presence of 5-methoxy-2-aminoindane (MEAI) in the wastewater indicates that drug dealers have recently sold this potential NPS to evade drug regulations. This study firstly reports the HRMS-based comprehensive profile of NPS, other illicit drugs, and drug-related compounds in Taiwan, which could be applied as biomarkers for estimating the consumption of drugs.

Endodontic malpractice litigations in the United States from 2000 to 2021.

Background/purpose: Little is known regarding the outcomes and distinguishing characteristics of lawsuits related to endodontic procedures. This study used a verdict-based data from United States of America to analyze the factors associated with endodontic malpractice lawsuits and mitigate the risk of litigation. Materials and methods: The LexisNexis legal database was used to search for endodontic malpractice cases from January 1, 2000 to December 31, 2021 using the terms "medical malpractice" and (I) "endodontist" (II) "endodontics" (III) "root canal" (IV) "dental pulp." Each case was reviewed for reported medical characteristics and litigation outcomes. Results: A total of 650 cases were initially identified, and 97 cases were included in the final analysis. Eighty-four (86.6%) of the 97 defendants were general practitioners; 42 cases favored the plaintiff, 53 (54.6%) favored the defendant, 1 was partial win/loss, and 1 was settled. The annual case mean was 4.41 ± 2.17 (Mean ± SD). The major allegations favored for the patients involving paresthesia, root perforation, rubber dam not use, wrong tooth therapy, and infections. Plaintiffs who claimed with post-procedural reasons had a significantly higher winning rate than non-post-procedural reasons (P < 0.05). Conclusion: In the present study, 54.6% of endodontic litigation favored the dentists in the US. The authors recommend that general practitioners refer complicated cases to endodontists and treat carefully to avoid paresthesia, canal perforation and infections. Clinicians should always diagnose and treat correctly, shared decision making with the patient, use rubber dam routinely, and timely management to prevent malpractice claims.

A carnivorous mushroom paralyzes and kills nematodes via a volatile ketone.

The carnivorous mushroom Pleurotus ostreatus uses an unknown toxin to rapidly paralyze and kill nematode prey upon contact. We report that small lollipop-shaped structures (toxocysts) on fungal hyphae are nematicidal and that a volatile ketone, 3-octanone, is detected in these fragile toxocysts. Treatment of Caenorhabditis elegans with 3-octanone recapitulates the rapid paralysis, calcium influx, and neuronal cell death arising from fungal contact. Moreover, 3-octanone disrupts cell membrane integrity, resulting in extracellular calcium influx into cytosol and mitochondria, propagating cell death throughout the entire organism. Last, we demonstrate that structurally related compounds are also biotoxic to C. elegans, with the length of the ketone carbon chain being crucial. Our work reveals that the oyster mushroom has evolved a specialized structure containing a volatile ketone to disrupt the cell membrane integrity of its prey, leading to rapid cell and organismal death in nematodes.

Wireless neuromodulation in vitro and in vivo by intrinsic TRPC-mediated magnetomechanical stimulation.

Various magnetic deep brain stimulation (DBS) methods have been developing rapidly in the last decade for minimizing the invasiveness of DBS. However, current magnetic DBS methods, such as magnetothermal and magnetomechanical stimulation, require overexpressing exogeneous ion channels in the central nervous system (CNS). It is unclear whether magnetomechanical stimulation can modulate non-transgenic CNS neurons or not. Here, we reveal that the torque of magnetic nanodiscs with weak and slow alternative magnetic field (50 mT at 10 Hz) could activate neurons through the intrinsic transient receptor potential canonical channels (TRPC), which are mechanosensitive ion channels widely expressed in the brain. The immunostaining with c-fos shows the increasement of neuronal activity by wireless DBS with magnetomechanical approach in vivo. Overall, this research demonstrates a magnetic nanodiscs-based magnetomechanical approach that can be used for wireless neuronal stimulation in vitro and untethered DBS in vivo without implants or genetic manipulation.

Phenytoin induces connective tissue growth factor (CTGF/CCN2) production through NADPH oxidase 4-mediated latent TGFß1 activation in human gingiva fibroblasts: Suppression by curcumin.

OBJECTIVE AND BACKGROUND: Gingival overgrowth (GO) is a common side effect of some drugs such as anticonvulsants, immunosuppressant, and calcium channel blockers. Among them, the antiepileptic agent phenytoin is the most common agent related to this condition due to its high incidence. Transforming growth factor ß (TGFß) importantly contributes to the pathogenesis of GO. Connective tissue growth factor (CTGF or CCN2) is a key mediator of tissue fibrosis and is positively associated with the degree of fibrosis in GO. We previously showed that Src, c-jun N-terminal kinase, and Smad3 mediate TGFß1-induced CCN2 protein expression in human gingival fibroblasts (HGFs). This study investigates whether phenytoin can induce CCN2 synthesis through activated latent TGFß in HGFs and its mechanisms. METHODS: CCN2 synthesis, latent TGFß1 activation, and cellular reactive oxygen species (ROS) generation in HGFs were studied using western blot analysis, a TGFß1 Emax® ImmunoAssay System, and 2',7'-dichlorodihydrofluorescein diacetate (an oxidation-sensitive fluorescent probe), respectively. RESULTS: Phenytoin significantly stimulated CCN2 synthesis, latent TGFß1 activation, and ROS generation in HGFs. Addition of an TGFß-neutralizing antibody, TGFß receptor kinase inhibitor SB431542, and Smad3 inhibitor SIS3 completely inhibited phenytoin-induced CCN2 synthesis. General antioxidant N-acetylcysteine, NADPH oxidase (NOX) inhibitor diphenylene iodonium, and specific NOX4 inhibitor plumbagin almost completely suppressed phenytoin-induced total cellular ROS and latent TGFß1 activation. Curcumin dose-dependently decreased phenytoin-induced TGFß1 activation and CCN2 synthesis in HGFs. CONCLUSIONS: Our findings indicated that NOX4-derived ROS play pivotal roles in phenytoin-induced latent TGFß1 activation. Molecular targeting the phenytoin/NOX4/ROS/TGFß1 pathway may provide promising strategies for the prevention and treatment of GO. Curcumin-inhibited phenytoin-induced CCN2 synthesis is caused by the suppression of latent TGFß1 activation.