Search

Clinical trials (CTs) often suffer from small sample sizes due to limited budgets and patient enrollment challenges. Using historical data for the CT data analysis may boost statistical power and reduce the required sample size. Existing methods on borrowing information from historical data with right-censored outcomes did not consider matching between historical data and CT data to reduce the heterogeneity. In addition, they studied the survival outcome only, not competing risk outcomes. Therefore, we propose a clustering-based commensurate prior model with random effects for both survival and competing risk outcomes that effectively borrows information based on the degree of comparability between historical and CT data. Simulation results show that the proposed method controls type I errors better and has a lower bias than some competing methods. We apply our method to a phase III CT which compares the effectiveness of bone marrow donated from family members with only partially matched bone marrow versus two partially matched cord blood units to treat leukemia and lymphoma., (© 2025 John Wiley & Sons Ltd.)

Competing risks data in clinical trial or observational studies often suffer from cluster effects such as center effects and matched pairs design. The proportional subdistribution hazards (PSH) model is one of the most widely used methods for competing risks data analyses. However, the current literature on the PSH model for clustered competing risks data is limited to covariate-independent censoring and the unstratified model. In practice, competing risks data often face covariate-dependent censoring and have the non-PSH structure. Thus, we propose a marginal stratified PSH model with covariate-adjusted censoring weight for clustered competing risks data. We use a marginal stratified proportional hazards model to estimate the survival probability of censoring by taking clusters and non-proportional hazards structure into account. Our simulation results show that, in the presence of covariate-dependent censoring, the parameter estimates of the proposed method are unbiased with approximate 95% coverage rates. We apply the proposed method to stem cell transplant data of leukemia patients to evaluate the clinical implications of donor-recipient HLA matching on chronic graft-versus-host disease.

Transpiration is a key process that couples the land-atmosphere exchange of water and carbon, and its maximum water transport ability affects plant productivity. Functional traits significantly influence the maximum transpiration rate; however, which factor plays the dominant role remains unknown. SAPFLUXNET dataset, which includes sap flux density of diverse species worldwide, provides fundamental data to test the importance of photosynthetic and hydraulic traits on maximum tree-level sap flux density (J s_max ). Here, we investigated variations in J s_max of 2194 trees across 129 species using data from the SAPFLUXNET dataset, and analysed the relationship of J s_max with photosynthetic and hydraulic traits. Our results indicated that J s_max was positively correlated with photosynthetic traits at both leaf and tree level. Regarding hydraulic traits, J s_max was positively related to xylem hydraulic conductivity (K s ), leaf-specific hydraulic conductivity (K l ), xylem pressure inducing 50 % loss of hydraulic conductivity (P 50 ), xylem vessel diameter (V dia ), and leaf-to-sapwood area ratio (A l A s ). Random forest model showed that 87 % of the variability in J s_max can be explained by functional traits, and hydraulic traits (e.g., P 50 and sapwood area, A s ) exerted larger effects on J s_max than photosynthetic traits. Moreover, trees with a lower sapwood area or depth could increase their sap flux density to compensate for the reduced whole-tree transpiration. J s_max of the angiosperms was significantly higher than that of the gymnosperms. Mean annual total precipitation (MAP) were positively related to J s_max with a weak correlation coefficient. Furthermore, J s_max showed a significant phylogenetic signal with Blomberg's K below 0.2. Overall, tree species with acquisitive resource economics or more efficient hydraulic systems show higher water transport capacity, and the efficiency of xylem hydraulic system rather than the demand for carbon uptake predominantly determines water transport capacity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Surgical planning for orthognathic procedures demands swift and accurate biomechanical modeling of facial soft tissues. Efficient simulations are vital in the clinical pipeline, as surgeons may iterate through multiple plans. Biomechanical simulations typically use the finite element method (FEM). Prior works divide FEM simulations into increments to enhance convergence and accuracy. However, this practice elongates simulation time, thereby impeding clinical integration. To accelerate simulations, deep learning (DL) models have been explored. Yet, previous efforts either perform simulations in a single step or neglect the temporal aspects in incremental simulations., Purpose: This study investigates the use of spatiotemporal incremental modeling for biomechanics simulations of facial soft tissue., Methods: We implement the method using a graph neural network. Our method synergizes spatial features with temporal aggregation using DL networks trained on incremental FEM simulations from 17 subjects that underwent orthognathic surgery., Results: Our proposed spatiotemporal incremental method achieved a mean accuracy of 0.37 mm with a mean computation time of 1.52 s. In comparison, a spatial-only incremental method yielded a mean accuracy of 0.44 mm and a mean computation time of 1.60 s, while a spatial-only single-step method yielded a mean accuracy of 0.41 mm and a mean computation time of 0.05 s., Conclusions: Statistical analysis demonstrated that the spatiotemporal incremental method reduced mean errors compared to the spatial-only incremental method, emphasizing the importance of incorporating temporal information in incremental simulations. Overall, we successfully implemented spatiotemporal incremental learning tailored to simulate soft tissue deformation while substantially reducing simulation time compared to FEM., (© 2024 American Association of Physicists in Medicine.)

GATA zinc finger domain containing 1 (GATAD1) is an as-yet uncharacterized zinc finger domain protein, which was initially identified as a histone 3 trimethylated at lysine 4 (H3K4me3) interactor. A recessive mutation in GATAD1 is associated with adult-onset dilated cardiomyopathy and heart failure, suggesting that GATAD1 is critical for maintaining normal cardiac structure and function. However, little is known as to the specific role of GATAD1 in cardiomyocytes. A mammalian Gatad1 knockout model has yet to be generated for investigating its specific role in the heart. To address this, we generated a Gatad1 cardiomyocyte-specific knockout (cKO) mouse model. Gatad1 cKO mutants exhibited normal cardiac function during the aging process up to 18 months of age. Unlike the abnormal nuclei shape observed in patients carrying GATAD1 mutations, the nuclei shape of cardiomyocytes remained unaffected by the loss of Gatad1. Furthermore, Gatad1 cKO mice responded normally to pressure overload induced by transverse aortic constriction (TAC) surgery. Together, these observations suggest that deletion of Gatad1 in cardiomyocytes does not induce cardiomyopathy during aging or affect the response to pressure overload stress in mice., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Disclosures: No conflicts of interest, financial or otherwise, are declared by the authors., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Atheroprotective shear stress preserves endothelial barrier function, while atheroprone shear stress enhances endothelial permeability. Yet, the underlying mechanisms through which distinct flow patterns regulate EC integrity remain to be clarified. This study aimed to investigate the involvement of Kindlin-2, a key component of focal adhesion and endothelial adherens junctions crucial for regulating endothelial cell (EC) integrity and vascular stability., Methods: Mouse models of atherosclerosis in EC-specific Kindlin-2 knockout mice ( Kindlin-2 iΔEC ) were used to study the role of Kindlin-2 in atherogenesis. Pulsatile shear (12±4 dynes/cm 2 ) or oscillatory shear (0.5±4 dynes/cm 2 ) were applied to culture ECs. Live-cell imaging, fluorescence recovery after photobleaching assay, and OptoDroplet assay were used to study the liquid-liquid phase separation (LLPS) of Kindlin-2. Co-immunoprecipitation, mutagenesis, proximity ligation assay, and transendothelial electrical resistance assay were used to explore the underlying mechanism of flow-regulated Kindlin-2 function., Results: We found that Kindlin-2 localization is altered under different flow patterns. Kindlin-2 iΔEC mice showed heightened vascular permeability. Kindlin-2 iΔEC were bred onto ApoE -/- mice to generate Kindlin-2 iΔEC ; ApoE - /- mice, which displayed a significant increase in atherosclerosis lesions. In vitro data showed that in ECs, Kindlin-2 underwent LLPS, a critical process for proper focal adhesion assembly, maturation, and junction formation. Mass spectrometry analysis revealed that oscillatory shear increased arginine methylation of Kindlin-2, catalyzed by PRMT5 (protein arginine methyltransferase 5). Functionally, arginine hypermethylation inhibits Kindlin-2 LLPS, impairing focal adhesion assembly and junction maturation. Notably, we identified R290 of Kindlin-2 as a crucial residue for LLPS and a key site for arginine methylation. Finally, pharmacologically inhibiting arginine methylation reduces EC activation and plaque formation., Conclusions: Collectively, our study elucidates that mechanical force induces arginine methylation of Kindlin-2, thereby regulating vascular stability through its impact on Kindlin-2 LLPS. Targeting Kindlin-2 arginine methylation emerges as a promising hemodynamic-based strategy for treating vascular disorders and atherosclerosis., Competing Interests: None.

In patients with multiple myeloma (MM) not-eligible for autologous haematopoietic cell transplantation (autoHCT), a simplified frailty index (SFI) identifies frail patients at risk for poor outcomes, but data are limited for transplant-eligible patients. In this registry-based retrospective study, we used an adapted version of the SFI to determine the prevalence of frailty in patients ≥65 years of age with MM undergoing autoHCT. Out of 5563 patients, 37.9% of patients were classified as frail and although they had increased non-relapse mortality (NRM) and inferior overall survival, the NRM at 100 days remained low (<2%) compared with non-frail patients., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Poultry meat, particularly Peking ducks, holds a significant global market share, prized for their high meat yield and fat content. However, understanding of the molecular genetic mechanisms influencing carcass yield in ducks is limited. This research aims to use genome-wide association analysis to uncover single-nucleotide polymorphisms influencing carcass yield in Peking ducks, followed by identifying candidate genes linked to carcass traits. In this study, we analyzed seven traits of 643 Peking ducks at age 42 days and identified novel loci associated with these traits. A total of 35 significant loci were detected, with eight SNPs reaching genome-wide significance. KIF20B, AGBL5, SGSM1, MRO, PLAG1, XKR4, and TGS1 were considered as important candidate genes influencing carcass yield in ducks. This study adds to the list of genes affecting Peking duck body traits, aiding marker-assisted breeding and enhancing economic yield., (© 2024 Stichting International Foundation for Animal Genetics.)

Background: Although earlier observational studies have revealed a connection between human papillomavirus (HPV) infection and several autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), the exact causative mechanism underlying this association is still unknown., Methods: This two-sample bidirectional MR study was conducted based on publicly released data from genome-wide association studies (GWAS). Our results were mainly derived from the inverse variance weighted (IVW) model, with the remaining three models also being calculated. The MR Steiger test was used to examine the correctness of our causal direction. Sensitivity analysis was performed using Mendelian randomized pleiotropy residual sum and outlier (MR-PRESSO), MR-Egger regression., Results: The IVW results showed that there was a positive causal association between HPV16 E7 protein and SLE (odds ratio (OR) = 1.075, 95% confidence interval (CI), 1.003-1.151, FDR-p = 0.04), however, there was a negative causal association between HPV18 E7 protein and SLE (OR = 0.884, 95% CI, 0.804-0.972, FDR-p = 0.02). No causal associations of HPV16 E7 protein and HPV18 E7 protein with RA, IBD was observed including its subtypes Ulcerative colitis (UC) and Crohn's disease (CD). Sensitivity analysis showed that there was no significant heterogeneity (p > 0.05) or genetic pleiotropy (p > 0.05)., Conclusion: Our two-sample bidirectional Mendelian randomization study identifies a causal association between HPV infection and SLE, but no causal association between HPV infection and RA and IBD., (© 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

The purpose of this study was to comprehensively analyze the genetic diversity of the Pekin duck conserved population with five generations and to evaluate the effectiveness of the current conservation strategy. In total, 277 Pekin duck conserved individuals and 40 Mallards as ancestral controls were collected. Each duck was sequenced at about 10X whole-genome coverage, while over 7.4 million single nucleotide polymorphisms (SNPs) in total were detected for genetic diversity analysis. Both the expected heterozygosity and observed heterozygosity values exceeded 0.3. The genetic differentiation (F ST ) values ranged from 0.007 to 0.039, and the Polymorphism information content (PIC) values ranged from 0.29 to 0.34. These results indicate no significant differentiation between generations, and the genetic diversity remains high. In particular, the inbreeding coefficient has been strictly controlled and has not increased rapidly during the conservation. Overall, the inbreeding coefficient of the conserved Pekin duck population was higher than that of its wild ancestors, indicating that domestication has resulted in reduced genetic diversity. This is the first report using whole genome resequencing data to systematically evaluate the genomic dynamics across several generations in ducks. The results show that the strategy of free mating and random seed retention within sire families is effective for maintaining the genetic diversity of the conserved Pekin duck population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could appear to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Maternal nutrition during the perinatal stage is critical to offspring brain development. Egg yolks are a balanced and nutrient-dense food that is rich in bioactive components crucial to optimal neurodevelopment early in life. Egg consumption is often recommended to pregnant women to enhance both maternal and fetal health. We hypothesized that maternal intake of egg yolk from late gestation and throughout lactation would enhance functional organization and cognitive developmental outcomes in offspring using a pig model. Sows were fed a control diet (n = 6) or a diet containing egg yolks (n = 5, 350 mg egg yolk powder/kg BW/day, equivalent to ∼3 eggs/day for humans) from late gestation through lactation. At weaning, piglet offspring (n = 2/sow, total n = 22) underwent structural magnetic resonance imaging (MRI) and resting-state-functional MRI. Piglets underwent novel object recognition testing to assess hippocampal-dependent learning and memory. Functional MRI results demonstrated that egg yolk significantly increased functional activation in the executive network (p = 0.0343) and cerebellar network (p = 0.0253) in piglets when compared to control. Diffusion tensor imaging analysis showed that perinatal intake of egg yolks significantly increased white matter fiber length in the hippocampus (p = 0.0363) and cerebellum (p = 0.0287) in piglet offspring compared to control piglets. Furthermore, piglets from egg yolk-fed sows spent significantly more proportional frequency exploring the novel object than the familiar object in novel object recognition testing (p = 0.0370). The findings from this study support egg yolk-altered activation of specific brain networks may be associated with functional cognitive outcomes in weaning piglets., Competing Interests: Author declarations The authors have no conflicts to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Skin injuries are a major healthcare problem that are not well understood or prevented in the critically ill, suggesting that underappreciated variables are contributing. This pilot study tested the hypothesis that perfusion-related factors contribute to skin injuries diagnosed as hospital-acquired pressure injuries (HAPIs). A total of 533 adult patients were followed over 2574 critical care days (mean age 62.4, standard deviation (SD) 14.3 years, mean body mass index 30.4 (SD 7.4) kg/m 2 , 36.4% female). This was a secondary analysis of prospective, non-randomised clinical data from an intensive care unit at a large urban teaching hospital. Factors related to perfusion, specifically two or more infusions of vasopressors/inotropes, temporary mechanical circulatory support (MCS), extracorporeal membrane oxygenation, and durable MCS, were analysed to determine whether they were more strongly associated with HAPIs than immobility due to prolonged mechanical ventilation (>72 h) or operating room time (>6 h). Patients diagnosed with a HAPI had a statistically significant higher risk of being exposed to variables related to perfusion and immobility ( P  < 0.05 for each variable). Perfusion-related variables, except durable MCS, had a larger effect on skin breakdown (number needed to harm (NNH) 4-10) than immobility-associated variables (NNH 12-17). The finding that perfusion-related variables predicted HAPIs may warrant consideration of alternative diagnoses, such as skin failure due to impaired perfusion as a pathophysiological process that occurs concurrently with multisystem organ failure. Differentiation of skin injuries primarily from circulatory malfunction, rather than external pressure, may guide the development of more effective treatment and prevention protocols. This pilot study suggests that the contribution of perfusion to skin injuries should be explored further.

Perinatal stage represents a critical period for brain development. Docosahexaenoic acid (DHA) is a ω-3 polyunsaturated fatty acid preferentially accumulated in the brain that may benefit neurodevelopment. Microbial colonization and maturation parallel with the rapid development of infant metabolic and brain function that may influence the effects of DHA on neurological development. This review aims to summarize the current literature on the mediating effects of DHA on brain and gut microbiome development and attempts to reevaluate the efficacy of DHA from a gut microbiome-mediated perspective. Specifically, the regulatory roles of DHA on hypothalamic-pituitary-adrenal axis, inflammation, and neuroactive mediators may be partly moderated through gut microbiome. Consideration of the gut microbiome and gut-brain communication, when evaluating the efficacy of DHA, may provide new insights in better understanding the mechanisms of DHA and impart advantages to future development of nutritional therapy based on the nutrient-microbiome interaction., Competing Interests: Author Declarations The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aim: Transcriptional regulation of gene expression plays a crucial role in orchestrating complex morphogenetic and molecular events during heart development and function. Mediator complex is an essential multi-subunit protein complex that governs gene expression in eukaryotic cells. Although Mediator subunits (MEDs) work integrally in the complex, individual MED component displays specialized functions. MED27, categorized as an Upper Tail subunit, possesses an as-yet-uncharacterized function. In this study, we aimed to investigate the physiological role of MED27 in cardiomyocytes., Materials and Methods: we generated a Med27 floxed mouse line, which was further used to generate constitutive (cKO) and inducible (icKO) cardiomyocyte-specific Med27 knockout mouse models. Morphological, histological analysis and cardiac physiological studies were performed in Med27 cKO and icKO mutants. Transcriptional profiles were determined by RNA sequencing (RNAseq) analysis., Key Fundings: Ablation of MED27 in developing mouse cardiomyocytes results in embryonic lethality, while its deletion in adult cardiomyocytes leads to heart failure and mortality. Similar to the ablation of another Upper Tail subunit, MED30 in cardiomyocytes, deletion of MED27 leads to decreased protein levels of most MEDs in cardiomyocytes. Interestingly, overexpression of MED30 fails to restore the protein levels of Mediator subunits in MED27-deficient cardiomyocytes, demonstrating that the role of MED27 in maintaining the integrity and stability of the Mediator complex is independent of MED30., Significance: Our results revealed an essential role of MED27 in cardiac development and function by maintaining the stability of the Mediator core., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Health workers (HWs) faced considerable psychosocial hazards during the COVID-19 pandemic, which profoundly affected their occupational health and job performance. The potential indirect relationship between workplace violence (WPV) and burnout among HWs needs to be further explored. The purpose of this study is to examine the chain mediating effects of sleep disturbance and work ability in the relationship between WPV and burnout among HWs., Methods: A cross-sectional study was conducted in a secondary hospital two years after the COVID-19 outbreak in Wuhan, China. A sample of 571 HWs was recruited using a cluster sampling method, achieving a response rate of 80.06%. Participants completed self-report questionnaires that included demographic information and measures of WPV, burnout, sleep disturbance, and work ability., Results: The prevalence rates of burnout and WPV among HWs two years after the COVID-19 outbreak were 37.30% and 31.52%, respectively. WPV was significantly associated with burnout (β = 0.446, p < 0.001). Sleep disturbance was identified as a mediator in the relationship between WPV and burnout (β = 0.063, 95% CI: 0.027-0.105), accounting for 14.13% of the total effect. Similarly, work ability also played a mediating role in this relationship (β = 0.142, 95% CI: 0.065-0.225), accounting for 31.84%. Additionally, both sleep disturbance and work ability exhibited a chain mediation effect on the association between WPV and burnout (β = 0.020, 95% CI: 0.008-0.036), and the total indirect effect accounted for 50.67%., Conclusions: Among Chinese HWs, WPV exerts significant direct and indirect effects on burnout symptoms, mediated by sleep disturbance and work ability. This finding provides valuable empirical insights for designing interventions to mitigate the adverse effects of psychosocial factors such as WPV and burnout among HWs. After exposure to WPV, measures focused on reducing sleep disturbance and enhancing work ability may prove effective in alleviating burnout in subsequent interventions.

Background and Aims: Nonampullary duodenal neuroendocrine tumors (NAD-NETs) are rare, with limited evidence regarding endoscopic treatment. This study investigated the efficacy and safety of endoscopic resection of well-differentiated NAD-NETs and evaluated long-term outcomes, including local recurrence and metastasis., Methods: Seventy-eight patients with NAD-NETs who underwent endoscopic resection between January 2011 and August 2022 were included. Clinicopathologic characteristics and treatment outcomes were collected and analyzed., Results: En-bloc resection was achieved for 74 tumors (94.9%) and R0 resection for 68 tumors (87.2%). Univariate analysis identified tumors in the second part of the duodenum, tumor size ≥10 mm, and muscularis propria invasion as risk factors for noncurative resection. Two patients with R1 resection (vertical margin involvement) and 2 patients with lymphovascular invasion underwent additional surgery. Four patients experienced adverse events (5.1%), including 2 cases of delayed bleeding and 2 cases of perforation, all successfully managed conservatively. During a median follow-up period of 62.6 months, recurrence and lymph node metastasis were only detected in 1 patient with R1 resection 3 months after the original procedure., Conclusions: Endoscopic resection is safe and effective and provides a favorable long-term outcome for patients with well-differentiated NAD-NETs without regional lymph node or distant metastasis., Competing Interests: Disclosure All authors disclosed no financial relationships. Research support for this study was provided by grants from the National Natural Science Foundation of China (82000623), Major Project of Shanghai Municipal Science and Technology Committee (23ZR1445500), Yangfan Program of Shanghai Municipal Science and Technology Committee (21YF1440100), and Outstanding Youth Foundation of Zhongshan Hospital, Fudan University (202ZSYQ12)., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Abstract: We evaluate the impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using the Center for International Blood and Marrow Transplant Research registry data for HCTs done between 2013 and 2019. In all 1597 patients, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study-eligible 1032 patients who received peripheral blood grafts for chronic-phase myelofibrosis, 38% of recipients of haploidentical HCT were non-White/Caucasian. Matched sibling donor (MSD)-HCTs were associated with superior overall survival (OS) in the first 3 months (haploidentical hazard ratio [HR], 5.80 [95% confidence interval (CI), 2.52-13.35]; matched unrelated (MUD) HR, 4.50 [95% CI, 2.24-9.03]; mismatched unrelated HR, 5.13 [95% CI, 1.44-18.31]; P < .001). This difference in OS aligns with lower graft failure with MSD (haploidentical HR, 6.11 [95% CI, 2.98-12.54]; matched unrelated HR, 2.33 [95% CI, 1.20-4.51]; mismatched unrelated HR, 1.82 [95% CI, 0.58-5.72]). There was no significant difference in OS among haploidentical, MUD, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months after HCT, relapse, disease-free survival, or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. Although MSD-HCTs were superior, there is no significant difference in HCT outcomes from haploidentical and MUDs. These results establish haploidentical HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Body size is an important growth indicator in ducks and is a primary selection criterion for physical improvement. An excessively rapid growth rate in meat ducks can result in excessive body size, which may hinder subsequent processing and slaughter operations. However, only a few molecular markers related to body size have been studied in meat ducks. In this study, we performed a genome-wide association study (GWAS) to identify candidate genes and QTLs affecting body length (BL), keel bone length (KBL), neck length (NL), and breast width (BrW) in Pekin ducks (Anas platyrhynchos domestica). Our results indicate the significant SNP for NL is located within a pseudogene, whereas the significant SNP for BrW is located in an intergenic region. More importantly, our analysis identified a haplotype that was significantly associated with both BL and KBL. This haplotype, containing 48 single-nucleotide polymorphisms (SNPs), is localized within the XKR4 gene. The identification of this haplotype suggests that XKR4 may be a key candidate gene influencing BL and KBL in Pekin ducks. These findings have important implications for the breeding and genetic improvement of Pekin ducks, and provide valuable insights into the genetic architecture of body size traits in this species.

Purpose: This study examines the application of Large Language Models (LLMs) in diagnosing jaw deformities, aiming to overcome the limitations of various diagnostic methods by harnessing the advanced capabilities of LLMs for enhanced data interpretation. The goal is to provide tools that simplify complex data analysis and make diagnostic processes more accessible and intuitive for clinical practitioners., Methods: An experiment involving patients with jaw deformities was conducted, where cephalometric measurements (SNB Angle, Facial Angle, Mandibular Unit Length) were converted into text for LLM analysis. Multiple LLMs, including LLAMA-2 variants, GPT models, and the Gemini-Pro model, were evaluated against various methods (Threshold-based, Machine Learning Models) using balanced accuracy and F1-score., Results: Our research demonstrates that larger LLMs efficiently adapt to diagnostic tasks, showing rapid performance saturation with minimal training examples and reducing ambiguous classification, which highlights their robust in-context learning abilities. The conversion of complex cephalometric measurements into intuitive text formats not only broadens the accessibility of the information but also enhances the interpretability, providing clinicians with clear and actionable insights., Conclusion: Integrating LLMs into the diagnosis of jaw deformities marks a significant advancement in making diagnostic processes more accessible and reducing reliance on specialized training. These models serve as valuable auxiliary tools, offering clear, understandable outputs that facilitate easier decision-making for clinicians, particularly those with less experience or in settings with limited access to specialized expertise. Future refinements and adaptations to include more comprehensive and medically specific datasets are expected to enhance the precision and utility of LLMs, potentially transforming the landscape of medical diagnostics., Competing Interests: Competing Interests The authors do not have other means of conflict of interest.

Purpose: Accurate estimation of reference bony shape models is fundamental for orthognathic surgical planning. Existing methods to derive this model are of two types: one determines the reference model by estimating the deformation field to correct the patient's deformed jaw, often introducing distortions in the predicted reference model; The other derives the reference model using a linear combination of their landmarks/vertices but overlooks the intricate nonlinear relationship between the subjects, compromising the model's precision and quality., Methods: We have created a self-supervised learning framework to estimate the reference model. The core of this framework is a deep query network, which estimates the similarity scores between the patient's midface and those of the normal subjects in a high-dimensional space. Subsequently, it aggregates high-dimensional features of these subjects and projects these features back to 3D structures, ultimately achieving a patient-specific reference model., Results: Our approach was trained using a dataset of 51 normal subjects and tested on 30 patient subjects to estimate their reference models. Performance assessment against the actual post-operative bone revealed a mean Chamfer distance error of 2.25 mm and an average surface distance error of 2.30 mm across the patient subjects., Conclusion: Our proposed method emphasizes the correlation between the patients and the normal subjects in a high-dimensional space, facilitating the generation of the patient-specific reference model. Both qualitative and quantitative results demonstrate its superiority over current state-of-the-art methods in reference model estimation., (© 2024. CARS.)

Egg production traits are crucial in the poultry industry, including age at first egg (AFE), egg number (EN) at different stages, and laying rate (LR). Ducks exhibit higher egg production capacity than other poultry species, but the genetic mechanisms are still poorly understood. In this study, we collected egg-laying data of 618 Peking ducks from 22 to 66 weeks of age and genotyped them by whole-genome resequencing. Genetic parameters were calculated based on SNPs, and a genome-wide association study (GWAS) was performed for these traits. The SNP-based heritability of egg production traits ranged from 0.09 to 0.54. The GWAS identified nine significant SNP loci associated with AFE and egg number from 22 to 66 weeks. These loci showed that the corresponding alleles were positively correlated with a decrease in the traits. Moreover, three potential candidate genes (ENSAPLG00020011445, ENSAPLG00020012564, TMEM260) were identified. Functional enrichment analyses suggest that specific immune responses may have a critical impact on egg production capacity by influencing ovarian function and oocyte maturation processes. In conclusion, this study deepens the understanding of egg-laying genetics in Peking duck and provides a sound theoretical basis for future genetic improvement and genomic selection strategies in poultry.

Background: Limited evidence exists regarding the link between platelet count and 30-day in-hospital mortality in acute respiratory failure (ARF) patients. Thus, this study aims to investigate this association among ICU patients experiencing acute respiratory failure., Methods: We conducted a retrospective cohort study across multiple centers, utilizing data from the US eICU-CRD v2.0 database covering 22,262 patients with ARF in the ICU from 2014 to 2015. Our aim was to investigate the correlation between platelet count and 30-day in-hospital mortality using binary logistic regression, subgroup analyses, and smooth curve fitting., Results: The 30-day in-hospital mortality rate was 19.73% (4393 out of 22,262), with a median platelet count of 213 × 10 9 /L. After adjusting for covariates, our analysis revealed an inverse association between platelet count and 30-day in-hospital mortality (OR = 0.99, 95% CI 0.99, 0.99). Subgroup analyses supported the robustness of these findings. Furthermore, a nonlinear relationship was identified between platelet count and 30-day in-hospital mortality, with the inflection point at 120 × 10 9 /L. Below the inflection point, the effect size (OR) was 0.89 (0.87, 0.91), indicating a significant association. However, beyond this point, the relationship was not statistically significant., Conclusion: This study establishes a clear negative association between platelet count and 30-day in-hospital mortality among ICU patients with ARF. Furthermore, we have identified a nonlinear relationship with saturation effects, indicating that among ICU patients with acute respiratory failure, the lowest 30-day in-hospital mortality rate occurs when the baseline platelet count is approximately 120 × 10 9 /L., (© 2024. The Author(s).)

To carry out an in-depth analysis of the scientific research on autoimmunity, we performed the first bibliometric analysis focusing on publications in journals dedicated to autoimmunity (JDTA) indexed by science citation index during the period 2004-2023. Using bibliometric analysis, we quantitatively and qualitatively analyzed the country, institution, author, reference and keywords information of publications in JDTA, so as to understand the quantity, publication pattern and publication characteristics of these publications. The co-occurrence networks, clustering map and timeline map were created by CiteSpace and VOSviewer software to visualize the results. The CiteSpace was also used to analyze the strongest citation burst of keywords, which could describe the frequency, intensity and time period of high-frequency keywords, and indicate the research hotspots in the field. A total of 5 710 publications were analyzed, and their annual distribution number was basically stable from 2004 to 2023, fluctuating around 300. The United States and Italy led the way in terms of the number of publications, followed by France and China. For international cooperation, the developed countries represented by the United States cooperate more closely, but the cooperation was localized, reflecting that there was no unified model of autoimmunity among countries. UDICE-French Research Universities had the greatest number of publications. Subsequently, the number of publications decreased slowly with the ranking, and the gradient was not large. Eric Gershwin and Yehuda Shoenfeld stood out among the authors. They had an excellent academic reputation and great influence in the field of autoimmunity. The results of keyword analysis showed that JDTA publications mainly studied a variety of autoimmune diseases, especially SLE and RA. At the same time, JDTA publications also paid special attention to the research of cell function, autoantibody expression, animal experiments, disease activity, pathogenesis and treatment. This study is the first to analyze the publications in JDTA from multiple indicators by bibliometrics, thus providing new insights into the research hotspots and development trends in the field of autoimmunity., (© 2024. The Author(s).)

In order to reveal the current status and future trends of lubricant additives, this study analyzes the structured and unstructured data of 77701 lubricant additive patents recorded by Patsnap. The results show that China is the country with the largest number of patents in this field, and the United States is the main exporting country of international technology flow; the current research and development of lubricant additives is dominated by multifunctional composite additives; environmentally friendly additive compositions are the current research hotspot; and more environmentally friendly and economically degradable additives have more development potential in the future. Overall, this study provides a comprehensive understanding of the research and application of lubricant additives and contributes to the future development of the lubricant industry., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: No conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication., (Copyright: © 2024 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Barth syndrome (BTHS) is a mitochondrial lipid disorder caused by mutations in TAFAZZIN ( TAZ ), required for cardiolipin (CL) remodeling. Cardiomyopathy is a major clinical feature, with no curative therapy. Linoleic acid (LA) supplementation is proposed to ameliorate BTHS cardiomyopathy by enhancing linoleoyl group incorporation into CL. While the beneficial effect of dietary LA supplementation in delaying the development of BTHS cardiomyopathy has been recently tested, its potential to reverse established BTHS cardiomyopathy remains unclear. Our study revealed that LA supplementation cannot rescue established BTHS cardiomyopathy in mice, highlighting the importance of early initiation of LA supplementation for maximum benefits., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Renal interstitial fibrosis (RIF) is a classic pathophysiological process of chronic kidney disease (CKD). However, the mechanisms underlying RIF remain unclear. The present study found that a novel circular RNA, cirInpp5b, might be involved in RIF by high-throughput sequencing. Subsequent experiments revealed that circInpp5b was reduced in UUO mouse kidney tissues and TGF-β1-treated proximal tubular cells. The overexpression of circInpp5b inhibited RIF in UUO mice and prevented extracellular matrix (ECM) deposition in TGF-β1-treated proximal tubular cells. Furthermore, overexpression of circInpp5b down-regulated the protein level of DDX1. Mechanistically, circInpp5b bound to the DDX1 protein and promoted its lysosomal degradation. Collectively, the findings of our study demonstrate that circInpp5b ameliorates RIF by binding to the DDX1 protein and promoting its lysosomal degradation.

Background: Dilated cardiomyopathy (DCM) is one of the most common causes of heart failure. Multiple identified mutations in nexilin (NEXN) have been suggested to be linked with severe DCM. However, the exact association between multiple mutations of Nexn and DCM remains unclear. Moreover, it is critical for the development of precise and effective therapeutics in treatments of DCM., Results: In our study, Nexn global knockout mice and mice carrying human equivalent G645del mutation are studied using functional gene rescue assays. AAV-mediated gene delivery is conducted through systemic intravenous injections at the neonatal stage. Heart tissues are analyzed by immunoblots, and functions are assessed by echocardiography. Here, we identify functional components of Nexilin and demonstrate that exogenous introduction could rescue the cardiac function and extend the lifespan of Nexn knockout mouse models. Similar therapeutic effects are also obtained in G645del mice, providing a promising intervention for future clinical therapeutics., Conclusions: In summary, we demonstrated that a single injection of AAV-Nexn was capable to restore the functions of cardiomyocytes and extended the lifespan of Nexn knockout and G645del mice. Our study represented a long-term gene replacement therapy for DCM that potentially covers all forms of loss-of-function mutations in NEXN., (© 2024. The Author(s).)

Plant glutamate receptor-like channels (GLRs) are homologs of animal ionotropic glutamate receptors. GLRs are critical in various plant biological functions, yet their genomic features and functions in disease resistance remain largely unknown in many crop species. Here, we report the results on a thorough genome-wide study of the GLR family in oilseed rape ( Brassica napus ) and their role in resistance to the fungal pathogen Sclerotinia sclerotiorum . A total of 61 GLRs were identified in oilseed rape. They comprised three groups, as in Arabidopsis thaliana . Detailed computational analyses, including prediction of domain and motifs, cellular localization, cis -acting elements, PTM sites, and amino acid ligands and their binding pockets in BnGLR proteins, unveiled a set of group-specific characteristics of the BnGLR family, which included chromosomal distribution, motif composition, intron number and size, and methylation sites. Functional dissection employing virus-induced gene silencing of BnGLRs in oilseed rape and Arabidopsis mutants of BnGLR homologs demonstrated that BnGLR35 / AtGLR2.5 positively, while BnGLR12 / AtGLR1.2 and BnGLR53 / AtGLR3.2 negatively, regulated plant resistance to S. sclerotiorum , indicating that GLR genes were differentially involved in this resistance. Our findings reveal the complex involvement of GLRs in B. napus resistance to S. sclerotiorum and provide clues for further functional characterization of BnGLRs .

Among cardiovascular diseases, hypertension is the most important risk factor for morbidity and mortality worldwide, and its pathogenesis is complex, involving genetic, dietary and environmental factors. The characteristics of the gut microbiota can vary in response to increased blood pressure (BP) and influence the development and progression of hypertension. This paper describes five aspects of the relationship between hypertension and the gut microbiota, namely, the different types of gut microbiota, metabolites of the gut microbiota, sympathetic activation, gut-brain interactions, the effects of exercise and dietary patterns and the treatment of the gut microbiota through probiotics, faecal microbiota transplantation (FMT) and herbal remedies, providing new clues for the future prevention of hypertension. Diet, exercise and traditional Chinese medicine may contribute to long-term improvements in hypertension, although the effects of probiotics and FMT still need to be validated in large populations., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Cui et al.)

Backgrounds: Long nonconding RNAs (lncRNAs) have been found to be a vital regulatory factor in the development process of human cancer, and could regarded as diagnostic or prognostic biomarkers for human cancers. Here, we aim to confirm the expression and molecular mechanism of RP11-171K16.5 (lnc171) in hepatocellular carcinoma (HCC)., Methods: Screening of differentially expressed lncRNAs by RNA sequencing. Expression level of gene was studied by quantitative real-time PCR (qRT-PCR). The effects of lnc171, mir-873-5p, and ethanol on migration and invasion activity of cells were studied used transwell assay, and luciferase reporter assay was used to confirm the binding site., Results: RNA sequencing showed that lnc171 was markedly up-regulated in HCC. siRNA-mediated knockdown of lnc171 repressed the migration and invasion ability of HCC cells. Bioinformatic analysis, dual luciferase reporter assay, and qRT-PCR indicated that lnc171 interacted with mir-873-5p in HCC cells, and Zin-finger E-box binding homeobox (ZEB1) was a downstream target gene of mir-873-5p. In addition, lnc171 could enhance migration and invasion ability of HCC cells by up-regulating ZEB1 via sponging mir-873-5p. More interestingly, ethanol stimulation could up-regulate the increase of lnc171, thereby regulating the expression of competing endogenous RNA (ceRNA) network factors which lnc171 participated in HCC cells., Conclusions: Our date demonstrates that lnc171 was a responsive factor of ethanol, and plays a vital role in development of HCC via binding of mir-873-5p., (© 2024. The Author(s).)

Background: Long non-coding RNAs (lncRNAs) are involved in many key bioprocesses, including the occurrence and development of rheumatoid arthritis (RA). We aimed to analyze the association of genetic variants of long non-coding RNA LOC553103 and its peripheral blood mononuclear cells (PBMC) expression with RA., Methods: We enrolled 457 RA patients and 551 healthy controls and conducted a case-control study to analyze the relationship between LOC553103 gene rs272879 and the susceptibility of RA by TaqMan single nucleotide polymorphism genotyping. Among them, we sampled 92 cases and 92 controls, respectively, to detect the PBMC level of LOC553103 using quantitative real-time polymerase chain reaction technology. We explored the association between LOC553103 rs272879 and its PBMC expression levels in 71 RA patients. Mann-Whitney, Chi-square, and Spearman correlation analysis were used for statistical analysis and P-value <.05 was considered statistically significant., Results: The genotype frequency of LOC553103 rs272879 CC was increased, and CG was decreased in RA patients compared to the control group (χ2 = 6.772, P = .034). The LOC553103 expression level in PBMC of RA patients was downregulated compared to healthy control (Z = -4.497, P < .001). Moreover, negative correlations were observed between the PBMC level of LOC553103 and erythrocyte sedimentation rate (rs = -0.262, P = .018), white blood cell count (rs = -0.382, P = .004), platelet (rs = -0.293, P = .030), and disease activity score in 28 joints (rs = -0.271, P = .016) in RA patients., Conclusions: This study provides the first evidence supporting an association between LOC553103 gene polymorphisms and susceptibility of RA and a relationship of PBMC level of LOC553103 with clinical manifestations and laboratory indicators of RA patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of Fellowship of Postgraduate Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Harmful algal blooms (HABs) are challenging to recognize because of their striped and uneven biomass distributions. To address this issue, a refined deep-learning algorithm termed HAB-Ne was developed for the recognition of HABs in GF-1 Wide Field of View (WFV) images using Noctiluca scintillans algal bloom as an example. First, a pretrained image super-resolution model was integrated to improve the spatial resolution of the GF-1 WFV images and minimize the impact of mixed pixels caused by the strip distribution. Side-window convolution was also explored to enhance the edge features of HABs and minimize the effects of uneven biomass distribution. In addition, a convolutional encoder-decoder network was constructed for threshold-free HAB recognition to address the dependence on thresholds in existing methods. HAB-Net effectively recognized HABs from GF-1 WFV images, achieving an average precision of 90.1% and an F1-score of 0.86. HAB-Net showed more fine-grained recognition results than those of existing methods, with over 4% improvement in the F1-Score, especially in the marginal areas of HAB distribution. The algorithm demonstrated its effectiveness in recognizing HABs in different marine environments, such as the Yellow Sea, East China Sea, and northern Vietnam. Additionally, the algorithm was proven suitable for detecting the macroalga Sargassum. This study demonstrates the potential of deep-learning-based fine-grained recognition of HABs, which can be extended to the recognition of other fine-scale and strip-distributed objects, such as oil spills and Ulva prolifera., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In orthognathic surgical planning for patients with jaw deformities, it is crucial to accurately simulate the changes in facial appearance that follow the bony movement. Compared with the traditional biomechanics-based methods like the finite-element method (FEM), which are both labor-intensive and computationally inefficient, deep learning-based methods offer an efficient and robust modeling alternative. However, current methods do not account for the physical relationship between facial soft tissue and bony structure, causing them to fall short in accuracy compared to FEM. In this work, we propose an Attentive Correspondence assisted Movement Transformation network (ACMT-Net) to predict facial changes by correlating facial soft tissue changes with bony movement through a point-to-point attentive correspondence matrix. To ensure efficient training, we also introduce a contrastive loss for self-supervised pre-training of the ACMT-Net with a k-Nearest Neighbors (k-NN) based clustering. Experimental results on patients with jaw deformities show that our proposed solution can achieve significantly improved computational efficiency over the state-of-the-art FEM-based method with comparable facial change prediction accuracy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jaime Gateno and Pingkun Yan reports financial support was provided by National Institutes of Health., (Copyright © 2024. Published by Elsevier B.V.)

Synthetic data generation is being increasingly used as a privacy preserving approach for sharing health data. In addition to protecting privacy, it is important to ensure that generated data has high utility. A common way to assess utility is the ability of synthetic data to replicate results from the real data. Replicability has been defined using two criteria: (a) replicate the results of the analyses on real data, and (b) ensure valid population inferences from the synthetic data. A simulation study using three heterogeneous real-world datasets evaluated the replicability of logistic regression workloads. Eight replicability metrics were evaluated: decision agreement, estimate agreement, standardized difference, confidence interval overlap, bias, confidence interval coverage, statistical power, and precision (empirical SE). The analysis of synthetic data used a multiple imputation approach whereby up to 20 datasets were generated and the fitted logistic regression models were combined using combining rules for fully synthetic datasets. The effects of synthetic data amplification were evaluated, and two types of generative models were used: sequential synthesis using boosted decision trees and a generative adversarial network (GAN). Privacy risk was evaluated using a membership disclosure metric. For sequential synthesis, adjusted model parameters after combining at least ten synthetic datasets gave high decision and estimate agreement, low standardized difference, as well as high confidence interval overlap, low bias, the confidence interval had nominal coverage, and power close to the nominal level. Amplification had only a marginal benefit. Confidence interval coverage from a single synthetic dataset without applying combining rules were erroneous, and statistical power, as expected, was artificially inflated when amplification was used. Sequential synthesis performed considerably better than the GAN across multiple datasets. Membership disclosure risk was low for all datasets and models. For replicable results, the statistical analysis of fully synthetic data should be based on at least ten generated datasets of the same size as the original whose analyses results are combined. Analysis results from synthetic data without applying combining rules can be misleading. Replicability results are dependent on the type of generative model used, with our study suggesting that sequential synthesis has good replicability characteristics for common health research workloads., (© 2024. The Author(s).)

Competing Interests: Disclosures None.

A lack of available information on heating, ventilation, and air-conditioning (HVAC) systems can affect the performance of data-driven fault-tolerant control (FTC) models. This study proposed an in situ selective incremental calibration (ISIC) strategy. Faults were introduced into the indoor air (Ttz1) thermostat and supply air temperature (Tsa) and chilled water supply air temperature (Tchws) sensors of a central air-conditioning system. The changes in the system performance after FTC were evaluated. Then, we considered the effects of the data quality, data volume, and variable number on the FTC results. For the Ttz1 thermostat and Tsa sensor, the system energy consumption was reduced by 2.98% and 3.72% with ISIC, respectively, and the predicted percentage dissatisfaction was reduced by 0.67% and 0.63%, respectively. Better FTC results were obtained using ISIC when the Ttz1 thermostat had low noise, a 7-day data volume, or sufficient variables and when the Tsa and Tchws sensors had low noise, a 14-day data volume, or limited variables.

Background: Skin cutaneous melanoma (SKCM) is one of the fastest developing malignancies with strong aggressive ability and no proper curative treatments. Numerous studies illustrated the importance of N6-methyladenosine (m6A) RNA modification to tumorigenesis. The aim of this study was to identify novel prognostic signature by using m6A-related lncRNAs, thus to improve the survival for SKCM patients and guide SKCM therapy., Methods: We downloaded the Presentational Matrix data from The Cancer Genome Atlas (TCGA) and analyzed all the expressed lncRNAs among 468 SKCM samples. Pearson correlation analysis was performed to assess the correlations between lncRNAs and 29 m6A-related genes. Least absolute shrinkage and selection operator (LASSO), univariate and multivariate Cox regression analysis were performed to construct m6A-related lncRNAs prognostic signature (m6A-LPS). The accuracy and prognostic value of this signature were validated by using receiver operating characteristic (ROC) curves, Kaplan-Meier (K-M) survival analysis, univariate COX or multivariate COX analyses. After calculating risk scores, patients were divided into low- and high-risk subgroups by the median value of risk scores., Results: A total of 2973 lncRNAs were found expressed among SKCM tissues. Prognostic analysis showed that 98 lncRNAs had a significant effect on the survival of SKCM patients. The m6A-LPS was validated using K-M and ROC analysis and the predictive accuracy of the risk score was also high according to the AUC of the ROC curve in training and testing sets. A nomogram based on tumor stage, gender and risk score that had a strong ability to forecast the 1-, 2-, 3-, 5-year OS of SKCM patients confirmed by calibrations. Enrichment analysis indicated that malignancy-associated biological processes and pathways were more common in the high-risk subgroup., Conclusion: Collectively, m6A-related lncRNAs exert as potential biomarkers for prognostic stratification of SKCM patients and may assist clinicians achieving individualized treatment for SKCM., Competing Interests: Declaration of Competing Interests The authors declare that they have no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Evidence regarding the relationship between blood urea nitrogen (BUN) and 3-month outcomes in acute ischemic stroke (AIS) patients is still scarce. Therefore, the present study was preformed to explore the link between the BUN and 3-month poor outcomes in patients with AIS., Methods: A retrospective study of 1866 participants with AIS enrolled from January 2010 to December 2016 at a hospital in South Korea. Binary logistic regression, smooth curve fitting, and a set of sensitivity analyses were used to analyze the association between BUN and 3-month poor outcomes., Results: After adjusting covariates, the results of the binary logistic regression model suggested that the relationship between the BUN and the risk of 3-month poor outcomes for AIS patients was not statistically significant. However, there was a special nonlinear relationship between them, and the inflection point of the BUN was 13 mg/dl. On the left side of the inflection point, every unit increase in the BUN reduces the risk of 3-month poor outcomes by 14.1 % (OR = 0.859, 95%CI: 0.780-0.945, p = 0.0019). On the right side of the inflection point, the relationship is not statistically significant., Conclusion: There is a nonlinear relationship with saturation effect between BUN level and 3-month poor outcomes in AIS patients. Maintaining the BUN at around 13 mg/dl can reduce the risk of 3-month poor outcome in AIS patients., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The case-cohort study design provides a cost-effective study design for a large cohort study with competing risk outcomes. The proportional subdistribution hazards model is widely used to estimate direct covariate effects on the cumulative incidence function for competing risk data. In biomedical studies, left truncation often occurs and brings extra challenges to the analysis. Existing inverse probability weighting methods for case-cohort studies with competing risk data not only have not addressed left truncation, but also are inefficient in regression parameter estimation for fully observed covariates. We propose an augmented inverse probability-weighted estimating equation for left-truncated competing risk data to address these limitations of the current literature. We further propose a more efficient estimator when extra information from the other causes is available. The proposed estimators are consistent and asymptotically normally distributed. Simulation studies show that the proposed estimator is unbiased and leads to estimation efficiency gain in the regression parameter estimation. We analyze the Atherosclerosis Risk in Communities study data using the proposed methods., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Biometric Society.)

Leaf carbon isotope composition (δ 13 C) provides an integrative record on the carbon and water balance of plants over long periods. Photosynthetic ability and hydraulic traits which are highly associated with stomatal behavior could affect leaf δ 13 C. Association between photosynthetic ability and leaf δ 13 C has been examined, however, how hydraulic traits influence leaf δ 13 C has not been fully understood. To fill this gap, we investigated the variations in leaf δ 13 C among 2591 woody species (547 shrub and 2044 tree species), and analyzed the link of leaf δ 13 C with leaf photosynthetic and xylem hydraulic traits. Our result showed that leaf δ 13 C was positively correlated to leaf photosynthetic ability and capacity. For hydraulic traits, leaf δ 13 C was negatively related to hydraulic conductivity (K s ), xylem pressure inducing 50 % loss of hydraulic conductivity (P 50 ) and vessel diameter (V dia ). Associations of leaf δ 13 C with xylem hydraulic traits indicate woody species with stronger hydraulic safety discriminated less against 13 C, while woody species with higher hydraulic efficiency had more negative leaf δ 13 C. Shrub species, which showed a lower V dia and P 50 , had a significant less negative leaf δ 13 C than tree species. Furthermore, woody species inhabiting in dry regions discriminated less against 13 C than those growing in humid regions. Moreover, leaf δ 13 C displayed a low phylogenetic signal based on Blomberg's K statistic. Overall, woody species with a higher leaf photosynthetic ability or stronger hydraulic safety system discriminated less against 13 C and adopt the provident water use strategy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Aim: This study investigated the molecular action mechanism of a compound herb, also known as the Dendrobium officinale throat-clearing formula (QYF), by using network pharmacology and animal experimental validation methods to treat chronic pharyngitis (CP)., Methods: The active ingredients and disease targets of QYF were determined by searching the Batman-TCM and GeneCards databases. Subsequently, the drug-active ingredient-target and protein-protein interaction networks were constructed, and the core targets were obtained through network topology. The Metascape database was screened, and the core targets were enriched with Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes., Results: In total, 1403 and 241 potential targets for drugs and diseases, respectively, and 81 intersecting targets were yielded. The core targets included TNF, IL-6, and IL-1β, and the core pathways included PI3K-Akt. The QYF treatment group exhibited effectively improved general signs, enhanced anti-inflammatory ability in vitro , reduced serum and tissue expressions of TNF- α, IL-6, and IL-1β inflammatory factors, and decreased blood LPS levels and Myd88, TLR4, PI3K, Akt, and NF-κB p65 protein expression in the tissues., Conclusion: QYF could inhibit LPS production, which regulated the expression of the TLR4/PI3K/Akt/NF-κB signaling pathway to suppress the expression of the related inflammatory factors (i.e., TNF-α, IL-6, and IL-1β), thereby alleviating the CP process., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background and Objectives: Cumulative lipid profile burden is designed to dynamically measure lipid accumulation, and its effect on hypertension has been poorly studied. Our main purpose was to investigate the effect of cumulative lipid profile burden on the incidence of essential hypertension (EH) and to investigate whether cumulative lipid burden mediates the pathogenesis of the effects of diet and obesity on EH., Subjects and Methods: A total of 1295 participants were included in the study, which started in 2017. The average follow-up time was 2.98 years. A total of 240 EH patients occurred during the follow-up period., Results: The HR (95% CI) of the highest quartile in cumulative Total cholesterol (TC), triglyceride (TG) and high density lipoprotein (HDL) burden were 1.747 (1.145 - 2.664), 1.502 (1.038 - 2.173), 0.615 (0.413 - 0.917) for incidence of EH respectively, compared to the respective reference groups. Participants with EH consumed more red meat and refined grains, and red meat was positively associated with cumulative TC burden. BMI and Waist-To-Height Ratio (WHtR) increased the incidence of EH, and obesity was positively correlated with cumulative TG burden. Mediating analysis showed that cumulative TG had a partial mediating effect in the causal relationship between obesity and EH, and Mendelian randomization (MR) also proved this result. Diet was not found to influence EHn through cumulative lipid profile burden., Conclusions: The cumulative TG burden partially mediates the effect of obesity on EH., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Thiotepa/carmustine (TT-BCNU) is a commonly used autologous transplant (ASCT) conditioning regimen for primary DLBCL of the CNS (PCNSL). The total thiotepa dose varies among TT-BCNU recipients, with some centers administering a total dose of 20 mg/kg, while others using 10 mg/kg. We retrospectively assessed the impact of thiotepa dose intensity on ASCT outcomes in 218 adult PCNSL patients who underwent a first ASCT with TT-BCNU conditioning and received either a total thiotepa dose of 10 mg/kg (TT-10 group; N = 90), or 20 mg/kg (TT-20 group; N = 128). The median follow-up of survivors was 22 months. The cumulative incidence of 1-year non-relapse mortality (NRM) for TT-10 and TT-20 cohorts were 6% (95%CI = 2-12%) vs. 4% (95%CI = 1-8%), respectively (p = 0.66). The 3-year cumulative incidence of relapse (15% vs. 13%; p = 0.67), progression-free survival (PFS) (71% vs. 80%; p = 0.25) and overall survival (OS) (79% vs. 83%; p = 0.56) were similar in the TT-10 and TT-20 groups, respectively. On multivariate analysis compared to TT-10, the TT-20 cohort was not associated with significantly different risk of NRM (Hazard ration [HR] = 0.77; p = 0.64), relapse/progression (HR = 0.87; p = 0.74), PFS (HR = 0.80; p = 0.48) or OS (HR = 1.10; p = 0.80). In conclusion thiotepa dose-intensity in TT-BCNU conditioning does not impact ASCT outcomes of PCNSL patients., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: There is strong interest from patients, researchers, the pharmaceutical industry, medical journal editors, funders of research, and regulators in sharing clinical trial data for secondary analysis. However, data access remains a challenge because of concerns about patient privacy. It has been argued that synthetic data generation (SDG) is an effective way to address these privacy concerns. There is a dearth of evidence supporting this on oncology clinical trial data sets, and on the utility of privacy-preserving synthetic data. The objective of the proposed study is to validate the utility and privacy risks of synthetic clinical trial data sets across multiple SDG techniques., Methods: We synthesized data sets from eight breast cancer clinical trial data sets using three types of generative models: sequential synthesis, conditional generative adversarial network, and variational autoencoder. Synthetic data utility was evaluated by replicating the published analyses on the synthetic data and assessing concordance of effect estimates and CIs between real and synthetic data. Privacy was evaluated by measuring attribution disclosure risk and membership disclosure risk., Results: Utility was highest using the sequential synthesis method where all results were replicable and the CI overlap most similar or higher for seven of eight data sets. Both types of privacy risks were low across all three types of generative models., Discussion: Synthetic data using sequential synthesis methods can act as a proxy for real clinical trial data sets, and simultaneously have low privacy risks. This type of generative model can be one way to enable broader sharing of clinical trial data.

It is common to study time-to-event data in cancer research such as hematopoietic cell transplantation (HCT) for leukemia. The extensive work has been done for the univariate survival outcome, that is, one event type. However, in practice a subject is often exposed to multiple types of outcomes. In this article, we review various types of right-censored data with multiple outcome types including competing risks data, recurrent event data, and composite endpoints. We also provide hematopoietic cell transplantation data examples., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

With the deepening of research on the correlation between meteorological factors and autoimmune diseases, the relationship between climate change and dermatomyositis (DM) has come to our attention. This study aimed to explore the short-term correlation between meteorological factors and DM outpatient visits. Daily records of hospital outpatient visits for DM, air pollutants, and meteorological factor data in Hefei from January 1, 2018 to December 31, 2021 were obtained. The mean temperature (MT), relative humidity (RH), diurnal temperature range (DTR), and temperature change between neighboring days (TCN) were used to quantify environmental temperature and humidity and their variations. And we performed a time series analysis using a generalized linear model (GLM) in combination with a distributed lag nonlinear model (DLNM). Furthermore, gender and age were further stratified for the analysis. The sensitivity analysis was also performed. A total of 4028 DM outpatient visits were recorded during this period. There were statistically significant associations of low temperature (5th, 1.5 °C), low RH (1st, 48.6%), high RH (99th, 99%), high DTR (75th, 12.6°c), and low TCN (10th, -2.7 °C) that were associated with risk of DM outpatient visits, with lag days of 30, 16, 16, 10, and 14, respectively. Moreover, women were more susceptible to high RH exposure and low TCN exposure, while the elderly were more susceptible to low temperature. This study concluded that exposure to low temperature, extreme RH, and temperature changes (especially high DTR and low TCN) was associated with an increased risk of DM outpatient visits., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: A large body of evidence highlights the importance of genetic variants in the development of psychiatric and metabolic conditions. Among these, the TaqIA polymorphism is one of the most commonly studied in psychiatry. TaqIA is located in the gene that codes for the ankyrin repeat and kinase domain containing 1 kinase (Ankk1) near the dopamine D 2 receptor (D2R) gene. Homozygous expression of the A1 allele correlates with a 30% to 40% reduction of striatal D2R, a typical feature of addiction, overeating, and other psychiatric pathologies. The mechanisms by which the variant influences dopamine signaling and behavior are unknown., Methods: Here, we used transgenic and viral-mediated strategies to reveal the role of Ankk1 in the regulation of activity and functions of the striatum., Results: We found that Ankk1 is preferentially enriched in striatal D2R-expressing neurons and that Ankk1 loss of function in the dorsal and ventral striatum leads to alteration in learning, impulsivity, and flexibility resembling endophenotypes described in A1 carriers. We also observed an unsuspected role of Ankk1 in striatal D2R-expressing neurons of the ventral striatum in the regulation of energy homeostasis and documented differential nutrient partitioning in humans with or without the A1 allele., Conclusions: Overall, our data demonstrate that the Ankk1 gene is necessary for the integrity of striatal functions and reveal a new role for Ankk1 in the regulation of body metabolism., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: FLNC (filamin C), a member of the filamin family predominantly expressed in striated muscles, plays a crucial role in bridging the cytoskeleton and ECM (extracellular matrix) in cardiomyocytes, thereby maintaining heart integrity and function. Although genetic variants within the N-terminal ABD (actin-binding domain) of FLNC have been identified in patients with cardiomyopathy, the precise contribution of the actin-binding capability to FLNC's function in mammalian hearts remains poorly understood., Methods: We conducted in silico analysis of the 3-dimensional structure of mouse FLNC to identify key amino acid residues within the ABD that are essential for FLNC's actin-binding capacity. Subsequently, we performed coimmunoprecipitation and immunofluorescent assays to validate the in silico findings and assess the impact of these mutations on the interactions with other binding partners and the subcellular localization of FLNC. Additionally, we generated and analyzed knock-in mouse models in which the FLNC-actin interaction was completely disrupted by these mutations., Results: Our findings revealed that F93A/L98E mutations completely disrupted FLNC-actin interaction while preserving FLNC's ability to interact with other binding partners ITGB1 (β1 integrin) and γ-SAG (γ-sarcoglycan), as well as maintaining FLNC subcellular localization. Loss of FLNC-actin interaction in embryonic cardiomyocytes resulted in embryonic lethality and cardiac developmental defects, including ventricular wall malformation and reduced cardiomyocyte proliferation. Moreover, disruption of FLNC-actin interaction in adult cardiomyocytes led to severe dilated cardiomyopathy, enhanced lethality and dysregulation of key cytoskeleton components., Conclusions: Our data strongly support the crucial role of FLNC as a bridge between actin filaments and ECM through its interactions with actin, ITGB1, γ-SAG, and other associated proteins in cardiomyocytes. Disruption of FLN-actin interaction may result in detachment of actin filaments from the extracellular matrix, ultimately impairing normal cardiac development and function. These findings also provide insights into mechanisms underlying cardiomyopathy associated with genetic variants in FLNC ABD and other regions., Competing Interests: Disclosures J. Chen consults for LEXEO Therapeutics and Morphic Therapeutic. The other authors report no conflicts.

Objective: The purpose of this study was to precisely evaluate the serum Dickkopf-1 (DKK-1) level in patients with ankylosing spondylitis (AS) relative to that in normal controls and to test the causal relationship between DKK-1 and the risk of AS., Methods: Embase, PubMed, Web of Science, WANFANG DATA, VIP, and China National Knowledge Infrastructure (CNKI) were comprehensively searched until July 2022 for pertinent studies. The pooled standardized mean difference (SMD) with a 95% confidence interval (CI) was calculated by the fixed or random-effect model. In Mendelian randomization (MR) analysis on the causal relationship between serum DKK-1 level and AS risk, the inverse variance weighting method (IVW), MR-Egger regression, weighted median method, and weighted pattern method were applied. Sensitivity analyses, including the horizontal pleiotropy test, heterogeneity test, and leave-one-out test, were also performed., Results: The meta-analysis of 40 studies containing 2,371 AS patients and 1,633 healthy controls showed that there was no significant difference in DKK-1 serum level between AS patients and normal controls (pooled SMD=0.207, 95% CI =-0.418-0.832, P= 0.516). The subgroup analysis of the CRP ≤ 10 mg/L group showed that AS patients had higher serum DKK-1 concentration than the healthy controls (SMD=2.267, 95% CI = 0.102-4.432, P =0.040). Similarly, MR analysis also demonstrated no significant association between DKK-1 serum level and AS (IVW OR =0.999, 95% CI = 0.989-1.008, P= 0.800). All sensitivity analyses revealed consistent results., Conclusions: There was no significant change in serum DKK-1 concentration between AS patients and healthy controls. In addition, no causal relationship exists between serum DKK-1 levels and AS risk., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fang, Chen, Wang, Zhao, Jiang, Fang, Zhang, Pan and Tao.)