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Abstract The pathogen Verticillium dahliae secreted effector V. dahliae Aspf2-like protein (VDAL) has been found to cause leaf wilting in cotton, but the ectopic expression of VDAL-encoding gene enhances the resistance to V. dahliae in cotton and Arabidopsis. The application of the VDAL protein powder with optimal dosage promotes the growth and yield in multiple crop species, such as rice and wheat. However, the promotive effects of VDAL on these aspects are sporadically reported in asexually propagated species, including potato, while the molecular regulatory network involved in the process remains unclear. In this study, we observed that VDAL promotes sprouting of the potato pre-basic seed (PBS) tubers and enhances the development of both above-ground and below-ground tissues. Strikingly, VDAL increases the tuber yield in both greenhouse and field trials by up to 18.97%. The time-course transcriptomic analysis and the endogenous phytohormone detection revealed that cytokinin may play an important role in response to VDAL-promoted growth. Interestingly, VDAL-treated PBS tubers show higher resistance to cold temperature (late-spring cold), a phenomenon that is diminished when the lovastatin, a cytokinin inhibitor is applied, indicating that the VDAL-promoted potato growth, particularly under low temperature, is associated with cytokinin.

Abstract Background Research has identified a link between the triglyceride-glucose index (TyG-i) and the risk of mortality in severely ill patients. However, it remains uncertain if the TyG-i affects mortality by influencing heart rate (HR). Methods This study enrolled 3,509 severely ill participants from the Medical Information Mart for Intensive Care (MIMIC-IV) database who had triglyceride, glucose, and HR data upon entering the ICU. Cox regression models were applied to estimate the effect of the TyG-i and HR on 28-day all-cause mortality (ACM) and 28-day in-hospital mortality (IHM). Additionally, Kaplan-Meier (K-M) survival analysis was employed to explore outcome variations among different patient groups. The association of the TyG-i with HR, Sequential Organ Failure Assessment (SOFA) score, and Simplified Acute Physiology Score (SAPS) II was explored through linear regression analysis. Subgroup analysis explored potential interactions among patient characteristics, while sensitivity analysis gauged the robustness of the findings. Additionally, mediation analysis was conducted to assess whether elevated HR acts as an intermediary factor linking the TyG-i to both 28-day ACM and 28-day IHM. Results During the 28-day follow-up, 586 cases (16.7%) died from all causes, and 439 cases (12.5%) died during hospitalisation. Cox results showed that individuals with a heightened TyG-i and elevated HR had the highest 28-day ACM (Hazard Ratio 1.70, P-value below 0.001) and 28-day IHM (Hazard Ratio 1.72, P-value below 0.001) compared to those with a reduced TyG-i and HR. The K-M curves showed that individuals with low TyG-i and low HR had the lowest incidence of 28-day ACM and 28-day IHM. The linear analysis results evidenced that the TyG-i was independently connected to HR (beta = 3.05, P-value below 0.001), and the TyG-i was also independently associated with SOFA score (beta = 0.39, P-value below 0.001) and SAPS II (beta = 1.79, P-value below 0.001). Subgroup analysis revealed a significant association in participants without hypertension, the interaction of an elevated TyG-i and HR strongly correlated with a higher 28-day death risk (interaction P-value below 0.05). Furthermore, HR mediated 29.5% of the connection between the TyG-i and 28-day ACM (P-value = 0.002), as well as 20.4% of the connection between the TyG-i and 28-day IHM (P-value = 0.002). Conclusion For severely ill patients, the TyG-i is distinctly correlated with HR, and elevated levels of both are strongly connected to greater 28-day ACM and 28-day IHM risks, especially in patients without hypertension. Furthermore, elevated HR mediates the connection between the TyG-i and 28-day mortality.

Abstract Objective An alternative metric for evaluating insulin resistance (IR) is the triglyceride glucose-body mass index (TyG-BMI). However, it is yet unclear how TyG-BMI and suicide attempts (SA) are related. The objective of this research was to explore the correlation between the TyG-BMI index and SA in individuals with untreated first-episode (UFE) major depressive disorder (MDD) in Shanxi Province. Methods This cross-sectional study was conducted from September 2016 to December 2018 in the psychiatric outpatient clinic of Taiyuan General Hospital and included 1718 patients with UFE MDD, with a mean age of 34.9 ± 12.4 years. The relationship between TyG-BMI and SA was assessed using logistic regression modeling. We investigated threshold effects using a two-piecewise linear regression model. Results Taking into consideration the potential influence of confounding variables, a comprehensive multivariate logistic regression analysis was conducted, which demonstrated the absence of a statistically significant association between the TyG-BMI index and the occurrence of SA, as evidenced by P-values that were all greater than 0.05. On the other hand, the visual analysis of the smoothed plots revealed a U-shaped relationship between the TyG-BMI index and the incidence of SA, with a notable inflection occurring at a TyG-BMI value of around 210. It was observed that the effect sizes flanking the inflection point, accompanied by their 95% confidence intervals, were 0.985 (95% CI: 0.972 to 0.999, P = 0.031) and 1.012 (95% CI: 1.003 to 1.047, P = 0.005), respectively. Conclusions In UFE MDD patients, a U-shaped link was observed between TyG-BMI and SA, with the minimal SA incidence noted at a TyG-BMI level of 210, signifying that an augmented risk for SA might be connected to both diminished and augmented TyG-BMI levels.

Abstract Osteoarthritis (OA) is a chronic degenerative joint condition characterised by cartilage deterioration and changes in bone morphology, resulting in pain and impaired joint mobility. Investigation into the pathophysiological mechanisms underlying OA has highlighted the significance of mitochondrial dysfunction in its progression. Mitochondria, which are cellular organelles, play a crucial role in regulating energy metabolism, generating reactive oxygen species, and facilitating essential biological processes including apoptosis. In recent years, the utilisation of exogenous drugs and MT to improve mitochondrial function in chondrocytes has shown great promise in OA treatment. Numerous studies have investigated the potential of stem cells and extracellular vesicles in mitochondrial transfer. This review aims to explore the underlying mechanisms of mitochondrial dysfunction in OA and assess the progress in utilising mitochondrial transfer as a therapeutic approach for this disease.

Abstract Background Endonucleases play a crucial role in plant growth and stress response by breaking down nuclear DNA. However, the specific members and biological functions of the endonuclease encoding genes in wheat remain to be determined. Results In this study, we identified a total of 26 TaENDO family genes at the wheat genome-wide level. These genes were located on chromosomes 2 A, 2B, 2D, 3 A, 3B, and 3D and classified into four groups, each sharing similar gene structures and conserved motifs. Furthermore, we identified diverse stress-response and growth-related cis-elements in the promoter of TaENDO genes, which were broadly expressed in different organs, and several TaENDO genes were significantly induced under drought and salt stresses. We further examined the biological function of TaENDO23 gene since it was rapidly induced under drought stress and exhibited high expression in spikes and grains. Subcellular localization analysis revealed that TaENDO23 was localized in the cytoplasm of wheat protoplasts. qRT-PCR results indicated that the expression of TaENDO23 increased under PEG6000 and abscisic acid treatments, but decreased under NaCl treatment. TaENDO23 mainly expressed in leaves and spikes. A kompetitive allele-specific PCR (KASP) marker was developed to identify single nucleotide polymorphisms in TaENDO23 gene in 256 wheat accessions. The alleles with TaENDO23-HapI haplotypes had higher grain weight and size compared to TaENDO23-HapII. The geographical and annual frequency distributions of the two TaENDO23 haplotypes revealed that the elite haplotype TaENDO23-HapI was positively selected in the wheat breeding process. Conclusion We systematically analyzed the evolutionary relationships, gene structure characteristics, and expression patterns of TaENDO genes in wheat. The expression of TaENDO23, in particular, was induced under drought stress, mainly expressed in the leaves and grains. The KASP marker of TaENDO23 gene successfully distinguished between the wheat accessions, revealing TaENDO23-HapI as the elite haplotype associated with improved grain weight and size. These findings provide insights into the evolution and characteristics of TaENDO genes at the genome-wide level in wheat, laying the foundation for further biological analysis of TaENDO23 gene, especially in response to drought stress and grain development.

Abstract Background Populations of Olea europaea subsp. europaea var. sylvestris, the ancestor of cultivated olives, are scattered across the Mediterranean Basin. However, after millennia of possible hybridization with cultivated varieties, the genetic identity of many of these populations remain questionable. In the southern Levant, the plausible primary domestication center of olives, many of the naturally growing olive (NGOs) are considered feral, having developed from nearby olive groves. Here, we investigated the genetic identity of NGOs population in the Carmel region, hypothesizing that their specific location, which limit anemophily, provided an opportunity for the persistence of genuine var. sylvestris. Results We mapped more than 1,000 NGOs on the Kurkar ridge along the Carmel coast, within and outside the residential area of Atlit and used simple sequence repeats of 14 loci to assess the spatial genetic structure of 129 NGOs. Genetic diversity parameters and genetic distances between NGO and cultivated olives, as well as phenotypic and morphometric analyses of their oil content and pits, respectively, indicated the presence of a genuine var. sylvestris population. However, NGOs within the residential area of Atlit and old settlements showed an intermediate admix genetic structure, indicating on hybridization with local varieties, a consequence of their proximity to cultivated trees. Conclusions Integrating the results of genetic and phenotypic analyses we provide crucial evidence of the presence of a genuine var. sylvestris population in the southern Levant, in close geographical proximity to archaeological sites with the earliest evidence of olive exploitation in the ancient world. We supplement the results with recommendations for a conservation program that combines municipal requirements and the urgent need to preserve the largest population of var. sylvestris in the southern Levant.

Abstract Background Cognitive impairment presents in both adolescent-onset(ado-OP) and adult-onset psychosis(adu-OP). Age and neurodevelopmental factors likely contribute to cognitive differences. This study aimed to characterize cognitive functions in ado-OP compared to adu-OP in a clinical population with drug-naive first-episode psychosis(FEP). Methods A total of 788 drug-naive patients with FEP and 774 sex- and age-matched healthy controls(HCs) were included. Participants were divided into four groups by whether they were under or over 21 years of age: adolescent-onset FEP(ado-FEP, n = 380), adult-onset FEP(adu-FEP, n = 408), adolescent HC(ado-HC, n = 334), and adult HC(adu-HC, n = 440). Comprehensive cognitive assessments were performed using the MATRICS Cognitive Consensus Battery(MCCB), covers six cognitive domains: speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning, and problem-solving. Data analyses were conducted using correlation analyses and binary logistic regression. Results The patterns of cognitive domain differences between ado-FEP and adu-FEP were found to be similar to those between ado-HC and adu-HC, whereas cognitive impairments appeared to be more pronounced in patients with adu-OP than ado-OP. The mazes subtest had the maximum effect size(ES) in the FEP(ES = 0.37) and HC(ES = 0.30) groups when comparing the adolescent and adult groups. Cognitive subtests were mostly significantly correlated with negative symptoms, especially for adolescents with FEP, in which all the subtests were significantly correlated with negative symptoms in the ado-FEP group. Better performance in the domains of spatial cognition and problem-solving abilities was more likely in the ado-FEP group than in the adu-FEP group. Conclusions These findings suggest cognitive differences between adolescents and adults but similar patterns of affected domains in HCs and patients with FEP. Therefore, the development of targeted cognitive interventions tailored to the specific needs of different age groups appears warranted.

Abstract Background Both body mass index (BMI) and genetic factors independently contribute to cardiovascular disease (CVD). However, it is unclear whether genetic risk modifies the association between BMI and the risk of incident CVD. This study aimed to investigate whether BMI categories and genetic risk jointly and interactively contribute to incident CVD events, including hypertension (HTN), atrial fibrillation (AF), coronary heart disease (CHD), stroke, and heart failure (HF). Methods A total of 496,851 participants from the UK Biobank with one or more new-onset CVD events were included in the analyses. BMI was categorized as normal weight (

Abstract Background Leukocyte immunoglobulin-like receptor B4 (LILRB4) plays a significant role in regulating immune responses. LILRB4 in microglia might influence the infiltration of peripheral T cells. However, whether and how LILRB4 expression aggravates brain damage after acute ischemic stroke remains unclear. This study investigates the role of LILRB4 in modulating the immune response and its potential protective effects against ischemic brain injury in mice. Methods and results Microglia-specific LILRB4 conditional knockout (LILRB4-KO) and overexpression transgenic (LILRB4-TG) mice were constructed by a Cre-loxP system. Then, they were used to investigate the role of LILRB4 after ischemic stroke using a transient middle cerebral artery occlusion (tMCAO) mouse model. Spatial transcriptomics analysis revealed increased LILRB4 expression in the ischemic hemisphere. Single-cell RNA sequencing (scRNA-seq) identified microglia-cluster3, an ischemia-associated microglia subcluster with elevated LILRB4 expression in the ischemic brain. Flow cytometry and immunofluorescence staining showed increased CD8+ T cell infiltration into the brain in LILRB4-KO-tMCAO mice. Behavioral tests, cortical perfusion maps, and infarct size measurements indicated that LILRB4-KO-tMCAO mice had more severe functional deficits and larger infarct sizes compared to Control-tMCAO and LILRB4-TG-tMCAO mice. T cell migration assays demonstrated that LILRB4-KD microglia promoted CD8+ T cell recruitment and activation in vitro, which was mitigated by CCL2 inhibition and recombinant arginase-1 addition. The scRNA-seq and spatial transcriptomics identified CCL2 was predominantly secreted from activated microglia/macrophage and increased CCL2 expression in LILRB4-KD microglia, suggesting a chemokine-mediated mechanism of LILRB4. Conclusion LILRB4 in microglia plays a crucial role in modulating the post-stroke immune response by regulating CD8+ T cell infiltration and activation. Knockout of LILRB4 exacerbates ischemic brain injury by promoting CD8+ T cell recruitment. Overexpression of LILRB4, conversely, offers neuroprotection. These findings highlight the therapeutic potential of targeting LILRB4 and its downstream pathways to mitigate immune-mediated damage in ischemic stroke.

Abstract The aim of this study was to develop a three-dimensional (3D) cell model in order to evaluate the effectiveness of a traditional Chinese medicine decoction in the treatment of arthritis. Chondrocytes (ATDC5) and osteoblasts (MC3T3-E1) were 3D printed separately using methacryloyl gelatin (GelMA) hydrogel bioinks to mimic the natural 3D cell environment. Both cell types showed good biocompatibility in GelMA. Lipopolysaccharide (LPS) was added to the cell models to create inflammation models, which resulted in increased expression of inflammatory factors IL-1β, TNF-α, iNOS, and IL-6, and decreased expression of cell functional genes such as Collagen II (COLII), transcription factor SOX-9 (Sox9), Aggrecan, alkaline phosphatase (ALP), RUNX family transcription factor 2 (Runx2), Collagen I (COLI), Osteopontin (OPN), and bone morphogenetic protein-2 (BMP-2). The created inflammation model was then used to evaluate the effectiveness of Dangguiniantongtang (DGNT) decoctions. The results showed that DGNT reduced the expression of inflammatory factors and increased the expression of functional genes in the cell model. In summary, this study established a 3D cell model to assess the effectiveness of traditional Chinese medicine (TCM) decoctions, characterized the gene expression profile of the inflammatory state model, and provided a practical reference for future research on TCM efficacy evaluation for arthritis treatment.

Abstract Background As an innovative lipid parameter, NHHR (the ratio of non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol) can serve as a valuable tool for assessing cardiovascular disease risk. Nevertheless, the relationship between NHHR and the risk of kidney stones remains unexplored. Methods A cross-sectional survey utilized data from the National Health and Population Survey (NHANES) database in the United States spanning from 2007 to 2018. Distinct statistical analyses were applied, including weighted logistic regression, stratified and interaction analysis and restricted cubic spline curve (RCS) models, to examine the correlation between NHHR and the incidence of kidney stones. Results This analysis encompassed 24,664 participants, with 9.63% reporting incidents of kidney stones. Following multivariate logistic regression and comprehensive adjustments, participants in NHHR quartile 4 (OR 1.34; 95% CI 1.12, 1.60, P

Abstract Background Human parasitic infections caused by Adenophorean nematodes encompass a range of diseases, including dioctophymiasis, trichuriasis, capillariasis, trichinellosis, and myositis. These infection can result in adverse impacts on human health and cause societal and economic concerns in tropical and subtropical regions. Methods This review conducted searches in PubMed, Embase and Google Scholar for relevant studies that published in established databases up to April 26, 2024. Studies that focused on the common morphology, life cycle, disease distribution, clinical manifestations, and prevention and control strategies for Adenophorean parasitic diseases in humans were included. Results Adenophorean nematodes exhibit shared morphological characteristics with a four-layered cuticle; uninucleate epidermal cells; pseudocoelom with six or more coelomocytes; generally three caudal glands; five esophageal glands; two testes in males with median-ventral supplementary glands in a single row; tail in males rarely possessing caudal alae; amphids always postlabial; presence of cephalic sensory organs; absence of phasmids; and a secretory-excretory system consisting of a single ventral gland cell, usually with a non-cuticularized terminal duct. Humans play two important roles in the life cycle of the nematode class, Adenophorea: 1) as a definitive host infected by ingesting undercooked paratenic hosts, embryonated eggs, infective larvae in fish tissue and meat contaminated with encysted or non-encysted larvae, and 2) as an accidental host infected by ingesting parasitic eggs in undercooked meat. Many organs are targeted by the Adenophorean nematode in humans such as the intestines, lungs, liver, kidneys, lymphatic circulation and blood vessels, resulting in gastrointestinal problems, excessive immunological responses, cell disruption, and even death. Most of these infections have significant incidence rates in the developing countries of Africa, Asia and Latin America; however, some parasitic diseases have restricted dissemination in outbreaks. To prevent these diseases, interventions together with education, sanitation, hygiene and animal control measures have been introduced in order to reduce and control parasite populations. Conclusions The common morphology, life cycle, global epidemiology and pathology of human Adenophorean nematode-borne parasitic diseases were highlighted, as well as their prevention and control. The findings of this review will contribute to improvement of monitoring and predicting human-parasitic infections, understanding the relationship between animals, humans and parasites, and preventing and controlling parasitic diseases. Graphical Abstract

Abstract Background Obesity is an important risk factor for kidney stones(KS). Chinese Visceral Adiposity Index (CVAI), as a specific indicator for visceral obesity in the Chinese population, can more accurately assess the visceral fat content in Chinese individuals compared to Visceral Adiposity Index (VAI). However, the association between CVAI and risk for KS has not been studied. Methods A total of 97,645 participants from a health screening cohort underwent ultrasound examinations for the diagnosis of kidney stones, along with measurements of their CVAI. Logistic regressions were utilized to determine the relationship between different quartiles of CVAI and the incidence of kidney stones. Simultaneously, subgroup analysis and the computation of dose-response curves were employed to pinpoint susceptible populations. Results Among the participants, 2,888 individuals (3.0%) were diagnosed with kidney stones. The mean CVAI values ± standard deviation for the four groups were: Q1 (18.42 ± 19.64), Q2 (65.24 ± 10.39), Q3 (98.20 ± 9.11), and Q4 (140.40 ± 21.73). In the fully adjusted multivariable model, CVAI was positively correlated with urolithiasis (OR = 1.001; 95% CI = 1.000, 1.002). Compared with the first quartile of CVAI, the population in the fourth quartile of CVAI had a higher prevalence of kidney stones (OR = 1.231; 95% CI = 1.066, 1.415). Through subgroup analysis, a positive correlation between CVAI and the risk of kidney stones was found in non-smokers (OR = 1.001, 95%CI:1.000, 1.002), non-drinkers (OR = 1.001, 95%CI:1.000, 1.002), non-hypertensive subgroups (OR = 1.003, 95%CI:1.002, 1.003), and non-diabetes subgroups (OR = 1.001, 95%CI:1.000, 1.002). Conclusion The findings suggest that CVAI could be a reliable and effective biomarker for assessing the potential risk of kidney stone prevalence, with significant implications for the primary prevention of kidney stones and public health.

Abstract Background Kawasaki disease (KD) is an immune vasculitis of unknown origin, characterized by transient inflammation. The activation of the cGAS-STING pathway, triggered by mitochondrial DNA (mtDNA) release, has been implicated in the onset of KD. However, its specific role in the progression of inflammation during KD's acute phase remains unclear. Methods We measured mtDNA and 2’3’-cGAMP expression in KD patient serum using RT-qPCR and ELISA. A murine model of KD was induced by injecting Lactobacillus casei cell wall extract (LCWE), after which cGAS-STING pathway activation and inflammatory markers were assessed via immunohistochemistry, western blot, and RT-qPCR. Human umbilical vein endothelial cells (HUVECs) were treated with KD serum and modulators of the cGAS-STING pathway for comparative analysis. Mitochondrial function was evaluated using Mitosox staining, mPTP opening was quantified by fluorescence microscopy, and mitochondrial membrane potential (MMP) was determined with JC-1 staining. Results KD patient serum exhibited increased mtDNA and 2’3’-cGAMP expression, with elevated levels of pathway-related proteins and inflammatory markers observed in both in vivo and in vitro models. TEM confirmed mitochondrial damage, and further studies demonstrated that inhibition of mPTP opening reduced mtDNA release, abrogated cGAS-STING pathway activation, and mitigated inflammation. Conclusion These findings indicate that mtDNA released through the mPTP is a critical activator of the cGAS-STING pathway, contributing significantly to KD-associated inflammation. Targeting mtDNA release or the cGAS-STING pathway may offer novel therapeutic approaches for KD management.

Abstract Background Cardiovascular disease (CVD) is closely associated with the triglyceride glucose (TyG) index and its related indicators, particularly its combination with obesity indices. However, there is limited research on the relationship between changes in TyG-related indices and CVD, as most studies have focused on baseline TyG-related indices. Methods The data for this prospective cohort study were obtained from the China Health and Retirement Longitudinal Study. The exposures were changes in TyG-related indices and cumulative TyG-related indices from 2012 to 2015. The K-means algorithm was used to classify changes in each TyG-related index into four classes (Class 1 to Class 4). Multivariate logistic regressions were used to evaluate the associations between the changes in TyG-related indices and the incidence of CVD. Results In total, 3243 participants were included in this study, of whom 1761 (54.4%) were female, with a mean age of 57.62 years at baseline. Over a 5-year follow-up, 637 (19.6%) participants developed CVD. Fully adjusted logistic regression analyses revealed significant positive associations between changes in TyG-related indices, cumulative TyG-related indices and the incidence of CVD. Among these changes in TyG-related indices, changes in TyG-waist circumference (WC) showed the strongest association with incident CVD. Compared to the participants in Class 1 of changes in TyG-WC, the odds ratio (OR) for participants in Class 2 was 1.41 (95% confidence interval (CI) 1.08–1.84), the OR for participants in Class 3 was 1.54 (95% CI 1.15–2.07), and the OR for participants in Class 4 was 1.94 (95% CI 1.34–2.80). Moreover, cumulative TyG-WC exhibited the strongest association with incident CVD among cumulative TyG-related indices. Compared to the participants in Quartile 1 of cumulative TyG-WC, the OR for participants in Quartile 2 was 1.33 (95% CI 1.00–1.76), the OR for participants in Quartile 3 was 1.46 (95% CI 1.09–1.96), and the OR for participants in Quartile 4 was 1.79 (95% CI 1.30–2.47). Conclusions Changes in TyG-related indices are independently associated with the risk of CVD. Changes in TyG-WC are expected to become more effective indicators for identifying individuals at a heightened risk of CVD.

Abstract Background Mind wandering is a common phenomenon in daily life. However, the manifestations and cognitive correlates of mind wandering in different subclinical populations remain unclear. In this study, these aspects were examined in individuals with schizotypal traits and individuals with depressive symptoms, i.e., subclinical populations of patients with schizophrenia and depression. Methods Forty-two individuals with schizotypal traits, 42 individuals with subclinical depression, and 42 controls were recruited to complete a mind wandering thought sampling task (state level) and a mind wandering questionnaire (trait level). Measures of rumination and cognitive functions (attention, inhibition, and working memory) were also completed by participants. Results Both subclinical groups exhibited more state and trait mind wandering than did the control group. Furthermore, individuals with schizotypal traits demonstrated more trait mind wandering than individuals with subclinical depression. Rumination, sustained attention, and working memory were associated with mind wandering. In addition, mind wandering in individuals with subclinical depression can be accounted for by rumination or attention, while mind wandering in individuals with high schizotypal traits cannot be accounted for by rumination, attention, or working memory. Conclusions The results suggest that individuals with high schizotypal traits and subclinical depression have different patterns of mind wandering and mechanisms. These findings have implications for understanding the unique profile of mind wandering in subclinical individuals.

Abstract Background Developmental dysplasia of the hip (DDH) is a common childhood health complaint, whose etiology is multifactorial. The incidence of DDH is variable and higher in Tibet plateau. Here, we collected plasma samples and studied the metabolomics signatures of DDH. Methods Fifty babies were enrolled: 25 with DDH and 25 age-matched non-DDH healthy controls (HC group). We collected plasma samples, laboratory parameters and conducted untargeted metabolomics profiling. Results There are many differential metabolites among patients with DDH, including 4-β-hydroxymethyl-4-α-methyl-5-α-cholest-7-en-3-beta-ol, β-cryptoxanthin, α-tocopherol, taurocholic acid, glycocholic acid, 2-(3,4-dihydroxybenzoyloxy)-4,6-dihydroxybenzoate, arabinosylhypoxanthine, leucyl-hydroxyproline, hypoxanthine. The main differential metabolic pathways focused on primary bile acid biosynthesis, arginine and proline metabolism, phenylalanine metabolism, histidine metabolism, purine metabolism. Conclusions To our knowledge, this is the first report of metabolomics profile in babies with DHH. By combining the α-tocopherol and taurocholic acid, we could achieve the differential diagnosis of DDH.

Abstract Dairy buffaloes are typically fed a high-forage, low-quality diet with high fiber. These conditions result in an inherent energy and protein inefficiency. In order to make full and rational use of feed resources and improve the production level and breeding efficiency of dairy buffaloes, the effects of various roughages on nutrient digestibility, ruminal fermentation parameters, and microorganisms in dairy buffaloes were studied in this experiment. Three ternary hybrid buffaloes, with an average body weight of 365 ± 22.1 kg, were selected and fitted with permanent rumen fistulas. They were fed six different diets, each consisting of 1 kg concentrate supplement and one of six types of roughage, including alfalfa hay (A diet), oat hay (O diet), whole corn silage (W diet), king grass (K diet), sugarcane shoot silage (S diet), and rice straw hay (R diet) according to an incomplete Latin square design of 3 × 6, respectively. The pre-feeding period of each period was 12 d. From day 13 to 15 was the official experimental period. During the prefeeding period, free feed intake for each roughage was determined, and during the experiment, the roughage was fed at 90% of the voluntary feed intake. Digestion and metabolism tests were carried out using the total manure collection method to determine the feed intake and fecal output of each buffalo, and to collect feed and fecal samples for chemical analysis. On day 15, rumen fluid samples were collected two hours after morning feeding to determine rumen fermentation parameters and bacterial 16 S rRNA high-throughput sequencing was performed. The results showed that DM and OM digestibility were greatest for the W diet and lowest for the S diet. The rumen pH of the O diet was significantly greater than that of the W diet. The concentration of rumen fluid NH3-N (mg/dL) increased with increased CP content. The concentration of total volatile fatty acids (mmol/L) in the rumen decreased with increased NDF content but increased with increased NFC content. The relative abundances of Bacteroidetes, Firmicutes, and Spirochaetes were 57.03-74.84%, 14.29-21.86%, and 0.44-1.43% in the different quality roughage groups. Bacteroidetes were mainly Prevotellaceae1 and Rikenellaceae RC_gut_group with relative abundances of 30.17-45.75% and 3.23-7.82%. The relative abundance of Patescibacteria and Spirochaetes decreased with increasing roughage quality. These results provide a theoretical and practical basis for evaluating the nutritional value of dairy buffalo feed, utilizing feed resources, matching rations, feeding scientifically, and protecting animal health.

Abstract Background Bacterial nanocellulose (BNC), a natural polymer material, gained significant popularity among researchers and industry. It has great potential in areas, such as textile manufacturing, fiber-based paper, and packaging products, food industry, biomedical materials, and advanced functional bionanocomposites. The main current fermentation methods for BNC involved static culture, as the agitated culture methods had lower raw material conversion rates and resulted in non-uniform product formation. Currently, studies have shown that the production of BNC can be enhanced by incorporating specific additives into the culture medium. These additives included organic acids or polysaccharides. γ-Polyglutamic acid (γ-PGA), known for its high polymerization, excellent biodegradability, and environmental friendliness, has found extensive application in various industries including daily chemicals, medicine, food, and agriculture. Results In this particular study, 0.15 g/L of γ-PGA was incorporated as a medium additive to cultivate BNC under agitated culture conditions of 120 rpm and 30 ℃. The BNC production increased remarkably by 209% in the medium with 0.15 g/L γ-PGA and initial pH of 5.0 compared to that in the standard medium, and BNC production increased by 7.3% in the medium with 0.06 g/L γ-PGA. The addition of γ-PGA as a medium additive resulted in significant improvements in BNC production. Similarly, at initial pH levels of 4.0 and 6.0, the BNC production also increased by 39.3% and 102.3%, respectively. To assess the characteristics of the BNC products, scanning electron microscopy, Fourier transform infrared spectroscopy, and thermogravimetric analysis were used. The average diameter of BNC fibers, which was prepared from the medium adding 0.15 g/L γ-PGA, was twice thicker than that of BNC fibers prepared from the control culture medium. That might be because that polyglutamic acid relieved the BNC synthesis from the shear stress from the agitation. Conclusions This experiment held great significance as it explored the use of a novel medium additive, γ-PGA, to improve the production and the glucose conversion rate in BNC fermentation. And the BNC fibers became thicker, with better thermal stability, higher crystallinity, and higher degree of polymerization (DPv). These findings lay a solid foundation for future large-scale fermentation production of BNC using bioreactors.

Abstract Background External fixation is widely used in the treatment of traumatic fractures; however, orthopedic surgeons encounter challenges in deciding the optimal time for fixator removal. The axial load-share ratio (LS) of the fixator is a quantitative index to evaluate the stiffness of callus healing. This paper introduces an innovative method for measuring the LS and assesses the method’s feasibility and efficacy. Based on a novel hexapod LS-measurement system, the proposed method is to improve the convenience and precision of measuring LS in vivo, hence facilitating the safe removal of external fixators. Methods A novel hexapod system is introduced, including its composition, theoretical model, and method for LS measurement. We conducted a retrospective study on 82 patients with tibial fractures treated by the Taylor Spatial Frame in our hospital from September 2018 to June 2020, of which 35 took LS measurements with our novel method (Group I), and 47 were with the traditional method (Group II). The external fixator was removed when the measurement outcome (LS 0.05), frame-wearing duration (mean 25.5 weeks vs. 25.8 weeks, P > 0.05), or LS measurement frequency (mean 1.1 times vs. 1.2 times, P > 0.05). The measurement system installation time in Group I was significantly shorter compared to Group II (mean 14.8 min vs. 81.3 min, P 0.05). Conclusion The novel hexapod LS-measurement system and involved method demonstrated enhanced convenience and precision in measuring the LS of the external fixator in vivo. The LS measurement indicates the callus stiffness of fracture healing, and is applicable to evaluate the safety of removing the fixator. Consequently, it is highly recommended for widespread adoption in clinical practice.

Abstract Background The effects of antipsychotic (AP) medications on cognitive functions in individuals at clinical high-risk (CHR) of psychosis are poorly understood. This study compared the effects of AP treatment on cognitive improvement in CHR adolescents and adults. Methods A total of 327 CHR participants, with an age range of 13 to 45 years, who underwent baseline neuropsychological assessments and a 1-year clinical follow-up were included. Participants with CHR were categorized into four groups based on their age: adolescents (aged

Abstract Background Ubiquitination is an important regulatory step of selective protein degradation in the plant UPS (ubiquitin–proteasome system), which is involved in various biological processes in eukaryotes. Ubiquitin-conjugating enzymes play an intermediate role in the process of protein ubiquitination reactions and thus play an essential role in regulating plant growth and response to adverse environmental conditions. However, a genome-wide analysis of the UBC gene family in wheat (Triticum aestivum L.) has not yet been performed. Results In this study, the number, physiochemical properties, gene structure, collinearity, and phylogenetic relationships of TaUBC family members in wheat were analyzed using bioinformatics methods. The expression pattern of TaUBC genes in different tissues/organs and developmental periods, as well as the transcript levels under abiotic stress treatment, were analyzed using RNA-Seq data and qRT-PCR. Meanwhile, favorable haplotypes of TaUBC25 were investigated based on wheat resequencing data of 681 wheat cultivars from the Wheat Union Database. The analyses identified a total of 93 TaUBC family members containing a UBC domain in wheat genome. These genes were unevenly distributed across 21 chromosomes, and numerous duplication events were observed between gene members. Based on phylogenetic analysis, the TaUBC family was divided into 13 E2 groups and a separate UEV group. We investigated the expression of TaUBC family genes under different tissue/organ and stress conditions by quantitative real-time PCR (qRT-PCR) analysis. The results showed that some TaUBC genes were specifically expressed in certain tissues/organs and that most TaUBC genes responded to NaCl, PEG6000, and ABA treatment with different levels of expression. In addition, we performed association analysis for the two haplotypes based on key agronomic traits such as thousand-kernel weight (TKW), kernel length (KL), kernel weight (KW), and kernel thickness (KT), examining 122 wheat accessions at three environmental sites. The results showed that TaUBC25-Hap II had significantly higher TKW, KL, KW, and KT than TaUBC25-Hap I. The distribution analysis of haplotypes showed that TaUBC25-Hap II was preferred in the natural population of wheat. Conclusion Our results identified 93 members of the TaUBC family in wheat, and several genes involved in grain development and abiotic stress response. Based on the SNPs detected in the TaUBC sequence, two haplotypes, TaUBC25-Hap I and TaUBC25-Hap II, were identified among wheat cultivars, and their potential value for wheat breeding was validated by association analysis. The above results provide a theoretical basis for elucidating the evolutionary relationships of the TaUBC gene family and lay the foundation for studying the functions of family members in the future.

Abstract Background The proximal femoral nail anti-rotation (PFNA) with cement enhancement enhances the anchorage ability of internal fixation in elderly with osteoporotic intertrochanteric fracture. However, whether it is superior to hemiarthroplasty is still controversial. The present study aimed to determine which treatment has better clinical outcomes among older patients. Methods We retrospectively analyzed 102 elderly patients with osteoporosis who developed intertrochanteric fractures and underwent PFNA combined with cement-enhanced internal fixation (n = 52, CE group), and hemiarthroplasty (n = 50, HA group) from September 2012 to October 2018. All the intertrochanteric fractures were classified according to the AO/OTA classification. Additionally, the operative time, intraoperative blood loss, intraoperative and postoperative blood transfusion rates, postoperative weight-bearing time, hospitalization time, Barthel Index of Activities Daily Living, Harris score of hip function, visual analog (VAS) pain score, and postoperative complications were compared between the two groups. Results The CE group had significantly shorter operative time, lesser intraoperative blood loss, lower blood transfusion rate, and longer postoperative weight-bearing time than the HA group. The CE group had lower Barthel’s Index of Activities of Daily Living, lower Harris’ score, and higher VAS scores in the first and third months after surgery than the HA group, but no difference was observed between the two groups from 6 months to 12 months. There was no significant difference in the total post-operative complications between the two groups. Conclusion The use of PFNA combined with a cement-enhanced internal fixation technique led to shorter operative time and lesser intraoperative blood loss and trauma in elderly patients as compared to HA.

Abstract Background Chimeric antigen receptor T (CAR-T) cell therapy, as an emerging anti-tumor treatment, has garnered extensive attention in the study of targeted therapy of multiple tumor-associated antigens in hepatocellular carcinoma (HCC). However, the suppressive microenvironment and individual heterogeneity results in downregulation of these antigens in certain patients’ cancer cells. Therefore, optimizing CAR-T cell therapy for HCC is imperative. Methods In this study, we administered FGFR4-ferritin (FGFR4-HPF) nanoparticles to the alpaca and constructed a phage library of nanobodies (Nbs) derived from alpaca, following which we screened for Nbs targeting FGFR4. Then, we conducted the functional validation of Nbs. Furthermore, we developed Nb-derived CAR-T cells and evaluated their anti-tumor ability against HCC through in vitro and in vivo validation. Results Our findings demonstrated that we successfully obtained high specificity and high affinity Nbs targeting FGFR4 after screening. And the specificity of Nbs targeting FGFR4 was markedly superior to their binding to other members of the FGFR family proteins. Furthermore, the Nb-derived CAR-T cells, targeting FGFR4, exhibited significantly enhanced anti-tumor efficacy in both experiments when in vitro and in vivo. Conclusions In summary, the results of this study suggest that the CAR-T cells derived from high specificity and high affinity Nbs, targeting FGFR4, exhibited significantly enhanced anti-tumor efficacy in vitro and in vivo. This is an exploration of FGFR4 in the field of Nb-derived CAR-T cell therapy for HCC, holding promise for enhancing safety and effectiveness in the clinical treatment of HCC in the future.

Abstract Background Papillary thyroid cancer (PTC) is an indolent disease with a favorable prognosis but characterized by a high recurrence rate. We aimed to improve precise stratification of recurrence risk in PTC patients with early stage using multi-gene signatures. Patients and methods The present study was performed using data from The Cancer Genome Atlas (TCGA) and multi-center datasets. Unsupervised consensus clustering was used to obtain the optimal molecular subtypes and least absolute shrinkage and selection operator (LASSO) analysis was performed to identify potential genes for the construction of recurrence signature. Kaplan-Meier survival analysis and the log-rank test was used to detect survival differences. Harrells concordance index (C-index) was used to assess the performance of the DNA damage repair (DDR) recurrence signature. Results Through screening 8 candidate gene sets, the entire cohort was successfully stratified into two recurrence-related molecular subtypes based on DDR genes: DDR-high subtype and DDR-low subtype. The recurrence rate of DDR-high subtype was significantly lower than DDR-low subtype [HR = 0.288 (95%CI, 0.084–0.986), P = 0.047]. Further, a two-gene DDR recurrence signature was constructed, including PER1 and EME2. The high-risk group showed a significantly worse recurrence-free survival (RFS) than the low-risk group [HR = 10.647 (95%CI, 1.363–83.197), P = 0.024]. The multi-center data demonstrated that proportion of patients with low expression of PER1 and EME2 was higher in the recurrence group than those in the non-recurrence group. Conclusions These findings could help accurately and reliably identify PTC patients with high risk of recurrence so that they could receive more radical and aggressive treatment strategies and more rigorous surveillance practices.

Abstract Autophagy is a cellular self-degradation process that plays a crucial role in maintaining metabolic functions in cells and organisms. Dysfunctional autophagy has been linked to various diseases, including cancer. In cancer, dysregulated autophagy is closely associated with the development of cancer and drug resistance, and it can have both oncogenic and oncostatic effects. Research evidence supports the connection between m6A modification and human diseases, particularly cancer. Abnormalities in m6A modification are involved in the initiation and progression of cancer by regulating the expression of oncogenes and oncostatic genes. There is an interaction between m6A modification and autophagy, both of which play significant roles in cancer. However, the molecular mechanisms underlying this relationship are still unclear. m6A modification can either directly inhibit autophagy or promote its initiation, but the complex relationship between m6A modification, autophagy, and cancer remains poorly understood. Therefore, this paper aims to review the dual role of m6A and autophagy in cancer, explore the impact of m6A modification on autophagy regulation, and discuss the crucial role of the m6A modification-autophagy axis in cancer progression and treatment resistance.

Abstract Background Chimeric antigen receptor-T (CAR-T) cells therapy is one of the novel immunotherapeutic approaches with significant clinical success. However, their applications are limited because of long preparation time, high cost, and interpersonal variations. Although the manufacture of universal CAR-T (U-CAR-T) cells have significantly improved, they are still not a stable and unified cell bank. Methods Here, we tried to further improve the convenience and flexibility of U-CAR-T cells by constructing novel modular universal CAR-T (MU-CAR-T) cells. For this purpose, we initially screened healthy donors and cultured their T cells to obtain a higher proportion of stem cell-like memory T (TSCM) cells, which exhibit robust self-renewal capacity, sustainability and cytotoxicity. To reduce the alloreactivity, the T cells were further edited by double knockout of the T cell receptor (TCR) and class I human leukocyte antigen (HLA-I) genes utilizing the CRISPR/Cas9 system. The well-growing and genetically stable universal cells carrying the CAR-moiety were then stored as a stable and unified cell bank. Subsequently, the SDcatcher/GVoptiTag system, which generate an isopeptide bond, was used to covalently connect the purified scFvs of antibody targeting different antigens to the recovered CAR-T cells. Results The resulting CAR-T cells can perform different functions by specifically targeting various cells, such as the eradication of human immunodeficiency virus type 1 (HIV-1)-latenly-infected cells or elimination of T lymphoma cells, with similar efficiency as the traditional CAR-T cells did. Conclusion Taken together, our strategy allows the production of CAR-T cells more modularization, and makes the quality control and pharmaceutic manufacture of CAR-T cells more feasible.

Abstract Background Observational studies have indicated an association between diabetes mellitus (DM), glycemic traits, and the occurrence of Parkinson’s disease (PD). However, the complex interactions between these factors and the presence of a causal relationship remain unclear. Therefore, we aim to systematically assess the causal relationship between diabetes, glycemic traits, and PD onset, risk, and progression. Method We used two-sample Mendelian randomization (MR) to investigate potential associations between diabetes, glycemic traits, and PD. We used summary statistics from genome-wide association studies (GWAS). In addition, we employed multivariable Mendelian randomization to evaluate the mediating effects of anti-diabetic medications on the relationship between diabetes, glycemic traits, and PD. To ensure the robustness of our findings, we performed a series of sensitivity analyses. Results In our univariable Mendelian randomization (MR) analysis, we found evidence of a causal relationship between genetic susceptibility to type 1 diabetes (T1DM) and a reduced risk of PD (OR = 0.9708; 95% CI: 0.9466, 0.9956; P = 0.0214). In our multivariable MR analysis, after considering the conditions of anti-diabetic drug use, this correlation disappeared with adjustment for potential mediators, including anti-diabetic medications, insulin use, and metformin use. Conclusion Our MR study confirms a potential protective causal relationship between genetically predicted type 1 diabetes and reduced risk of PD, which may be mediated by factors related to anti-diabetic medications.

Abstract Background The distal transradial access (dTRA) has become an attractive and alternative access to the conventional transradial access (TRA) for cardiovascular interventional diagnosis and/or treatment. There was a lack of randomized clinical trials to evaluate the effect of the dTRA on the long-term radial artery occlusion (RAO). Methods This was a prospective, randomized controlled study. The primary endpoint was the incidence of long-term RAO at 3 months after discharge. The secondary endpoints included the successful puncture rate, puncture time, and other access-related complications. Results The incidence of long-term RAO was 0.8% (3/361) for dTRA and 3.3% (12/365) for TRA (risk ratio = 0.25, 95% confidence interval = 0.07–0.88, P = 0.02). The incidence of RAO at 24 h was significantly lower in the dTRA group than in the TRA group (2.5% vs. 6.7%, P

Abstract Background γ-glutamylcyclotransferase (GGCT), an enzyme to maintain glutathione homeostasis, plays a vital role in the response to plant growth and development as well as the adaptation to various stresses. Although the GGCT gene family analysis has been conducted in Arabidopsis and rice, the family genes have not yet been well identified and analyzed at the genome-wide level in wheat (Triticum aestivum L.). Results In the present study, 20 TaGGCT genes were identified in the wheat genome and widely distributed on chromosomes 2A, 2B, 2D, 3A, 4A, 5A, 5B, 5D, 6A, 6B, 6D, 7A, 7B, and 7D. Phylogenetic and structural analyses showed that these TaGGCT genes could be classified into three subfamilies: ChaC, GGGACT, and GGCT-PS. They exhibited similar motif compositions and distribution patterns in the same subgroup. Gene duplication analysis suggested that the expansion of TaGGCT family genes was facilitated by segmental duplications and tandem repeats in the wheat evolutionary events. Identification of diverse cis-acting response elements in TaGGCT promoters indicated their potential fundamental roles in response to plant development and abiotic stresses. The analysis of transcriptome data combined with RT-qPCR results revealed that the TaGGCTs genes exhibited ubiquitous expression across plant organs, with highly expressed in roots, stems, and developing grains. Most TaGGCT genes were up-regulated after 6 h under 20% PEG6000 and ABA treatments. Association analysis revealed that two haplotypes of TaGGCT20 gene displayed significantly different Thousand-kernel weight (TKW), Kernel length (KL), and Kernel width (KW) in wheat. The geographical and annual distribution of the two haplotypes of TaGGCT20 gene further revealed that the frequency of the favorable haplotype TaGGCT20-Hap-I was positively selected in the historical breeding process of wheat. Conclusion This study investigated the genome-wide identification, structure, evolution, and expression analysis of TaGGCT genes in wheat. The motifs of TaGGCTs were highly conserved throughout the evolutionary history of wheat. Most TaGGCT genes were highly expressed in roots, stems, and developing grains, and involved in the response to drought stresses. Two haplotypes were developed in the TaGGCT20 gene, where TaGGCT20-Hap-I, as a favorable haplotype, was significantly associated with higher TKW, KL, and KW in wheat, suggesting that the haplotype is used as a function marker for the selection in grain yield in wheat breeding.

Abstract Background Suanzaoren Decoction (SZRD), a well-known formula from traditional Chinese medicine, has been shown to have reasonable cognitive effects while relaxing and alleviating insomnia. Several studies have demonstrated significant therapeutic effects of SZRD on diabetes and Alzheimer’s disease (AD). However, the active ingredients and probable processes of SZRD in treating Alzheimer’s with diabetes are unknown. This study aims to preliminarily elucidate the potential mechanisms and potential active ingredients of SZRD in the treatment of Alzheimer’s with diabetes. Methods The main components and corresponding protein targets of SZRD were searched on the TCMSP database. Differential gene expression analysis for diabetes and Alzheimer’s disease was conducted using the Gene Expression Omnibus database, with supplementation from OMIM and genecards databases for differentially expressed genes. The drug-compound-target-disease network was constructed using Cytoscape 3.8.0. Disease and SZRD targets were imported into the STRING database to construct a protein-protein interaction network. Further, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed on the intersection of genes. Molecular docking and molecular dynamics simulations were conducted on the Hub gene and active compounds. Gene Set Enrichment Analysis was performed to further analyze key genes. Results Through the Gene Expression Omnibus database, we obtained 1977 diabetes related genes and 622 AD related genes. Among drugs, diabetes and AD, 97 genes were identified. The drug-compound-target-disease network revealed that quercetin, kaempferol, licochalcone a, isorhamnetin, formononetin, and naringenin may be the core components exerting effects. PPI network analysis identified hub genes such as IL6, TNF, IL1B, CXCL8, IL10, CCL2, ICAM1, STAT3, and IL4. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that SZRD in the treatment of Alzheimer’s with diabetes is mainly involved in biological processes such as response to drug, aging, response to xenobiotic, and enzyme binding; as well as signaling pathways such as Pathways in cancer, Chemical carcinogenesis - receptor activation, and Fluid shear stress and atherosclerosis. Molecular docking results showed that licochalcone a, isorhamnetin, kaempferol, quercetin, and formononetin have high affinity with CXCL8, IL1B, and CCL2. Molecular dynamics simulations also confirmed a strong interaction between CXCL8 and licochalcone a, isorhamnetin, and kaempferol. Gene Set Enrichment Analysis revealed that CXCL8, IL1B, and CCL2 have significant potential in diabetes. Conclusion This study provides, for the first time, insights into the active ingredients and potential molecular mechanisms of SZRD in the treatment of Alzheimer’s with diabetes, laying a theoretical foundation for future basic research. Graphical Abstract

Abstract Background Suicide was an important cause of death in prostate cancer. This study intended to investigate trends in suicide mortality among prostate cancer (PCa) survivors from 1975 to 2019 in the United States. Method We identified PCa survivors from the Surveillance, Epidemiology, and End Results (SEER) program from January 1975 to December 2019. Standardized mortality rate (SMR) was calculated d to assess the relative risk of suicide in PCa survivors compared with the general men population. Poisson regression model was performed to test for trend of SMRs. The cumulative mortality rate of suicide was calculated to assess the clinical burden of suicide mortality. Results 7108 (0.2%) cases were death from suicide cause, and 2,308,923(65.04%%) cases recorded as dying from non-suicidal causes. Overall, a slightly higher suicide mortality rate among PCa survivors was observed compared with general male population (SMR: 1.15, 95%CI: 1.09–1.2). The suicide mortality rate declined significantly relative to the general population by the calendar year of diagnosis, from an SMR of 1.74(95%CI: 1.17–2.51) in 1975–1979 to 0.99(0.89–1.1) in 2015–2019 (Ptrend 0.05). The cumulative suicide mortality during 1975–1994 was distinctly higher than in 1995–2019(P

Abstract Background This study aimed to investigate the relationship between serum testosterone levels and the risk of congestive heart failure (CHF) in adult males. Previous research has suggested a potential link between serum testosterone and cardiovascular health, but the findings have been inconclusive. Methods This study was cross-sectional, and the data were obtained from the 2011–2016 cycle of the National Health and Nutrition Examination Survey (NHANES), which included a sample of 6,841 male participants. Serum testosterone levels were measured using a standardized assay, and CHF status was assessed through self-reporting. Covariates such as age, ethnicity, lifestyle factors, and health conditions were considered in the analysis. Results Among the participants, 242 individuals had a documented history of CHF. We observed a linear correlation between serum testosterone levels and CHF occurrence, with higher serum testosterone levels associated with a decreased risk of CHF (Q4 vs. Q1, OR = 0.29, 95% CI: 0.19–0.47, P

Abstract Objective To explore the relative sensitivity of different methods for detecting cervical glandular lesions. Methods A total of 225 patients with cervical glandular lesions diagnosed from January 2018 to February 2023 were retrieved from the pathology database of Guangdong Maternal and Child Health Hospital, and their clinicopathological features were reviewed. Results Four human papillomavirus (HPV) genotypes: HPV18, 16, 45, and 52, dominated all glandular lesions, and accounting for 74.10% of HPV-positive tumors. Furthermore, 36.89% of abnormal squamous cells were diagnosed as abnormal based on cytological examinations leading to the detection of cervical glandular lesions; only 16.89% were diagnosed based on the initial detection of abnormal glandular cytology. The most common abnormal cervical screening result was ASC-US on cytology (14.22%), followed by HSIL (11.56%). Only few number of patients were diagnosed with or suspected of having cervical adenopathy via a Pap test (18.22%). Nearly one-third of cervical glandular lesions cases were not detected on the Pap test; but were diagnosed upon cervical biopsy or based on the histological examination of ECC, LEEP, or CKC specimens. The LEEP or CKC biopsy specimens had negative margins in 49 cases (40.83%), while the margins were positive in the other 71 cases (59.17%). Five cases (10.20%) with negative margins still had residual lesions following total hysterectomy, and 19 (26.76%) with positive margins had no residual lesions after total hysterectomy. Conclusion The ability to detect cervical glandular lesions varies for routine HPV genotyping, Pap test, or biopsy/ECC, with different sensitivities and advantages and disadvantages for each method.

Abstract Objective To evaluate effect of inoculum size of extended-spectrum β-Lactamase (ESBL)-producing-, AmpC-producing-, and KPC-producing Escherichia coli and Klebsiella pneumoniae on the in vitro antibacterial effects of imipenem/relebactam (IMR) and ceftazidime/avibactam (CZA). Methods We compared the impact of inoculum size on IMR and CZA of sixteen clinical isolates and three standard isolates through antimicrobial susceptibility tests, time-kill assays and in vitro PK/PD studies. Results When inoculum size increased from 105 to 107 CFU/mL, an inoculum effect was observed for 26.3% (5/19) and 52.6% (10/19) of IMR and CZA, respectively; time-kill assays revealed that the concentration of CZA increased from ≥ 4 × MIC to 16 × MIC to reach 99.9% killing rate against K. pneumoniae ATCC-BAA 1705 (KPC-2-, OXA-9- and SHV-182-producing) and 60,700 (SHV-27- and DHA-1-producing). While for IMR, a concentration from 1 × MIC to 4 × MIC killed 99.9% of the four strains. When the inoculum size increased to 109 CFU/mL, neither IMR nor CZA showed a detectable antibacterial effect, even at a high concentration. An in vitro PK/PD study revealed a clear bactericidal effect when IMR administered as 1.25 g q6h when inoculum size increased. Conclusion An inoculum effect on CZA was observed more frequent than that on IMR. Among the β-lactamase-producing strains, the inoculum effect was most common for SHV-producing and KPC-producing strains.

Abstract Context Inflammation has been identified as a key factor contributing to the development of numerous diseases. Several anti-inflammatory drugs have been developed to treat inflammation-related diseases. However, some of such drugs are associated with varying degrees of side effects. Therefore, it is imperative to develop new anti-inflammatory drugs with reducing side effects for the treatment of inflammation-related diseases. Natural anti-inflammatory drugs have emerged as an important area of research in recent years. The study was to determine the anti-inflammatory mechanism of Paridis rhizoma extract (PRE) in rat models of acute inflammation induced by carrageenan and RAW264.7 cells models induced by lipopolysaccharide (LPS). Materials and methods PRE was investigated using the carrageenan-induced paw oedema model on rats in vivo. Histopathology examined the extent of inflammatory infiltration and tissue damage. The effect of PRE on the levels of specific cytokines was determined using enzyme-linked immunosorbent assay (ELISA). The Cell Counting Kit (CCK)-8 assay evaluated the cytotoxic effects of PRE on Raw264.7 cells. The mRNA expression levels of cytokines were quantified using quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR). Western blot measured TNF-α, IL6, TLR4, p-P65, p-IKB, HO1, SOD1 and SOD2. Fluorescence measured the cellular levels of reactive oxygen species (ROS). Results PRE treatment reduced interstitial edema and structural damage in a dose-dependent manner in vivo. PRE inhibited inflammatory responses in vivo and in vitro, as evidenced by the decreased expression of inflammatory factors, production of ROS, and increased expression of SOD1, SOD2, and HO1. Moreover, PRE inhibited the activity of the nuclear factor kappa B (NF-kB) pathway. Conclusion The anti-inflammatory activity and potential mechanism of PRE were demonstrated according to the results. PRE reduced LPS-induced inflammation in RAW264.7 cells by inhibiting the NF-KB signaling pathway and ROS production in vitro. PRE alleviated interstitial edema and structural damage in the carrageenan-induced paw edema model on rats in vivo. This study provided an idea for future development of PR-based anti-inflammatory drugs.

Abstract Purpose To investigate prognostic values of prostatic urethra involvement (PUI) and construct a prognostic model that estimates the probability of cancer-specific survival for T1 bladder cancer patients. Method and materials We investigated the national Surveillance, Epidemiology, and End Results (SEER) database (2004–2015) to get patients diagnosed with T1 bladder cancer. An external validation cohort was obtained from the First Affiliated Hospital of Nanchang University. The Kaplan–Meier method with the log-rank test was applied to assess cancer-specific survival (CSS) and overall survival (OS). Moreover, the propensity score matching (PSM) and multivariable Cox proportional hazard model were performed. All patients were randomly divided into the development cohort and validation group at the ratio of 7:3. The performance of the model was internally validated by calibration curves and the concordance index (C-index). Results The PUI group had a lower survival rate of both CSS and overall survival OS before and after PSM when compared to non-involved patients (All P

Abstract Background There is an increasing number of cases of aldosterone- and cortisol-producing adenomas (A/CPAs) reported in the context of primary aldosteronism (PA). Most of these patients have PA complicated with subclinical Cushing's syndrome; cases of apparent Cushing's syndrome (CS) complicated with aldosteronism are less reported. However, Co-secretory tumors were present in the right adrenal gland, a cortisol-secreting adenoma and an aldosterone-producing nodule (APN) were present in the left adrenal gland, and aldosterone-producing micronodules (APMs) were present in both adrenal glands, which has not been reported. Here, we report such a case, offering profound insight into the diversity of clinical and pathological features of this disease. Case presentation The case was a 45-year-old female from the adrenal disease diagnosis and treatment centre in West China Hospital of Sichuan University. The patient presented with hypertension, moon-shaped face, central obesity, fat accumulation on the back of the neck, disappearance of cortisol circadian rhythm, ACTH 30 (ng/dL)/(ng/mL/h), and plasma aldosterone concentration > 10 ng/dL after saline infusion testing. Based on the above, she was diagnosed with non-ACTH-dependent CS complicated with PA. Adrenal vein sampling showed no lateralization for cortisol and aldosterone secretion in the bilateral adrenal glands. The left adrenocortical adenoma was removed by robot-assisted laparoscopic resection. However, hypertension, fatigue and weight gain were not alleviated after surgery; additionally, purple striae appeared in the lower abdomen, groin area and inner thigh, accompanied by systemic joint pain. One month later, the right adrenocortical adenoma was also removed. CYP11B1 were expressed in the bilateral adrenocortical adenomas, and CYP11B2 was also expressed in the right adrenocortical adenomas. APN existed in the left adrenal gland and APMs in the adrenal cortex adjacent to bilateral adrenocortical adenomas. After another surgery, her serum cortisol and plasma aldosterone returned to normal ranges, except for slightly higher ACTH. Conclusions This case suggests that it is necessary to assess the presence of PA, even in CS with apparent symptoms. As patients with CS and PA may have more complicated adrenal lesions, more data are required for diagnosis.

Abstract Background Previous studies have demonstrated that natural killer (NK) cells migrated into the liver from peripheral organs and exerted cytotoxic effects on hepatocytes in virus-induced liver failure. Aim This study aimed to investigate the potential therapeutic role of chemokine receptors in the migration of NK cells in a murine hepatitis virus strain 3 (MHV-3)-induced fulminant hepatic failure (MHV-3-FHF) model and its mechanism. Results By gene array analysis, chemokine (C–C motif) receptor 5 (CCR5) was found to have remarkably elevated expression levels in hepatic NK cells after MHV-3 infection. The number of hepatic CCR5+ conventional NK (cNK) cells increased and peaked at 48 h after MHV-3 infection, while the number of hepatic resident NK (rNK) cells steadily declined. Moreover, the expression of CCR5-related chemokines, including macrophage inflammatory protein (MIP)-1α, MIP-1β and regulated on activation, normal T-cell expressed and secreted (RANTES) was significantly upregulated in MHV-3-infected hepatocytes. In an in vitro Transwell migration assay, CCR5-blocked splenic cNK cells showed decreased migration towards MHV-3-infected hepatocytes, and inhibition of MIP-1β or RANTES but not MIP-1α decreased cNK cell migration. Moreover, CCR5 knockout (KO) mice displayed reduced infiltration of hepatic cNK cells after MHV-3 infection, accompanied by attenuated liver injury and improved mouse survival time. Adoptive transfer of cNK cells from wild-type mice into CCR5 KO mice resulted in the abundant accumulation of hepatic cNK cells and aggravated liver injury. Moreover, pharmacological inhibition of CCR5 by maraviroc reduced cNK cell infiltration in the liver and liver injury in the MHV-3-FHF model. Conclusion The CCR5-MIP-1β/RANTES axis played a critical role in the recruitment of cNK cells to the liver during MHV-3-induced liver injury. Targeted inhibition of CCR5 provides a therapeutic approach to ameliorate liver damage during virus-induced acute liver injury.

Abstract Objective The current diagnosis of central precocious puberty (CPP) relies on the gonadotropin-releasing hormone analogue (GnRHa) stimulation test, which requires multiple invasive blood sampling procedures. The aim of this study was to construct machine learning models incorporating basal pubertal hormone levels, pituitary magnetic resonance imaging (MRI), and pelvic ultrasound parameters to predict the response of precocious girls to GnRHa stimulation test. Methods This retrospective study included 455 girls diagnosed with precocious puberty who underwent transabdominal pelvic ultrasound, brain MRI examinations and GnRHa stimulation testing were retrospectively reviewed. They were randomly assigned to the training or internal validation set in an 8:2 ratio. Four machine learning classifiers were developed to identify girls with CPP, including logistic regression, random forest, light gradient boosting (LightGBM), and eXtreme gradient boosting (XGBoost). The accuracy, sensitivity, specificity, positive predictive value, negative predictive value, area under receiver operating characteristic (AUC) and F1 score of the models were measured. Results The participates were divided into an idiopathic CPP group (n = 263) and a non-CPP group (n = 192). All machine learning classifiers used achieved good performance in distinguishing CPP group and non-CPP group, with the area under the curve (AUC) ranging from 0.72 to 0.81 in validation set. XGBoost had the highest diagnostic efficacy, with sensitivity of 0.81, specificity of 0.72, and F1 score of 0.80. Basal pubertal hormone levels (including luteinizing hormone, follicle-stimulating hormone, and estradiol), averaged ovarian volume, and several uterine parameters were predictors in the model. Conclusion The machine learning prediction model we developed has good efficacy for predicting response to GnRHa stimulation tests which could help in the diagnosis of CPP.

Abstract Background Inflammation plays an important role in the pathogenesis of atrial fibrillation (AF) after myocardial infarction (MI). The role of USP38, a member of the ubiquitin-specific protease family, on MI-induced atrial inflammation, fibrosis, and associated AF is unclear. Methods In this study, we surgically constructed a mouse MI model using USP38 cardiac conditional knockout (USP38-CKO) and cardiac-specific overexpression (USP38-TG) mice and applied biochemical, histological, electrophysiological characterization and molecular biology to investigate the effects of USP38 on atrial inflammation, fibrosis, and AF and its mechanisms. Results Our results revealed that USP38-CKO attenuates atrial inflammation, thereby ameliorating fibrosis, and abnormal electrophysiologic properties, and reducing susceptibility to AF on day 7 after MI. USP38-TG showed the opposite effect. Mechanistically, The TAK1/NF-κB signaling pathway in the atria was significantly activated after MI, and phosphorylated TAK1, P65, and IκBα protein expression was significantly upregulated. USP38-CKO inhibited the activation of the TAK1/NF-κB signaling pathway, whereas USP38-TG overactivated the TAK1/NF-κB signaling pathway after MI. USP38 is dependent on the TAK1/NF-κB signaling pathway and regulates atrial inflammation, fibrosis, and arrhythmias after MI to some extent. Conclusions USP38 plays an important role in atrial inflammation, fibrosis, and AF susceptibility after MI, providing a promising target for the treatment of AF after MI.

Abstract Background Respiratory infectious diseases (RIDs) remain a pressing public health concern, posing a significant threat to the well-being and lives of individuals. This study delves into the incidence of seven primary RIDs during the period 2017–2021, aiming to gain deeper insights into their epidemiological characteristics for the purpose of enhancing control and prevention strategies. Methods Data pertaining to seven notifiable RIDs, namely, seasonal influenza, pulmonary tuberculosis (PTB), mumps, scarlet fever, pertussis, rubella and measles, in the mainland of China between 2017 and 2021 were obtained from the National Notifiable Disease Reporting System (NNDRS). Joinpoint regression software was utilized to analyze temporal trends, while SaTScan software with a Poisson probability model was used to assess seasonal and spatial patterns. Results A total of 11,963,886 cases of the seven RIDs were reported during 2017–2021, and yielding a five-year average incidence rate of 170.73 per 100,000 individuals. Among these RIDs, seasonal influenza exhibited the highest average incidence rate (94.14 per 100,000), followed by PTB (55.52 per 100,000), mumps (15.16 per 100,000), scarlet fever (4.02 per 100,000), pertussis (1.10 per 100,000), rubella (0.59 per 100,000), and measles (0.21 per 100,000). Males experienced higher incidence rates across all seven RIDs. PTB incidence was notably elevated among farmers and individuals aged over 65, whereas the other RIDs primarily affected children and students under 15 years of age. The incidences of PTB and measles exhibited a declining trend from 2017 to 2021 (APC = −7.53%, P = 0.009; APC = −40.87%, P = 0.02), while the other five RIDs peaked in 2019. Concerning seasonal and spatial distribution, the seven RIDs displayed distinct characteristics, with variations observed for the same RIDs across different regions. The proportion of laboratory-confirmed cases fluctuated among the seven RIDs from 2017 to 2021, with measles and rubella exhibiting higher proportions and mumps and scarlet fever showing lower proportions. Conclusions The incidence of PTB and measles demonstrated a decrease in the mainland of China between 2017 and 2021, while the remaining five RIDs reached a peak in 2019. Overall, RIDs continue to pose a significant public health challenge. Urgent action is required to bolster capacity-building efforts and enhance control and prevention strategies for RIDs, taking into account regional disparities and epidemiological nuances. With the rapid advancement of high-tech solutions, the development and effective implementation of a digital/intelligent RIDs control and prevention system are imperative to facilitate precise surveillance, early warnings, and swift responses. Graphical Abstract

Abstract Inflammatory pain is a commonly observed clinical symptom in a range of acute and chronic diseases. However, the mechanism of inflammatory pain is far from clear yet. Rab11a, a small molecule guanosine triphosphate enzyme, is reported to regulate orofacial inflammatory pain in our previous works. However, the mechanism of Rab11a’s involvement in the regulation of inflammatory pain remains obscure. Here, we aim to elucidate the potential mechanisms through which Rab11a contributes to the development of inflammatory pain in the spinal level. It’s shown that neurons, rather than glial cells, were the primary cell type expressing Rab11a in the spinal dorsal horn (SDH). After intra-plantar injection of CFA, both the number of Fos/Rab11a-immunopositive neurons and the expression of Rab11a were increased. Administration of Rab11a-shRNA into the SDH resulted in significantly analgesic effect in mice with CFA injection. Application of Rab11a-shRNA also reduced the NMDA receptor-mediated excitatory post-synaptic current (EPSC) and the spike number of neurons in lamina II of the SDH in mice with CFA injection, without affecting the presynaptic glutamate release and the postsynaptic AMPA receptor-mediated EPSC. Our results thus suggest that the enhanced expression of neuronal Rab11a may be important for the process of inflammatory pain in mice with CFA injection, which is likely mediated by Rab11a’s potentiation of the competence of post-synaptic NMDAR and spiking of SDH neurons.

Abstract Background Primary bilateral macronodular adrenal hyperplasia (PMAH) combined with infection by an opportunistic pathogen is complicated. Clinical evidence on managing PMAH patients with infections by opportunistic pathogens is insufficient. Case presentation A 66-year-old male was admitted with bilateral adrenal masses and was diagnosed with PMAH. Fever and disturbance of consciousness appeared after laparoscopic left adrenalectomy. Cryptococcal meningitis was confirmed by cerebrospinal fluid (CSF) culture. The exacerbation of his medical condition was suspected to result from immune reconstitution inflammatory syndrome (IRIS), and he had been treated with antifungal therapy and glucocorticoid replacement, but he responded poorly and eventually died of multiorgan failure. We summarized the clinical observations of 12 Cushing's syndrome (CS) patients infected by Cryptococcus. Seven out of nine patients who were treated for cryptococcus infection before receiving CS survived, while three patients treated for cryptococcus infection after CS treatment developed signs of IRIS and eventually died. Conclusion Cushing's syndrome, complicated with cryptococcal infection, has a high mortality rate, mainly when IRIS emerges. Carefully identifying the presence of the suspected infection, and controlling cryptococcal infection before removing the culprit adrenals could be the rational choice.

Abstract Background To achieve potential financial savings and avoid exposing the patients to unnecessary risk, an optimal diagnostic strategy to identify low risk individual who may derive minimal benefit from further cardiac imaging testing (CIT) is important for patients with stable chest pain (SCP) suggestive of chronic coronary syndrome (CCS). Although several diagnostic strategies have been recommended by the most recent guidelines, few randomized controlled trials (RCTs) have prospectively investigated the actual effect of applying these strategies in clinical practice. Methods OPERATE (OPtimal Evaluation of stable chest pain to Reduce unnecessAry utilization of cardiac imaging TEsting) trial is an investigator-initiated, multicenter, coronary computed tomography angiography (CCTA)-based, 2-arm parallel-group, double-blind, pragmatic and confirmative RCT planning to include 800 subjects with SCP suggestive of CCS. After enrollment, all subjects will be randomized to two arms (2016 U.K. National Institute of Health and Care Excellence guideline-determined and 2019 European Society of Cardiology guideline-determined diagnostic strategy) on a 1:1 basis. According to each strategy, CCTA should be referred and deferred for a subject in high and low risk group, respectively. The primary (effectiveness) endpoint is CCTA without obstructive coronary artery disease. Safety of each strategy will be mainly assessed by 1-year major adverse cardiovascular event rates. Discussion The OPERATE trial will provide comparative effectiveness and safety evidences for two different diagnostic strategies for patients with SCP suggestive of CCS, with the intension of improving the diagnostic yield of CCTA at no expense of safety. Clinical trial registration ClinicalTrial.org Identifier NCT05640752.

Abstract Background The lack of trained mental health professionals is a key barrier to scale-up of evidence-based psychological interventions in low and middle-income countries. We have developed an app that allows a peer with no prior experience of health-care delivery to deliver the cognitive therapy-based intervention for perinatal depression, the Thinking Healthy Programme (THP). This trial aims to assess the effectiveness and cost-effectiveness of this Technology-assisted peer-delivered THP versus standard face-to-face Thinking Healthy Programme delivered by trained health workers. Methods We will employ a non-inferiority stratified cluster randomized controlled trial design comparing the two formats of intervention delivery. A total of 980 women in the second or third trimester of pregnancy with a diagnosis of Major Depressive Episode, evaluated with the Structured Clinical Interview for DSM-V Disorders (SCID), will be recruited into the trial. The unit of randomization will be 70 village clusters randomly allocated in a 1:1 ratio to the intervention and control arms. The primary outcome is defined as remission from major depressive episode at 3 months postnatal measured with the SCID. Data will also be collected on symptoms of anxiety, disability, quality of life, service use and costs, and infant-related outcomes such as exclusive breastfeeding and immunization rates. Data will be collected on the primary outcome and selected secondary outcomes (depression and anxiety scores, exclusive breastfeeding) at 6 months postnatal to evaluate if the improvements are sustained in the longer-term. We are especially interested in sustained improvement (recovery) from major depressive episode. Discussion This trial will evaluate the effectiveness and cost-effectiveness of a technology-assisted peer-delivered cognitive behavioral therapy-based intervention in rural Pakistan. If shown to be effective, the novel delivery format could play a role in reducing the treatment gap for perinatal depression and other common mental disorders in LMIC. Trial registration The trial was registered at Clinicaltrials.gov (NCT05353491) on 29 April 2022.

Abstract Background The perineural invasion (PNI)-mediated inflammation of the tumor microenvironment (TME) varies among gastric cancer (GC) patients and exhibits a close relationship with prognosis and immunotherapy. Assessing the neuroinflammation of TME is important in predicting the response to immunotherapy in GC patients. Methods Fifteen independent cohorts were enrolled in this study. An inflammatory score was developed and validated in GC. Based on PNI-related prognostic inflammatory signatures, patients were divided into Clusters A and B using unsupervised clustering. The characteristics of clusters and the potential regulatory mechanism of key genes were verified by RT-PCR, western-blot, immunohistochemistry and immunofluorescence in cell and tumor tissue samples.The neuroinflammation infiltration (NII) scoring system was developed based on principal component analysis (PCA) and visualized in a nomogram together with other clinical characteristics. Results Inflammatory scores were higher in GC patients with PNI compared with those without PNI (P

Abstract The outbreak of coronavirus disease 2019 (COVID-19) posed an unprecedented challenge on public health systems. Despite the measures put in place to contain it, COVID-19 is likely to continue experiencing sporadic outbreaks for some time, and individuals will remain susceptible to recurrent infections. Chimeric antigen receptor (CAR)-T recipients are characterized by durable B-cell aplasia, hypogammaglobulinemia and loss of T-cell diversity, which lead to an increased proportion of severe/critical cases and a high mortality rate after COVID-19 infection. Thus, treatment decisions have become much more complex and require greater caution when considering CAR T-cell immunotherapy. Hence, we reviewed the current understanding of COVID-19 and reported clinical experience in the management of COVID-19 and CAR-T therapy. After a panel discussion, we proposed a rational procedure pertaining to CAR-T recipients with the aim of maximizing the benefit of CAR-T therapy in the post COVID-19 pandemic era.

Abstract Background The associations of sedentary time and patterns with functional disability among older adults remain unclear, and few studies have accounted for the co-dependency of sedentary behavior and physical activities when modeling sedentary behavior with risk of functional disability. We aimed to examine the associations between sedentary time and patterns and risk of incident functional disability, and assess whether replacing sedentary time with light physical activity (LPA) or moderate-to-vigorous intensity physical activity (MVPA) is associated with reduced risk of functional disability in community-dwelling older adults. Methods A total of 1,687 Japanese adults aged ≥ 65 years without functional disability at baseline were prospectively followed-up for 9 years (2011–2020). Functional disability was ascertained using the national database of Japan’s Long-term Care Insurance System. Sedentary time and patterns, LPA, and MVPA were measured using a tri-axial accelerometer secured to participants’ waists. Results During follow-up, 466 participants developed functional disability. Compared with the lowest quartile of total sedentary time, the multivariable-adjusted hazard ratios (95% confidence intervals) of functional disability for the second, third, and top quartiles were 1.21 (0.91‒1.62), 1.45 (1.10‒1.92), and 1.40 (1.05‒1.88) (p for trend = 0.01). After further adjusting for MVPA, total sedentary time was no longer significantly associated with the risk of functional disability (p for trend = 0.41). Replacing 10 min/day of sedentary time with the same amount of MVPA (but not LPA) was significantly associated with a 12% reduced risk of functional disability (hazard ratio [95% confidence interval]: 0.88 [0.84‒0.92]). No significant association was observed between sedentary bout length and functional disability. Conclusion Higher levels of total sedentary time were associated with an increased risk of incident functional disability. However, this association was not independent of MVPA. Replacing sedentary time with MVPA, but not LPA, was associated with reduced risk of functional disability in older adults.