Enhancing Precision in Detecting Severe Immune-Related Adverse Events: Comparative Analysis of Large Language Models and International Classification of Disease Codes in Patient Records.

PURPOSE: Current approaches to accurately identify immune-related adverse events (irAEs) in large retrospective studies are limited. Large language models (LLMs) offer a potential solution to this challenge, given their high performance in natural language comprehension tasks. Therefore, we investigated the use of an LLM to identify irAEs among hospitalized patients, comparing its performance with manual adjudication and International Classification of Disease (ICD) codes. METHODS: Hospital admissions of patients receiving immune checkpoint inhibitor (ICI) therapy at a single institution from February 5, 2011, to September 5, 2023, were individually reviewed and adjudicated for the presence of irAEs. ICD codes and an LLM with retrieval-augmented generation were applied to detect frequent irAEs (ICI-induced colitis, hepatitis, and pneumonitis) and the most fatal irAE (ICI-myocarditis) from electronic health records. The performance between ICD codes and LLM was compared via sensitivity and specificity with an α = .05, relative to the gold standard of manual adjudication. External validation was performed using a data set of hospital admissions from June 1, 2018, to May 31, 2019, from a second institution. RESULTS: Of the 7,555 admissions for patients on ICI therapy in the initial cohort, 2.0% were adjudicated to be due to ICI-colitis, 1.1% ICI-hepatitis, 0.7% ICI-pneumonitis, and 0.8% ICI-myocarditis. The LLM demonstrated higher sensitivity than ICD codes (94.7% v 68.7%), achieving significance for ICI-hepatitis (P < .001), myocarditis (P < .001), and pneumonitis (P = .003) while yielding similar specificities (93.7% v 92.4%). The LLM spent an average of 9.53 seconds/chart in comparison with an estimated 15 minutes for adjudication. In the validation cohort (N = 1,270), the mean LLM sensitivity and specificity were 98.1% and 95.7%, respectively. CONCLUSION: LLMs are a useful tool for the detection of irAEs, outperforming ICD codes in sensitivity and adjudication in efficiency.

Correction: The Untranslated Regions of Classic Swine Fever Virus RNA Trigger Apoptosis.

[This corrects the article DOI: 10.1371/journal.pone.0088863.].

Direct Growth of Wafer-Scale Self-Separated GaN on Reusable 2D Material Substrates.

Free-standing gallium nitride has been prepared using various methods; however, the removal of the original substrate is still challenging with low success rates. In this work, 2-inch free-standing GaN films are obtained by direct growth on a fluoro phlogopite mica by hydride vapor-phase epitaxy. Depending on the van der Waals (vdW) interaction between GaN and mica, the effect of the significant lattice mismatch is effectively reduced; thus, enabling the production of a high-quality wafer-scale GaN film on mica. The vdW-induced cracks at GaN-mica interface are found to be initiated near the interface so that GaN can easily separate from mica during rapid cooling. Owing to the hydrophilic nature of mica, the residual GaN on the mica can be lifted off by following deionized water treatment, and the mica substrate can be repeatedly used to grow free-standing GaN films. The self-separated GaN films grown on both pristine and used mica substrates are single crystallinity and strain-free. Additionally, a fully functional ultraviolet light-emitting diode is demonstrated to show that the self-separated GaN films are of device quality. The proposed approach achieves epitaxial growth of wafer-scale single-crystalline GaN on 2D materials and provides a new substrate option in the technology of III-V materials.

Gravitational change-induced alteration of the vestibular function and gene expression in the vestibular ganglion of mice.

Gravity has profoundly influenced life on Earth, yet how organisms adapt to changes in gravity remains largely unknown. This study examines vestibular plasticity, specifically how the vestibular system responds to altered gravity. We subjected male C57BL/6J mice to hypergravity (2 G) followed by normal gravity (1 G) to analyze changes in vestibular function and gene expression. Mice showed significant vestibular dysfunction, assessed by righting reflex tests, which persisted for days but reversed at 1 G after exposure to 2 G. Gene expression analysis in the vestibular ganglion identified significant changes in 212 genes out of 49,585 due to gravitational changes. Specifically, 25 genes were upregulated under 2 G and recovered at 1 G after 2 G exposure, while one gene showed the opposite trend. Key neural function genes like Shisa3, Slc25a37, Ntn4, and Snca were involved. Our results reveal that hypergravity-induced vestibular dysfunction is reversible and highlight genes critical for adaptation.

Clinical, sonographic and molecular changes in calcific tendinitis of the shoulder following extracorporeal shockwave therapy: a prospective case-control study.

BACKGROUND: Extracorporeal shockwave therapy (ESWT) is the primary treatment for calcific tendinitis of the shoulders, but what are the effects of clinical, sonographic, and molecular markers following ESWT in treating calcific tendinitis of the shoulder? METHODS: Twenty-eight patients were categorized into radiodense and radiolucent subgroups. In addition, clinical assessments included the visual analogue scale (VAS), Constant-Murley (CM) score, American Shoulder and Elbow Surgeon (ASES) score, sonographic evaluation, and serum enzyme-linked immunosorbent assay (ELISA). The participants completed a one-year follow-up. All data were collected before and after treatment. RESULTS: After one year of follow-up, all patients showed notable improvement in VAS, CM, and ASES scores, with no significant clinical variations among the subgroups. However, the radiolucent group showed significant complete resorption and size reduction at the final follow-up. Sonographic evaluation revealed improved tissue perfusion and reduced calcification from 3 to 12 months in all patients, including those in the radiolucent group, but complete resorption of calcific deposits did not occur. The percentage of tissue perfusion was improved at 1 and 3 months after ESWT. There were no significant differences in the levels of the molecular markers interleukin-1 beta (IL-1 ß) or IL-33, but the level of insulin-like growth factor 1 (IGF-1) was notably increased at 1 and 3 months post-ESWT. The BMP7 level was increased at 3 months and was then decreased significantly at 6 and 12 months. CONCLUSION: ESWT improved symptoms, reduced calcification, enhanced tissue perfusion, and promoted angiogenesis and BMP7 activity. In particular, it benefited radiolucent type patients with better calcification resorption. Partial resorption led to improvements in transparency, and a second ESWT session at 3 months was recommended for optimal results.

Vascular heterogeneity of tight junction Claudins guides organotropic metastasis.

Carcinomas are associated with metastasis to specific organs while sparing others. Breast cancer presents with lung metastasis but rarely kidney metastasis. Using this difference as an example, we queried the mechanism(s) behind the proclivity for organ-specific metastasis. We used spontaneous and implant models of metastatic mammary carcinoma coupled with inflammatory tissue fibrosis, single-cell sequencing analyses and functional studies to unravel the causal determinants of organ-specific metastasis. Here we show that lung metastasis is facilitated by angiopoietin 2 (Ang2)-mediated suppression of lung-specific endothelial tight junction protein Claudin 5, which is augmented by the inflammatory fibrotic microenvironment and prevented by anti-Ang2 blocking antibodies, while kidney metastasis is prevented by non-Ang2-responsive Claudins 2 and 10. Suppression of Claudins 2 and 10 was sufficient to induce the emergence of kidney metastasis. This study illustrates the influence of organ-specific vascular heterogeneity in determining organotropic metastasis, independent of cancer cell-intrinsic mechanisms.

Risk of Traumatic Intracranial Hemorrhage After Stroke: A Nationwide Population-Based Cohort Study in Taiwan.

BACKGROUND: Stroke and traumatic intracranial hemorrhage (tICH) are major causes of disability worldwide, with stroke exerting significant negative effects on the brain, potentially elevating tICH risk. In this study, we investigated tICH risk in stroke survivors. METHODS AND RESULTS: Using relevant data (2017-2019) from Taiwan's National Health Insurance Research Database, we conducted a population-based retrospective cohort study. Patients were categorized into stroke and nonstroke groups, and tICH risk was compared using a Cox proportional-hazards model. Among 164 628 patients with stroke, 1004 experienced tICH. Patients with stroke had a higher tICH risk than nonstroke counterparts (adjusted hazard ratio [HR], 3.49 [95% CI, 3.17-3.84]). Subgroup analysis by stroke type revealed higher tICH risk in hemorrhagic stroke survivors compared with ischemic stroke survivors (HR, 5.64 [95% CI, 4.97-6.39] versus 2.87 [95% CI, 2.58-3.18], respectively). Older patients (≥45 years) with stroke had a higher tICH risk compared with their younger counterparts (<45 years), in contrast to younger patients without stroke (HR, 7.89 [95% CI, 6.41-9.70] versus 4.44 [95% CI, 2.99-6.59], respectively). Dementia and Parkinson disease emerged as significant tICH risk factors (HR, 1.69 [95% CI, 1.44-2.00] versus 2.17 [95% CI, 1.71-2.75], respectively). In the stroke group, the highest tICH incidence density occurred 3 months after stroke, particularly in patients aged >65 years. CONCLUSIONS: Stroke survivors, particularly those with hemorrhagic stroke and those aged ≥45 years, face elevated tICH risk. Interventions targeting the high-risk period are vital, with fall injuries potentially contributing to tICH incidence.

Concurrent abnormalities in galvanic cervical and ocular vestibular-evoked myogenic potentials as a predictive marker for prolonged dizziness in vestibular neuritis.

BACKGROUND: Despite the growing use of cervical (cVEMP) and ocular (oVEMP) VEMP tests, their effectiveness in predicting chronic dizziness in vestibular neuritis (VN) patients remains unclear. Our research examines the link between long-lasting dizziness and inner ear assessments, encompassing VEMPs induced by air-conducted sound (ACS), bone-conducted vibration (BCV), and galvanic vestibular stimulation (GVS). OBJECTIVES: This study explores prognostic markers by examining the relationship between the persistence of dizziness symptoms and various inner ear test findings in VN patients. MATERIAL AND METHODS: A retrospective cohort of 60 unilateral VN patients underwent comprehensive audiovestibular tests, including pure tone audiometry, cVEMP and oVEMP induced by ACS, BCV, GVS, and caloric tests. Patient subgroups were established based on dizziness duration: short-term (<3 months) and long-term (≥3 months). RESULTS: No substantial correlation existed between the dizziness duration and the outcomes of any particular single inner ear test. However, patients exhibiting concurrent abnormal GVS-cVEMP and GVS-oVEMP were more likely to experience prolonged dizziness, indicating more extensive vestibular system involvement. CONCLUSIONS: Concurrent abnormalities in GVS-cVEMP and GVS-oVEMP may indicate a higher chance of long-term dizziness in VN. SIGNIFICANCE: This study identifies concurrent abnormalities in GVS-cVEMP and GVS-VEMP as a potential prognostic marker for prolonged dizziness in VN.

The G protein-coupled receptor ADGRG6 maintains mouse growth plate homeostasis through IHH Signaling.

The cartilage growth plate is essential for maintaining skeletal growth; however, the mechanisms governing postnatal growth plate homeostasis are still poorly understood. Using approaches of molecular mouse genetics and spatial transcriptomics applied to formalin-fixed, paraffin-embedded (FFPE) tissues, we show that ADGRG6/GPR126, a cartilage-enriched adhesion G protein-coupled receptor (GPCR), is essential for maintaining slow-cycling resting zone cells, appropriate chondrocyte proliferation and differentiation, and growth plate homeostasis in mice. Constitutive ablation of Adgrg6 in osteochondral progenitor cells with Col2a1Cre leads to a shortened resting zone, formation of cell clusters within the proliferative zone, and an elongated hypertrophic growth plate, marked by limited expression of PTHrP but increased IHH signaling throughout the growth plate. Attenuation of Smoothened (SMO)-dependent hedgehog signaling restored the Adgrg6 deficiency-induced expansion of hypertrophic chondrocytes, confirming that IHH signaling can promote chondrocyte hypertrophy in a PTHrP-independent manner. In contrast, postnatal ablation of Adgrg6 in mature chondrocytes with AcanCreERT2, induced after the formation of the resting zone, does not affect PTHrP expression but causes an overall reduction of growth plate thickness marked by increased cell death specifically in the resting zone cells and a general reduction of chondrocyte proliferation and differentiation. Spatial transcriptomics reveals that ADGRG6 is essential for maintaining chondrocyte homeostasis by regulating osteogenic and catabolic genes in all the zones of the postnatal growth plates, potentially through positive regulation of SOX9 expression. Our findings elucidate the essential role of a cartilage-enriched adhesion GPCR in regulating cell proliferation and hypertrophic differentiation by regulation of PTHrP/IHH signaling, maintenance of slow-cycle resting zone chondrocytes, and safeguarding chondrocyte homeostasis in postnatal mouse growth plates.

The cartilage growth plate is an essential structure for skeletal growth, however, the mechanisms that govern growth plate homeostasis are still poorly understood. In this study, we showed that an adhesion G protein-coupled receptor (GPCR) named ADGRG6 plays an essential role in maintaining the slow-cycling cells in the resting zone of the growth plate and directing appropriate proliferation and differentiation of the growth plate chondrocytes. Using a technique called spatial transcriptomics, we compared the gene expression profiles in control and Adgrg6 mutant growth plates and found that ADGRG6 prevents premature hypertrophic differentiation of the growth plate chondrocytes by negatively regulating Indian Hedgehog (IHH) signaling. In summary, our findings highlighted the essential role of a cartilage-enriched GPCR in maintaining growth plate homeostasis through IHH signaling.

Endovascular management of intracranial carotid blowout syndrome in patients with head and neck cancer.

BACKGROUND: Carotid blowout syndrome is a serious complication of head and neck cancer (HNC) that may involve the intracranial or extracranial internal carotid artery (ICA). Although parent artery occlusion (PAO) is the major endovascular treatment for intracranial carotid blowout syndrome (iCBS), the efficacy of using a balloon-expandable coronary stent-graft (BES) remains unclear. METHODS: This was a quasi-randomized trial, prospective study that included patients with iCBS treated by BES or PAO between 2018 and 2024. Patients were allocated to either group based on the last digit of their chart number; even numbers went to the BES group and odd numbers to the PAO group. The inclusion criteria of iCBS included the pathological process of CBS involving petrous and/or cavernous ICA detected by both imaging and clinical features. The primary outcome was defined as rebleeding events after intervention. The secondary outcome was defined as neurological complication after intervention. RESULTS: Fifty-nine patients with 61 iCBS lesions were enrolled. Thirty-three iCBS lesions were treated with BES and 28 underwent PAO. The results for the BES group versus the PAO group, respectively, were: rebleeding events, 5/33 (15.1%) vs 5/28 (17.8%) (p=0.78); neurological complication, 5/33 (15.1%) vs 5/28 (17.8%) (p=0.78); median hemostatic time (months), 10.0 vs 11.5 (p=0.22); and median survival time (months), 10.0 vs 11.5 (p=0.39). CONCLUSIONS: No significant difference in rebleeding risk or neurological complication was observed between the BES and PAO groups. Our study confirmed the safety and effectiveness of applying BES for iCBS in HNC patients.

Shikonin, a natural naphthoquinone phytochemical, exerts anti-leukemia effects in human CBF-AML cell lines and zebrafish xenograft models.

Core binding factor acute myeloid leukemia (CBF-AML) stands out as the most common type of adult AML, characterized by specific chromosomal rearrangements involving CBF genes, particularly t(8;21). Shikonin (SHK), a naphthoquinone phytochemical widely employed as a food colorant and traditional Chinese herbal medicine, exhibits antioxidant, anti-inflammatory, and anti-cancer activities. In this study, we aim to investigate the antileukemic effects of SHK and its underlying mechanisms in human CBF-AML cells and zebrafish xenograft models. Our study revealed that SHK reduced the viability of CBF-AML cells. SHK induced cell cycle arrest, promoted cell apoptosis, and induced differentiation in Kasumi-1 cells. Additionally, SHK downregulated the gene expression of AML1-ETO and c-KIT in Kasumi-1 cells. In animal studies, SHK showed no toxic effects in zebrafish and markedly inhibited the growth of leukemia cells in zebrafish xenografts. Transcriptomic analysis showed that differentially expressed genes (DEGs) altered by SHK are linked to key biological processes like DNA repair, replication, cell cycle regulation, apoptosis, and division. Furthermore, KEGG pathways associated with cell growth, such as the cell cycle and p53 signaling pathway, were significantly enriched by DEGs. Analysis of AML-associated genes in response to SHK treatment using DisGeNET and the STRING database indicated that SHK downregulates the expression of cell division regulators regarding AML progression. Finally, we found that SHK combined with cytarabine synergistically reduced the viability of Kasumi-1 cells. In conclusion, our findings provide novel insights into the mechanisms of SHK in suppressing leukemia cell growth, suggesting its potential as a chemotherapeutic agent for human CBF-AML.

Aphrodisiac Principles and other Constituents from the Roots of Panax quinguefolium and Panax ginseng.

Bioassay-guided fractionation of P. quinquefolium and P. ginseng root extracts afforded six compounds. Among these, two bioactive compounds ginsenoside Re (1) and (20S)-ginsenoside Rg2 (5) exhibiting significant relaxation in rabbit corpus cavernosum with EC50 values of 95.1 and 114.7 µM, respectively. In addition, the phytochemical composition of the water extract of the roots of P. quinquefolium was investigated, and thirty-one compounds were characterized, including four undescribed compounds panajaponol B (18) and panaxjapynes D-F (21-23). Moreover, the spectral characteristics and biosynthetic pathway of Panax triterpene saponins were discussed according to our results and some previous reports.

Embedded Hybrid-Dimensional Heterointerface for Filament Modulation in 2D Material-Based Artificial Nociceptor.

Nociceptors are key sensory receptors that transmit warning signals to the central nervous system in response to painful stimuli. This fundamental process is emulated in an electronic device by developing a novel artificial nociceptor with an ultrathin, nonstoichiometric gallium oxide (GaOx)-silicon oxide heterostructure. A large-area 2D-GaOx film is printed on a substrate through liquid metal printing to facilitate the production of conductive filaments. This nociceptive structure exhibits a unique short-term temporal response following stimulation, enabling a facile demonstration of threshold-switching physics. The developed heterointerface 2D-GaOx film enables the fabrication of fast-switching, low-energy, and compliance-free 2D-GaOx nociceptors, as confirmed through experiments. The accumulation and extrusion of Ag in the oxide matrix are significant for inducing plastic changes in artificial biological sensors. High-resolution transmission electron microscopy and electron energy loss spectroscopy demonstrate that Ag clusters in the material dispersed under electrical bias and regrouped spontaneously when the bias is removed owing to interfacial energy minimization. Moreover, 2D nociceptors are stable; thus, heterointerface engineering can enable effective control of charge transfer in 2D heterostructural devices. Furthermore, the diffusive 2D-GaOx device and its Ag dynamics enable the direct emulation of biological nociceptors, marking an advancement in the hardware implementation of artificial human sensory systems.

Effects of training methods on performance of a scaffolding task for workers with different spatial ability.

With software developments and advances in display technologies substantially improved, augmented reality (AR) application has gained popularity. In this study, we discuss using classic PowerPoint and AR for two kinds of scaffolding tasks (task-lifeline assembly and hedge assembly) for users with different spatial ability. We considered both objective and subjective measures of performance, i.e., correct rate and system usability and the ITC-sense of presence inventory (ITC-SOPI) scale. The results of the study show that participants using AR achieved higher operating performance than those using PowerPoint. Furthermore, the users' learning effect was influenced by spatial ability when using PowerPoint. Participants with high spatial ability achieved higher performance than participants with low spatial ability in PowerPoint. However, participants who used AR as a training method did not show significantly different operating performance at different levels of spatial ability. Consequently, AR was believed to be a potential method for enhancing training performance.

Early Improvement in Interstitial Fluid Flow in Patients With Severe Carotid Stenosis After Angioplasty and Stenting.

Background and Purpose: This study aimed to investigate early changes in interstitial fluid (ISF) flow in patients with severe carotid stenosis after carotid angioplasty and stenting (CAS). Methods: We prospectively recruited participants with carotid stenosis ≥80% undergoing CAS at our institute between October 2019 and March 2023. Magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI), and the Mini-Mental State Examination (MMSE) were performed 3 days before CAS. MRI with DTI and MMSE were conducted within 24 hours and 2 months after CAS, respectively. The diffusion tensor image analysis along the perivascular space (DTI-ALPS) index was calculated from the DTI data to determine the ISF status. Increments were defined as the ratio of the difference between post- and preprocedural values to preprocedural values. Results: In total, 102 participants (age: 67.1±8.9 years; stenosis: 89.5%±5.7%) with longitudinal data were evaluated. The DTI-ALPS index increased after CAS (0.85±0.15; 0.85 [0.22] vs. 0.86±0.14; 0.86 [0.21]; P=0.022), as did the MMSE score (25.9±3.7; 24.0 [4.0] vs. 26.9±3.4; 26.0 [3.0]; P<0.001). Positive correlations between increments in the DTI-ALPS index and MMSE score were found in all patients (rs=0.468; P<0.001). Conclusion An increased 24-hour post-CAS DTI-ALPS index suggests early improvement in ISF flow efficiency. The positive correlation between the 24-hour DTI-ALPS index and 2-month MMSE score increments suggests that early ISF flow improvement may contribute to long-term cognitive improvement after CAS.

Lysophosphatidylcholine Impairs the Mitochondria Homeostasis Leading to Trophoblast Dysfunction in Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is a common pregnancy disorder associated with an increased risk of pre-eclampsia and macrosomia. Recent research has shown that the buildup of excess lipids within the placental trophoblast impairs mitochondrial function. However, the exact lipids that impact the placental trophoblast and the underlying mechanism remain unclear. GDM cases and healthy controls were recruited at Kaohsiung Medical University Hospital. The placenta and cord blood were taken during birth. Confocal and electron microscopy were utilized to examine the morphology of the placenta and mitochondria. We determined the lipid composition using liquid chromatography-mass spectrometry in data-independent analysis mode (LC/MSE). In vitro studies were carried out on choriocarcinoma cells (JEG3) to investigate the mechanism of trophoblast mitochondrial dysfunction. Results showed that the GDM placenta was distinguished by increased syncytial knots, chorangiosis, lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) overexpression, and mitochondrial dysfunction. Lysophosphatidylcholine (LPC) 16:0 was significantly elevated in the cord blood LDL of GDM patients. In vitro, we demonstrated that LPC dose-dependently disrupts mitochondrial function by increasing reactive oxygen species (ROS) levels and HIF-1α signaling. In conclusion, highly elevated LPC in cord blood plays a pivotal role in GDM, contributing to trophoblast impairment and pregnancy complications.

Long-Term Survival and Regeneration Following Transplantation of 3D-Printed Biodegradable PCL Tracheal Grafts in Large-Scale Porcine Models.

Polycaprolactone (PCL) implants in large animals show great promise for tracheal transplantation. However, the longest survival time achieved to date is only about three weeks. To meet clinical application standards, it is essential to extend the survival time and ensure the complete integration and functionality of the implant. Our study investigates the use of three-dimensional (3D)-printed, biodegradable, PCL-based tracheal grafts for large-scale porcine tracheal transplantation, assessing the feasibility and early structural integrity crucial for long-term survival experiments. A biodegradable PCL tracheal graft was fabricated using a BIOX bioprinter and transplanted into large-scale porcine models. The grafts, measuring 20 × 20 × 1.5 mm, were implanted following a 2 cm circumferential resection of the porcine trachea. The experiment design was traditionally implanted in eight porcines to replace four-ring tracheal segments, only two of which survived more than three months. Data were collected on the graft construction and clinical outcomes. The 3D-printed biosynthetic grafts replicated the native organ with high fidelity. The implantations were successful, without immediate complications. At two weeks, bronchoscopy revealed significant granulation tissue around the anastomosis, which was managed with laser ablation. The presence of neocartilage, neoglands, and partial epithelialization near the anastomosis was verified in the final pathology findings. Our study demonstrates in situ regenerative tissue growth with intact cartilage following transplantation, marked by neotissue formation on the graft's exterior. The 90-day survival milestone was achieved due to innovative surgical strategies, reinforced with strap muscle attached to the distal trachea. Further improvements in graft design and granulation tissue management are essential to optimize outcomes.

Benchmark Dose of Melamine Exposure for a Renal Injury Marker Mediated by Oxidative Stress: Examples in Patients with Urolithiasis and Occupational Workers.

Establishing a safe exposure level from epidemiological studies while providing direct hazard characterization in humans often faces uncertainty in causality, especially cross-sectional data. With advances in molecular epidemiology, it is reasonable to integrate identified intermediate biomarkers into health risk assessment. In this study, by considering the mediation of the oxidative stress marker malondialdehyde (MDA), we explored the exposure threshold of melamine on the early renal injury marker N-acetyl-ß-D glucosaminidase (NAG). The benchmark dose (BMD) was derived from model averaging of the composite direct effect of melamine exposure and the indirect effect through the mediation of MDA on NAG levels. As illustrative examples, we analyzed 309 adult patients with calcium urolithiasis and 80 occupational workers for the corresponding exposure thresholds. The derived threshold was subpopulation-dependent, with the one-sided lower bound BMDL10 for the patients with urolithiasis with (without) the mediator MDA for the patients with kidney stones and the occupational workers being 0.88 (0.96) µg/kg_bw/day and 22.82 (18.09) µg/kg_bw/day, respectively. The derived threshold levels, considering the oxidative stress marker MDA, were consistent with those without adjusting for the mediation effect. However, the study outcomes were further supported by the suggested mechanism pathway. The threshold for the patients with urolithiasis was up to two orders lower than the current tolerable daily intake level of 200 µg/kg_bw/day recommended by the WHO (EFSA).

African swine fever; insights into genomic aspects, reservoirs and transmission patterns of virus.

African swine fever is a hemorrhagic disease of pigs with high mortality rates. Since its first characterization in 1921, there has been sufficient information about African swine fever virus (ASFV) and related diseases. The virus has been found and maintained in the sylvatic cycle involving ticks and domestic and wild boars in affected regions. The ASFV is spread through direct and indirect contact with infected pigs, their products and carrier vectors especially Ornithodoros ticks. Severe economic losses and a decline in pig production have been observed in ASFV affected countries, particularly in sub-Saharan Africa and Europe. At the end of 2018, the ASFV adversely affected China, the world's leading pork-producer. Control strategies for the disease remained challenging due to the unavailability of effective vaccines and the lack of successful therapeutic measures. However, considerable efforts have been made in recent years to understand the biology of the virus, surveillance and effective control measures. This review emphasizes and summarizes the current state of information regarding the knowledge of etiology, epidemiology, transmission, and vaccine-based control measures against ASFV.

Whole genome and reverse protein phase array landscapes of patient derived osteosarcoma xenograft models.

Osteosarcoma is the most common primary bone malignancy in children and young adults, and it has few treatment options. As a result, there has been little improvement in survival outcomes in the past few decades. The need for models to test novel therapies is especially great in this disease since it is both rare and does not respond to most therapies. To address this, an NCI-funded consortium has characterized and utilized a panel of patient-derived xenograft models of osteosarcoma for drug testing. The exomes, transcriptomes, and copy number landscapes of these models have been presented previously. This study now adds whole genome sequencing and reverse-phase protein array profiling data, which can be correlated with drug testing results. In addition, four additional osteosarcoma models are described for use in the research community.