Combining the probabilistic finite element model and artificial neural network to study nutrient levels in the human intervertebral discs.

BACKGROUND: Diffusion distance and diffusivity are known to affect nutrient transport rates, but the probabilistic analysis of these two factors remains vacant. There is a lack of effective tools to evaluate disc nutrient levels. METHODS: Five-hundred-disc samples with different combinations of morphological and water content parameters were generated, which were used to evaluate nutrient levels in unloaded and loaded states. Spearman correlation coefficients between inputs and responses were calculated. Artificial neural networks were trained to predict nutrient concentrations based on the dataset generated by the probabilistic finite element model. FINDINGS: In unloaded and loaded states, the minimum oxygen concentration of nucleus pulposus was negatively correlated with disc height (r = -0.83, p < 0.01 and r = -0.76, p < 0.01, respectively), and the minimum glucose concentration of annulus fibrosus was positively correlated with its water content (r = 0.68, p < 0.01 and r = 0.73, p < 0.01, respectively). The maximum lactate concentration of cartilage endplate was affected by endplate thickness (r = 0.94, p < 0.01 and r = 0.95, p < 0.01, respectively). For trained neural networks, nutrient concentrations could be well predicted, with coefficients of determination greater than 0.95 and mean absolute percentage errors less than 5 %. INTERPRETATION: This study underscores the importance of disc height, annulus fibrosus water content, and endplate thickness in regulating nutrient levels, and precise control of these parameters should be prioritized in the design of tissue-engineered discs. Moreover, artificial neural networks might be a promising tool for evaluating nutrient levels.

Use of physiologically based kinetic modeling to predict neurotoxicity and genotoxicity of methylglyoxal in humans.

This study aimed to evaluate human neurotoxicity and genotoxicity risks from dietary and endogenous methylglyoxal (MGO), utilizing physiologically based kinetic (PBK) modeling-facilitated reverse dosimetry as a new approach methodology (NAM) to extrapolate in vitro toxicity data to in vivo dose-response predictions. A human PBK model was defined based on a newly developed and evaluated mouse model enabling the translation of in vitro toxicity data for MGO from human stem cell-derived neurons and WM-266-4 melanoma cells into quantitative human in vivo toxicity data and subsequent risk assessment by the margin of exposure (MOE) approach. The results show that the MOEs resulting from daily dietary intake did not raise a concern for endpoints for neurotoxicity including mitochondrial function, cytotoxicity, and apoptosis, while those for DNA adduct formation could not exclude a concern over genotoxicity. Endogenous MGO formation, especially under diabetic conditions, resulted in MOEs that raised concern not only for genotoxicity but also for some of the neurotoxicity endpoints evaluated. Thus, the results also point to the importance of taking the endogenous levels into account in the risk assessment of MGO.

Association of hospital safety climate and compliance with occupational safety practices among nurse interns: A cross-sectional study using canonical correlation analysis.

Background and Aims: Nurse interns may be at a similar or higher risk than registered nurses. The key elements and mechanisms involved in the effects of safety climate on safety performance are not well understood. This study explores the relationship between the perceived hospital safety climate and compliance with occupational safety practices among nurse interns. Methods: A cross-sectional study was conducted among 178 nurse interns in three tertiary university hospitals in Chongqing city, China. The Chinese version of the Hospital Safety Climate Scale (HSCS) was used to measure the perceived hospital safety climate of nurse interns. Compliance behavior was measured using the Compliance with Occupational Safety Practice Scale (COSPS). Canonical correlation analysis and multiple linear regression modeling were used to examine their relationship. Results: Total scores for the HSCS and COSPS were 92 (80,100) and 185 (175,185) [M (P25, P75)], respectively. Canonical correlation coefficients for canonical variates 1 and 2 were 0.636 (p < 0.001) and 0.414 (p < 0.001), respectively. Nurse interns' compliance with occupational safety practices was mainly influenced by management support, feedback/training, personal protective and engineering control equipment availability, and absence of job hindrance. Multiple linear regression showed that management support of HSCS accounted for 37.1% of the variance in compliance (ß = 0.283, p = 0.039). Conclusion: Nurse interns reported high levels of perceived hospital safety climate and compliance with occupational safety practices. Younger nurse interns reported a lower level of perceived hospital safety climate. Nurse educators can improve interns' compliance by promoting better management support, feedback/training, personal protective and engineering control equipment availability, and fewer job hindrance.

Bone marrow mesenchymal stem cells-derived exosomal miR-381 alleviates lung ischemia-reperfusion injury by activating Treg differentiation through inhibiting YTHDF1 expression.

AIM: Our study aimed to investigate whether BMSCs-derived exosomal miR-381 promotes Treg cell differentiation in lung ischemia-reperfusion injury (LIRI), and the underlying mechanism. METHODS: The in vitro and in vivo models of LIRI were established by hypoxia/reoxygenation (H/R) treatment and lung ischemia/reperfusion (I/R) surgery, respectively. BMSCs-derived exosomes were isolated and identified by western blot, nanoparticle tracking analysis, and transmission electron microscopy. Cell viability, proliferation, and apoptosis were assessed by CCK-8, EdU, and flow cytometry assay, respectively. IL-18 secretion level in lung microvascular endothelial cells (LMECs) and lung tissue homogenate was examined by ELISA. Treg cell differentiation was determined using flow cytometry. The relationships between miR-381, YTHDF1, and IL-18 were investigated using dual-luciferase reporter gene, RIP, and/or RNA pull-down assays. MeRIP assay was employed to determine m6A modification of IL-18 mRNA in LMECs. The ubiquitination level of Foxp3 protein in CD4+ T cells was analyzed by Co-IP assay. RESULTS: BMSCs-derived exosomes reduced LMECs injury and increased Treg cell differentiation in LIRI, whereas miR-381 inhibition in BMSCs weakened these impacts. Mechanistically, miR-381 inhibited IL-18 translation in LMECs by inhibiting YTHDF1 expression via binding to its 3'-UTR. As expected, YTHDF1 overexpression in LMECs abolished the effects of miR-381-overexpressed exosomes on LMECs injury and Treg cell differentiation. Moreover, LMECs-secreted IL-18 inhibited Treg cell differentiation by promoting the ubiquitination degradation of Foxp3 protein. CONCLUSION: BMSCs-derived exosomal miR-381 suppressed IL-18 translation in LMECs through binding to YTHDF1 3'-UTR, thus suppressing the ubiquitination degradation of Foxp3 in CD4+ T cells, which promoted Treg cell differentiation and mitigated LIRI development.

Obesity and survival in advanced non-small cell lung cancer patients treated with chemotherapy, immunotherapy, or chemoimmunotherapy: a multicenter cohort study.

BACKGROUND: The association of body mass index (BMI) with survival outcomes in patients with advanced non-small cell lung cancer (NSCLC) treated with first-line chemotherapy, immunotherapy, or chemoimmunotherapy is controversial. We aimed to investigate these associations, including associations in male and female patients specifically, in a multicenter cohort study. METHODS: We retrospectively analyzed data from seven cohorts comprising 7021 advanced non-small cell lung cancer patients who received chemotherapy (three cohorts), immunotherapy (two cohorts), and chemoimmunotherapy (two cohorts) from five data sources, including a de-identified nationwide (US-based) NSCLC clinico-genomic database and two randomized, double-blind, phase 3 clinical trials. BMI was categorized as underweight, normal weight, overweight, or obese. Underweight patients were excluded because of their small proportion. The primary endpoints were the associations between BMI and progression-free survival (PFS) and overall survival (OS) stratified by treatment type and sex, which were assessed using Kaplan-Meier methods and adjusted Cox modeling. Meta-analyses were performed to combine the adjusted hazard ratios. RESULTS: In the pooled analysis, obesity was significantly associated with improved OS in patients receiving chemotherapy (hazard ratios [HR] = 0.84, 95% confidence interval (CI) 0.76-0.93), but there was no association with PFS (HR = 0.91, 95% CI 0.82-1.02). The association of BMI with OS for patients receiving chemotherapy differed by sex, with an inverse association in men (HR = 0.74, 95% CI 0.64-0.84), but no association observed in women (HR = 0.96, 95% CI 0.81-1.13, Pinteraction = 0.018). No impact of BMI on OS or PFS was detected in patients receiving immunotherapy or chemoimmunotherapy. Obese patients had the lowest level of tumor mutational burden, similar level of programmed death-ligand 1 expression and ESTIMATE scores. CONCLUSIONS: Obesity may be associated with an increased overall survival among male patients treated with chemotherapy, whereas not associated with the outcomes in patients treated with immunotherapy or chemoimmunotherapy.

Stability analysis of deep foundation pit with a double-row cast-in-place piles and diagonal steel lattice braces under sloped excavation conditions.

Existing deep foundation pit support structures are commonly composed of external earth-retaining structures, internal horizontal bracings, and vertical columns. A closed bracing system, often formed by a horizontal support through a bracket board, frequently impedes vertical excavation and soil removal operations in the foundation pit, and the processes of assembly and dismantling are complex and time-consuming. This study presents a combined support system and construction method consisting of cast-in-place piles and diagonal steel lattice braces. For sloped excavation, diagonal braces were constructed by slotting through the reserved soil, allowing the use of a single layer of support within the excavation depth. This approach significantly optimizes the construction process, reducing both project duration and overall cost. The field monitoring results indicated that the support method effectively controlled the lateral displacement of the pile bodies. Field monitoring results demonstrated that the proposed support system effectively controlled the lateral displacement of the pile bodies. The adoption of a support-first, excavation-second approach significantly controlled the settlement of the ground surface around the foundation pit, thereby preventing excessive increments in the axial force of the supports due to the large longitudinal depth excavation. The calculation results of the three-dimensional finite element model for foundation pit excavation and support indicate that the proposed support method results in a decreasing ratio of the maximum lateral deformation depth of the pile body, denoted as δh-m, to the excavation depth He as the excavation depth increases. This implied that the displacement of the pile body was strictly controlled. When the depth of the foundation pit excavation exceeded 10 m, the maximum lateral deformation occurred below 10 m along the pile shaft. The diagonal steel lattice braces transferred the load to the top of the cast-in-place piles at the bottom of the pit, where the stress concentration occurred. During construction, special attention must be paid to the strength of the connection between the pile top and the connecting beams.

Porcine epidemic diarrhea virus E protein induces unfolded protein response through activating both PERK and ATF6 rather than IRE1 signaling pathway.

Porcine epidemic diarrhea virus (PEDV) small envelope protein (E) plays important roles in virus budding, assembly, and release. Our previous study found that PEDV E protein localizes in the endoplasmic reticulum (ER) to trigger the unfolded protein response (UPR). However, how UPR is directly regulated by PEDV E protein remains elusive. Thus, in this study, we investigated the expression of ER chaperone glucose-regulated protein 78 (GRP78) and activations of the three main UPR signaling pathways to elucidate the underlying mechanisms of UPR triggered by PEDV E protein. The results showed that over-expression of PEDV E protein increased expression of GRP78 and induced stronger phosphorylation of both protein kinase RNA-like ER kinase (PERK) and eukaryotic initiation factor-2α (eIF2α), as well as caused the significant degradation of activating transcription factor 6 (ATF6), in both dose- and time-dependent manners. However, PEDV E protein did not induce UPR through the inositol-requiring enzyme 1 (IRE1) signaling pathway, as revealed by the splicing of XBP1 remaining unaffected and unchanged when PEDV E protein was overexpressed. Taken together, these results demonstrate that PEDV E protein induces UPR through activation of both PERK and ATF6 pathways rather than IRE1 signaling. This study not only provides mechanistic details of UPR induced by the PEDV E protein, but also provides insights into these new biologic functions to help us better understand the interactions between PEDV and host cells.

Efficacy of prophylactic antibiotics in the adjuvant treatment of alcohol-related liver disease (ALD): A systematic review and meta-analysisProphylactic antibiotics in ALD.

INTRODUCTION AND OBJECTIVES: This research aims to evaluate the efficacy and safety of prophylactic antibiotics in patients with alcohol-related liver disease (ALD). MATERIALS AND METHODS: We systematically searched databases including PubMed, Embase, Cochrane, and Web of Science up to October 2023. Our scope encompassed the influence of prophylactic antibiotics on all-cause mortality, infection, variceal bleeding, hepatic encephalopathy (HE), hepatorenal syndrome (HRS), adverse events (AE), fungal infection, clostridioides difficile infection (CDI), and multidrug-resistant (MDR) bacterial infection. Additionally, total bilirubin, creatinine, platelet counts, and plasma endotoxin levels were also analyzed. RESULTS: After comprehensive selection, 10 studies with 974 participants were included for further analysis. The study demonstrated that prophylactic antibiotic therapy was associated with reductions in infection rates, HE incidence, variceal bleeding, and all-cause mortality. The treatment did not increase the incidence of AE, fungal infection, and CDI, but it did raise the MDR bacteria infection rate. The analysis revealed no significant protective effect of antibiotic prophylaxis on total bilirubin and creatinine levels. Furthermore, the administration of antibiotics led to marginal increases in platelet counts, a minor reduction in endotoxin concentrations, and a subtle enhancement in HRS; however, these changes did not reach statistical significance. CONCLUSIONS: Prophylactic antibiotic therapy was an effective and safe treatment for advanced ALD. To mitigate the risk of MDR bacterial infections, a strategy of selective intestinal decontamination could be advisable. Future investigations should prioritize varied ALD patient populations with extended follow-up periods and assorted antibiotic regimens to solidify the efficacy and safety of ALD treatments.

Exploring the J-shaped relationship between HALP score and mortality in cancer patients: A NHANES 1999-2018 cohort study.

Background: The recent hemoglobin, albumin, lymphocyte, and platelet (HALP) scores, combined with various clinically available indicators, can comprehensively evaluate the nutritional and immune status of patients. Some observational studies have found a positive correlation between HALP score and cancer prognosis, but the clinical application of HALP score has raised concerns due to the presence of confounding factors. The aim of this study is to explore the relationship between HALP score and long-term mortality in cancer patients. Methods: We extracted 3832 cancer patients with complete baseline information from the National Health and Nutrition Examination Survey (NHANES). The COX regressions and restricted cubic spline (RCS) curves were used to explore the nonlinear relationship between HALP score and long-term mortality risk in cancer patients. Kaplan-Meier (K-M) curve was conducted to evaluate the impact of HALP score on long-term mortality risk. Additionally, subgroup analysis was conducted to verify the stability of the above results. Results: We divided participants into 4 groups based on HALP score, and the COX regression results showed that risk of long-term mortality tended to be lower in cancer patients with high HALP scores. Meanwhile, the RCS curves showed that there was a nonlinear association. The results remained stable in subgroup analyses and in breast cancer, colorectal cancer, cervix and uterus cancer, melanoma, prostate cancer and skin cancer. Conclusions: HALP score were independently associated with the risk of long-term mortality in cancer patients, and there is also a non-linear association. This will provide new perspectives on clinical and nutritional interventions for cancer patients.

The prognosis and metabolite changes of NSCLC patients receiving first-line immunotherapy combined chemotherapy in different M1c categories according to 9th edition of TNM classification.

BACKGROUND: The 9th edition of the TNM Classification for lung cancer delineates M1c into two subcategories: M1c1 (Multiple extrathoracic lesions within a single organ system) and M1c2 (Multiple extrathoracic lesions involving multiple organ systems). Existing research indicates that patients with lung cancer in stage M1c1 exhibit superior overall survival compared to those in stage M1c2. The primary frontline therapy for patients with advanced non-small cell lung cancer (NSCLC), lacking driver gene mutations, involves the use of immune checkpoint inhibitors (ICIs) combined with chemotherapy. Nevertheless, a dearth of evidence exists regarding potential survival disparities between NSCLC patients with M1c1 and M1c2 undergoing first-line immune-chemotherapy, and reliable biomarkers for predicting treatment outcomes are elusive. Serum metabolic profiles may elucidate distinct prognostic mechanisms, necessitating the identification of divergent metabolites in M1c1 and M1c2 undergoing combination therapy. This study seeks to scrutinize survival discrepancies between various metastatic patterns (M1c1 and M1c2) and pinpoint metabolites associated with treatment outcomes in NSCLC patients undergoing first-line ICIs combined with chemotherapy. METHOD: In this study, 33 NSCLC patients lacking driver gene mutations diagnosed with M1c1, and 22 similarly diagnosed with M1c2 according to the 9th edition of TNM Classification, were enrolled. These patients received first-line PD-1 inhibitor plus chemotherapy. The relationship between metastatic patterns and progression-free survival (PFS) in patients undergoing combination therapy was analyzed using univariate and multivariate Cox regression models. Serum samples were obtained from all patients before treatment initiation for untargeted metabolomics analysis, aiming to identify differential metabolites. RESULTS: In the univariate analysis of PFS, NSCLC patients in M1c1 receiving first-line PD-1 inhibitor plus chemotherapy exhibited an extended PFS (HR = 0.49, 95% CI, 0.27-0.88, p = 0.017). In multivariate PFS analyses, these M1c1 patients receiving first-line PD-1 inhibitor plus chemotherapy also demonstrated prolonged PFS (HR = 0.45, 95% CI, 0.22-0.92, p = 0.028). The serum metabolic profiles of M1c1 and M1c2 undergoing first-line PD-1 inhibitors plus chemotherapy displayed notable distinctions. In comparison to M1c1 patients, M1c2 patients exhibited alterations in various pathways pretreatment, including platelet activation, linoleic acid metabolism, and the VEGF signaling pathway. Diminished levels of lipid-associated metabolites (diacylglycerol, sphingomyelin) were correlated with adverse outcomes. CONCLUSION: NSCLC patients in M1c1, devoid of driver gene mutations, receiving first-line PD-1 inhibitors combined with chemotherapy, experienced superior outcomes compared to M1c2 patients. Moreover, metabolomic profiles strongly correlated with the prognosis of these patients, and M1c2 patients with unfavorable outcomes manifested distinct changes in metabolic pathways before treatment. These changes predominantly involved alterations in lipid metabolism, such as decreased diacylglycerol and sphingomyelin, which may impact tumor migration and invasion.

The ability of SPEEK to promote the proliferation and osteogenic differentiation of BMSCs on PEEK surfaces.

To investigate the ability of sulfonated polyetheretherketone (SPEEK) to promote the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and compare the effects of different degrees of sulfonation (DS), SPEEK was made with two different DS. The L-SPEEK group had a lower DS, while the H-SPEEK group had a higher DS. The physicochemical properties of both species were evaluated by scanning electron microscopy (SEM), capitilize Fourier transform infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA), X-ray diffraction (XRD) and differential scanning calorimetry (DSC). Then, proliferation and osteogenic differentiation between the two groups and with pure polyetheretherketone (PEEK) were compared after surface inoculation of bone marrow mesenchymal stem cells (BMSCs). Scanning electron microscopy (SEM) revealed that the surface of the PEEK substrates could be smooth or coarse, and the degree of roughness increased with increasing sulfonation. FTIR spectroscopy showed that both the L-SPEEK and H-SPEEK samples contained sulfonic acid. TGA and XRD revealed that the components in the two groups were the same, but the intensities were different. After BMSC inoculation, a CCK8 assay revealed that the cells proliferated more on the H-SPEEK surface and little on the L-SPEEK surface compared with the PEEK surface. Then, osteogenic differentiation was verified by immunofluorescence staining for OCN and Runx2, which indicated that H-SPEEK had the greatest effect on improving differentiation. The results of alizarin red staining (ARS) and alkaline phosphatase staining (APS) also revealed this trend. Sulfonation can change the microsurface of PEEK, which can improve both BMSC proliferation and osteogenic differentiation.

A Randomized, Double-Blind, Parallel-Group Phase I Study Comparing the Pharmacokinetics, Safety, and Immunogenicity of CMAB015, a Candidate Secukinumab Biosimilar, with Its Reference Product Cosentyx® in Healthy Chinese Male Subjects.

Purpose: Secukinumab, a monoclonal antibody targeting interleukin (IL)-17A, is approved for the treatment of psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, enthesitis-related arthritis, and hidradenitis suppurativa. This study compared the pharmacokinetics (PK), safety, and immunogenicity of CMAB015, a candidate secukinumab biosimilar, with the reference product secukinumab (Cosentyx®) in healthy Chinese male subjects. Patients and methods: This double-blind, parallel-group study randomized healthy Chinese male subjects (N=130) to receive either a single dose of 150 mg CMAB015 or secukinumab subcutaneously. Primary study endpoints were PK parameters such as the maximum concentration (Cmax) and area under the curve from zero to infinity (AUC0-inf), while safety and immunogenicity were secondary endpoints. Results: The 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of Cmax and AUC0-inf for CMAB015 to secukinumab were all within the bioequivalence limits (80.00-125.00%). Other PK parameters were comparable between the groups. The safety profile of CMAB015 was similar to that of secukinumab, with no serious adverse events related to treatment. The incidence of TEAEs was slightly higher in the CMAB015 group, but these events were mild to moderate in severity and did not lead to any withdrawals from the study. Immunogenicity analysis revealed low rates of anti-drug antibody (ADA) positivity, with similar rates between CMAB015 and secukinumab. Conclusion: This study demonstrated equivalent PK, comparable safety, and immunogenicity of CMAB015 to secukinumab in healthy Chinese male subjects. These findings support further clinical evaluation of CMAB015 as a secukinumab biosimilar. Trial Registration: The trial was registered on Clinicaltrials.gov (Identifier No. NCT05734482) and Chinadrugtrials.org.cn (Identifier No. CTR20230105).

Association of baseline serum sodium with long-term outcomes in newly diagnosed coronary heart disease patients without heart failure: a prospective cohort study.

Sodium is crucial for maintaining cardiovascular health, especially in relation to heart failure. The impact of baseline serum sodium concentrations on the outcomes of newly diagnosed coronary heart disease (CHD) without heart failure remains unclear. This prospective cohort study included 681 patients who were newly diagnosed with CHD. Cox proportional hazards models and restricted cubic spline (RCS) analysis were used to assess the relationship between serum sodium concentrations and major adverse cardiovascular events. The improvement in traditional prediction models by the addition of serum sodium concentrations was assessed using changes in the C-statistic, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). During a median follow-up of 51.04 months (IQR: 40.88-53.80 months), 131 events were recorded. Multivariate Cox proportional hazards models showed that the L2 group (136-138.9 mmol/L) had the highest MACE risk. Compared to L2, the hazard ratios (HRs) and 95% confidence intervals (CIs) for the L1 (130-135.9 mmol/L), L3 (139-140.9 mmol/L), L4 (141-142.9 mmol/L), and L5 (143-147.0 mmol/L) groups were 0.31 (0.14-0.70, P = 0.005), 0.48 (030-0.78, P = 0.003), 0.56 (0.34-0.92, P = 0.022), and 0.37 (0.22-0.64, P < 0.001), respectively. Including serum sodium concentrations in the prediction model significantly improved the C-statistic from 0.647 to 0.679 (P = 0.022), with an NRI of 0.338 (P < 0.001) and an IDI of 0.026 (P < 0.001). RCS analysis showed a nonlinear relationship: within the 130-138 mmol/L sodium range, MACE risk gradually increased with higher sodium levels (HR 1.39, 95% CI 1.09-1.76, P = 0.008); whereas within the 138-147 mmol/L range, the risk gradually decreased (HR 0.88, 95% CI 0.80-0.98, P = 0.014). Baseline serum sodium concentrations are significantly associated with long-term cardiovascular risk in newly diagnosed CHD patients, showing an inverted U-shaped relationship, whereas low serum sodium may be specifically linked to higher risks of death and nonfatal myocardial infarction. Further research is needed to explore the impact of long-term changes in serum sodium concentrations on disease prognosis.

External validation of a novel nomogram for diagnosis of Protein Energy Wasting in adult hemodialysis patients.

Background: Protein Energy Wasting (PEW) has high incidence in adult hemodialysis patients and refers to a state of decreased protein and energy substance. It has been demonstrated that PEW highly affects the quality of survival and increases the risk of death. Nevertheless, its diagnostic criteria are complex in clinic. To simplify the diagnosis method of PEW in adult hemodialysis patients, we previously established a novel clinical prediction model that was well-validated internally using bootstrapping. In this multicenter cross-sectional study, we aimed to externally validate this nomogram in a new cohort of adult hemodialysis patients. Methods: The novel prediction model was built by combining four independent variables with part of the International Society of Renal Nutrition and Metabolism (ISRNM) diagnostic criteria including albumin, total cholesterol, and body mass index (BMI). We evaluated the performance of the new model using discrimination (Concordance Index), calibration plots, and Clinical Impact Curve to assess its predictive utility. Results: From September 1st, 2022 to August 31st, 2023, 1,158 patients were screened in five medical centers in Shanghai. 622 (53.7%) hemodialysis patients were included for analysis. The PEW predictive model was acceptable discrimination with the area under the curve of 0.777 (95% CI 0.741-0.814). Additionally, the model revealed well-fitted calibration curves. The McNemar test showed the novel model had similar diagnostic efficacy with the gold standard diagnostic method (p > 0.05). Conclusion: Our results from this cross-sectional external validation study further demonstrate that the novel model is a valid tool to identify PEW in adult hemodialysis patients effectively.

Contextual Deprivation, Race and Ethnicity, and Income in Air Pollution and Cardiovascular Disease.

Importance: Socioeconomically disadvantaged subpopulations are more vulnerable to fine particulate matter (PM2.5) exposure. However, as prior studies focused on individual-level socioeconomic characteristics, how contextual deprivation modifies the association of PM2.5 exposure with cardiovascular health remains unclear. Objective: To assess disparities in PM2.5 exposure association with cardiovascular disease among subpopulations defined by different socioeconomic characteristics. Design, Setting, and Participants: This cohort study used longitudinal data on participants with electronic health records (EHRs) from the All of Us Research Program between calendar years 2016 and 2022. Statistical analysis was performed from September 25, 2023, through February 23, 2024. Exposure: Satellite-derived 5-year mean PM2.5 exposure at the 3-digit zip code level according to participants' residential address. Main Outcome and Measures: Incident myocardial infarction (MI) and stroke were obtained from the EHRs. Stratified Cox proportional hazards regression models were used to estimate the hazard ratio (HR) between PM2.5 exposure and incident MI or stroke. We evaluated subpopulations defined by 3 socioeconomic characteristics: contextual deprivation (less deprived, more deprived), annual household income (≥$50 000, <$50 000), and race and ethnicity (non-Hispanic Black, non-Hispanic White). We calculated the ratio of HRs (RHR) to quantify disparities between these subpopulations. Results: A total of 210 554 participants were analyzed (40% age >60 years; 59.4% female; 16.7% Hispanic, 19.4% Non-Hispanic Black, 56.1% Non-Hispanic White, 7.9% other [American Indian, Asian, more than 1 race and ethnicity]), among whom 954 MI and 1407 stroke cases were identified. Higher PM2.5 levels were associated with higher MI and stroke risks. However, disadvantaged groups (more deprived, income <$50 000 per year, Black race) were more vulnerable to high PM2.5 levels. The disparities were most pronounced between groups defined by contextual deprivation. For instance, increasing PM2.5 from 6 to 10 µg/m3, the HR for stroke was 1.13 (95% CI, 0.85-1.51) in the less-deprived vs 2.57 (95% CI, 2.06-3.21) in the more-deprived cohort; 1.46 (95% CI, 1.07-2.01) in the $50 000 or more per year vs 2.27 (95% CI, 1.73-2.97) in the under $50 000 per year cohort; and 1.70 (95% CI, 1.35-2.16) in White individuals vs 2.76 (95% CI, 1.89-4.02) in Black individuals. The RHR was highest for contextual deprivation (2.27; 95% CI, 1.59-3.24), compared with income (1.55; 95% CI, 1.05-2.29) and race and ethnicity (1.62; 95% CI, 1.02-2.58). Conclusions and Relevance: In this cohort study, while individual race and ethnicity and income remained crucial in the adverse association of PM2.5 with cardiovascular risks, contextual deprivation was a more robust socioeconomic characteristic modifying the association of PM2.5 exposure.

Folylpolyglutamate synthetase inactivation in relapsed ALL induces a druggable folate metabolic vulnerability.

AIMS: The antifolate methotrexate (MTX) is an anchor drug used in acute lymphoblastic leukemia (ALL) with poorly understood chemoresistance mechanisms in relapse. Herein we find decreased folate polyglutamylation network activities and inactivating FPGS mutations, both of which could induce MTX resistance and folate metabolic vulnerability in relapsed ALL. METHODS: We utilized integrated systems biology analysis of transcriptomic and genomic data from relapse ALL cohorts to infer hidden ALL relapse drivers and related genetic alternations during clonal evolution. The drug sensitivity assay was used to determine the impact of relapse-specific FPGS mutations on sensitivity to different antifolates and chemotherapeutics in ALL cells. We used liquid chromatography-mass spectrometry (LC-MS) to quantify MTX and folate polyglutamate levels in folylpoly-γ-glutamate synthetase (FPGS) mutant ALL cells. Enzymatic activity and protein degradation assays were also conducted to characterize the catalytic properties and protein stabilities of FPGS mutants. An ALL cell line-derived mouse leukemia xenograft model was used to evaluate the in vivo impact of FPGS inactivation on leukemogenesis and sensitivity to the polyglutamatable antifolate MTX as well as non-polyglutamatble lipophilic antifolate trimetrexate (TMQ). RESULTS: We found a significant decrease in folate polyglutamylation network activities during ALL relapse using RNA-seq data. Supported by functional evidence, we identified multifactorial mechanisms of FPGS inactivation in relapsed ALL, including its decreased network activity and gene expression, focal gene deletion, impaired catalytic activity, and increased protein degradation. These deleterious FPGS alterations induce MTX resistance and inevitably cause marked intracellular folate shrinkage, which could be efficiently targeted by a polyglutamylation-independent lipophilic antifolate TMQ in vitro and in vivo. CONCLUSIONS: MTX resistance in relapsed ALL relies on FPGS inactivation, which inevitably induces a folate metabolic vulnerability, allowing for an efficacious antifolate ALL treatment strategy that is based upon TMQ, thereby surmounting chemoresistance in relapsed ALL.

Association between the triglyceride glucose-body mass index and future cardiovascular disease risk in a population with Cardiovascular-Kidney-Metabolic syndrome stage 0-3: a nationwide prospective cohort study.

BACKGROUND: The American Heart Association (AHA) has recently introduced the concept of Cardiovascular-Kidney-Metabolic (CKM) syndrome, which is the result of an increasing emphasis on the interplay of metabolic, renal and cardiovascular diseases (CVD). Furthermore, there is substantial evidence of a correlation between the triglyceride glucose-body mass index (TyG-BMI ) and CVD as an assessment of insulin resistance (IR). However, it remains unknown whether this correlation exists in population with CKM syndrome. METHODS: All data for this study were obtained from the China Health and Retirement Longitudinal Study (CHARLS). The exposure was the participants' TyG-BMI at baseline, which was calculated using a combination of triglycerides (TG), fasting blood glucose (FBG) and body mass index (BMI). The primary outcome was CVD, which were determined by the use of a standardised questionnaire during follow-up. To examine the relationship between TyG-BMI and CVD incidence in population with CKM syndrome, both Cox regression analyses and restricted cubic spline (RCS) regression analyses were performed. RESULTS: A total of 7376 participants were included in the final analysis. Of these, 1139, 1515, 1839, and 2883 were in CKM syndrome stages 0, 1, 2, and 3, respectively, at baseline. The gender distribution was 52.62% female, and the mean age was 59.17 ± 9.28 (years). The results of the fully adjusted COX regression analyses indicated that there was a 6.5% increase in the risk of developing CVD for each 10-unit increase in TyG-BMI,95% confidence interval (CI):1.041-1.090. The RCS regression analyses demonstrated a positive linear association between TyG-BMI and the incidence of CVD in the CKM syndrome population (P for overall < 0.001, P for nonlinear = 0.355). CONCLUSIONS: This cohort study demonstrated a positive linear association between TyG-BMI index and increased CVD incidence in a population with CKM syndrome stage 0-3. This finding suggests that enhanced assessment of TyG-BMI index may provide a more convenient and effective tool for individuals at risk for CVD in CKM syndrome stage 0-3.

CACNA1H restrains chemotherapy resistance in ovarian clear cell carcinoma cells by repressing autophagy.

Ovarian clear cell carcinoma (OCCC) is a subtype of ovarian cancer and is highly malignant with high chemoresistance. CACNA1H is pivotal in tumor development. However, the role of CACNA1H in the acquisition process of chemotherapeutic resistance in OCCC cells is rarely reported. Therefore, this study aimed to explore the role of CACNA1H in chemotherapy resistance of OCCC cells and its related mechanism. Based on bioinformatics analysis, we found that CACNA1H was downregulated in chemoresistant OCCC patients compared to chemosensitive OCCC patients. Comparing DDP-resistant and sensitive OCCC cell lines, the resistant strain showed lower CACNA1H mRNA expression. CACNA1H expression was associated with calcium signaling pathways in chemoresistant OCCC patients. CACNA1H mRNA expression was significantly downregulated in OCCC cells compared to normal ovarian epithelial cells. When CACNA1H was overexpressed, intracellular Ca2+ concentration and protein levels of p-CaMKII and p-Akt were significantly upregulated, while protein levels of LC3-II/LC3-I and Beclin1 were downregulated, indicating a repression of autophagy. The rescue experiment revealed that CACNA1H overexpression in drug-resistant OCCC cells reduced autophagy-induced DDP resistance via CaMKII/Akt signaling. Overall, CACNA1H increased intracellular Ca2+ concentration and activated CaMKII/Akt signaling pathway in OCCC, thereby repressing autophagy to maintain the sensitivity of OCCC cells to DDP.

Chemiluminescent/photothermal dual-mode lateral flow immunoassay based on CoFe PBAs/WS2 nanozyme for rapid and highly sensitive point-of-care testing of gentamicin.

Serious adverse drug reactions of gentamicin (GM) significantly limit its clinical use, thus there is an urgent demand to develop reliable strategies to detect its concentration. In this study, we have developed a novel highly sensitive and portable lateral flow immunoassay (LFIA) based on CoFe PBAs/WS2 nanozyme mediated chemiluminescence (CL) and photothermal (PT) dual-mode POCT biosensor for the detection of GM, which successfully combines sensitive laboratory analyses with portable in situ analyses in the field. In this proof-of-principle work, the dynamic detection ranges of CL-LFIA and PT-LFIA mode were 1 pg mL-1 to 100 ng mL-1 and 50 pg mL-1 to 100 ng mL-1 with the limits of detection of 0.33 and 16.67 pg mL-1, respectively. The whole detection of CL-LFIA and PT-LFIA could be completed within 15 min and 30 min, respectively. The recoveries of GM spiked into complex matrices including milk, urine, and serum for CL-LFIA and PT-LFIA were 90.94%-109.74% and 94.49%-109.31%, respectively, indicating the reliability and applicability of the dual-mode LFIA in real samples. The dual-mode POCT biosensor could effectively overcome the false problems with improving accuracy and sensitivity, enabling user to precisely detect GM by laboratory analysis or on-site analysis depending on the source condition. Due to the complementary properties of CL-LFIA and PT-LFIA, the developed POCT biosensor can effectively ensure high-performance detection, showing the potential application of accurately detecting drug concentration in clinical practice.