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Abstract Background The immunogenicity of allogeneic mesenchymal stem cells (MSCs) is significantly enhanced after transplantation or differentiation, and these cells can be recognized and cleared by recipient immune cells. Graft rejection has become a major obstacle to improving the therapeutic effect of allogeneic MSCs or, after their differentiation, transplantation in the treatment of diabetes and other diseases. Solving this problem is helpful for prolonging the time that cells play a role in the recipient body and for significantly improving the clinical therapeutic effect. Methods In this study, canine adipose-derived mesenchymal stem cells (ADSCs) were used as seed cells, and gene editing technology was used to knock out the B2M gene in these cells and cooperate with the overexpression of the PD-L1 gene. Gene-edited ADSCs (GeADSCs), whose biological characteristics and safety are not different from those of normal canine ADSCs, have been obtained. Results The immunogenicity of GeADSCs is reduced, the immune escape ability of GeADSCs is enhanced, and GeADSCs can remain in the body for a longer time. Using the optimized induction program, the efficiency of the differentiation of GeADSCs into new islet β-cells was increased, and the maturity of the new islet β-cells was increased. The immunogenicity of new islet β-cells decreased, and their immune escape ability was enhanced after the cells were transplanted into diabetic dogs (the graft site was prevascularized by the implantation of a scaffold to form a vascularized pouch). The number of infiltrating immune cells and the content of immune factors were decreased at the graft site. Conclusions New islet β-cell transplantation, which has low immunogenicity, can reverse diabetes in dogs, and the therapeutic effect of cell transplantation is significantly enhanced. This study provides a new method for prolonging the survival and functional time of cells in transplant recipients and significantly improving the clinical therapeutic effect.

Abstract Diabetic kidney disease (DKD) is a prevalent microvascular complication of diabetes mellitus and a primary cause of end-stage renal disease (ESRD). Increasing studies suggest that immune cells are involved in regulating renal inflammation, which contributes to the progression of DKD. Compared with conventional methods, single-cell sequencing technology is more developed technique that has advantages in resolving cellular heterogeneity, parallel multi-omics studies, and discovering new cell types. ScRNA-seq helps researchers to analyze specifically gene expressions, signaling pathways, intercellular communication as well as their regulations in various immune cells of kidney biopsy and urine samples. It is still challenging to investigate the function of each cell type in the pathophysiology of kidney due to its complex and heterogeneous structure and function. Here, we discuss the application of single-cell transcriptomics in the field of DKD and highlight several recent studies that explore the important role of immune cells including macrophage, T cells, B cells etc. in DKD through scRNA-seq analyses. Through combing the researches of scRNA-seq on immune cells in DKD, this review provides novel perspectives on the pathogenesis and immune therapeutic strategy for DKD.

Abstract Objectives Internships in the pharmacy departments of training hospitals represent a crucial stage in the professional development of pharmacy students. However, the quality of internship training varies significantly across training hospitals in China, and there is a lack of standardized readiness evaluation tools. Therefore, the purpose of this study was to develop a self-assessment tool to evaluate the preparedness of training hospitals for providing internship training. Methods This study employed an exploratory mixed-methods approach and was conducted in two phases. In the first phase, during 2021, focus groups were conducted with 16 interns from three tertiary hospitals in Henan Province. In 2022, 14 preceptors from tertiary hospitals in various provinces were interviewed either one-on-one or in focus groups. The interview data were analyzed using thematic analysis to compile a set of self-assessment indicators for internship training readiness. Subsequently, the initial draft of the self-assessment tool for internship training readiness was developed by integrating the indicators derived from the interviews and literature review. In the second phase, the Delphi method was utilized. In 2023, the experts participated in two rounds of correspondence (21 experts in the first round and 19 in the second round), and consensus was reached on the indicators of the self-assessment tool after the two rounds. Meanwhile, these experts assessed the current status of internship training in training hospitals across China. Results The qualitative findings of the first phase included five themes and 22 sub-themes, which were integrated with the indicators derived from the literature review to develop an initial indicator framework for the second phase. This initial framework comprised five domains and 37 items. The second phase involved two rounds of expert surveys, with effective response rates of 90.48% and 89.47%, respectively. Ultimately, the self-assessment tool for evaluating the readiness of pharmacy departments in training hospitals for internships included five dimensions and 35 secondary indicators: (1) organizational structure, (2) training content, (3) training mode, (4) effectiveness evaluation, and (5) emergency management. Additionally, experts assessed the readiness of pharmacy departments in Chinese training hospitals for internships, yielding varied results. Emergency management preparedness scored the highest, followed by organizational structure and training content preparation. However, the modes of internship training and the evaluation of training effectiveness received lower scores. Conclusion The developed tool provides a comprehensive self-assessment checklist for the pharmacy departments of training hospitals and possesses the potential to enhance the development of more effective internship training programs.

Abstract Background Occludin, a crucial component of tight junctions, has emerged as a promising biomarker for the diagnosis of acute ischemic disease, highlighting its significant potential in clinical applications. In the diabetes, Occludin serves as a downstream target gene intricately regulated by the adiponectin (APN) signaling pathway. However, the specific mechanism by which adiponectin regulates Occludin expression remains unclear. Methods and results Endothelial-specific Ocln knockdown reduced APN-mediated blood flow recovery after femoral artery ligation and nullified APN's protection against high-fat diet (HFD)-triggered apoptosis and angiogenesis inhibition in vivo. Mechanically, we have meticulously elucidated APN's regulatory role in Occludin expression through a comprehensive analysis spanning transcriptional and post-translational dimensions. Foxo1 has been elucidated as a crucial transcriptional regulator of Occludin that is modulated by the APN/APPL1 signaling axis, as evidenced by validation through ChIP-qPCR assays and Western blot analysis. APN hindered Occludin degradation via the ubiquitin–proteasome pathway. Mass spectrometry analysis has recently uncovered a novel phosphorylation site, Tyr467, on Occludin. This site responds to APN, playing a crucial role in inhibiting Occludin ubiquitination by APN. The anti-apoptotic and pro-angiogenic effects of APN were attenuated in vitro and in vivo following Foxo1 knockdown or expression of a non-phosphorylatable mutant, OccludinY467A. Clinically, elevated plasma concentrations of Occludin were observed in patients with diabetes. A significant negative correlation was found between Occludin levels and APN concentrations. Conclusion Our study proposes that APN modulates Occludin expression through mechanisms involving both transcriptional and post-translational interactions, thereby conferring a protective effect on endothelial integrity within diabetic vasculature. Graphical abstract

Abstract Purpose This study aims to determine the learning curve for lumbar discectomy and nerve root decompression using the unilateral biportal endoscopic (UBE) technique on fresh frozen cadavers through linear regression and cumulative sum (CUSUM) analyses. Methods The analysis was conducted on three spine surgeons without UBE experience. They performed lumbar discectomy using the unilateral endoscopic technique on fresh frozen cadavers. Each physician performed operations on 40 lumbar spine segments, recording the time it took each physician to complete a segment of lumbar discectomy by UBE. The learning curve was assessed by linear regression and CUSUM analysis using SPSS 27.0 software and GraphPad Prism 8.0 software. Results According to the CUSUM analysis of the learning curve, the number of segments required to complete the learning phase for the three surgeons was 20, 16, and 20, respectively. With the increased number of operated segments, the operation time for each lumbar vertebral segment gradually decreased and stabilized. Conclusions In our study, spine surgeons without experience in UBE require 20 segments of surgery to overcome the UBE learning curve. Additionally, fresh frozen cadavers can effectively simulate real surgeries. Whenever possible, we should reasonably use fresh frozen cadavers for early UBE training of doctors, thereby better protecting the health and safety of patients.

Abstract This study explores the main surface markers in the hemodialysis puncture catheterization pathway and the relative spatial position of venous vessels in the puncture results, providing data support for venous puncture. Seventy cadavers were studied; angles of vertical axis with superior vena cava, left and right brachiocephalic vein at the confluence and circumference of superior vena cava were the primary parameters. Bivariate correlation analysis was used to determine in relation to other body parameters, and a regression equation was also obtained. The angle of the vertical axis with the superior vena cava at the confluence was linearly correlated with the distances between the coracoid processes and the jugular notch to coracoid processes. The angle of the vertical axis with left brachiocephalic vein was linearly correlated with the thickness of thorax and the length from the upper pericardial margin to the confluence. The angle of the vertical axis with right brachiocephalic vein was correlated with clavicular midline length, acromial distance, intersection point of clavicle to clavicular midline, confluence to clavicular midline, superior edge of the blood vessels to superior edge of clavicle at the right intersection, and superior edge of pericardium to confluence. There is a linear relationship between the superior vena cava circumference and the distance from the superior vena cava to the aorta. A number of parameters influence angles of the vertical axis with superior vena cava, left and right brachiocephalic veins and the superior vena cava circumference which can provide guidance for intubation.

Abstract Importance Evidence from systematic reviews of the cardioprotective effect of omega-3 polyunsaturated fatty acid (PUFA) remains controversial, and interventions including PUFAs dietary supplements or prescription medications cannot accurately reflect the role of PUFA RX in cardiovascular disease (CVD) prevention. Objective We conducted a meta-analysis of randomized clinical trials (RCTs) to evaluate the efficacy of PUFA prescription medication in preventing CVD. Methods Two reviewers conducted a literature search of Embase, MEDLINE/PubMed, and the Cochrane Library from their inception to September 2023. The inclusion criteria were RCTs evaluating long-term supplementation (≥ 1 year) with PUFA prescriptions and reporting cardiovascular outcomes. Data were extracted independently by two authors, and the certainty of evidence for each outcome was assessed using the GRADE system. Random-effects models were used to estimate the risk ratios (RRs) and 95% confidence intervals (CIs). The primary outcomes were cardiovascular events. Secondary endpoints included major adverse cardiovascular events (MACEs), cardiac death, all-cause mortality, myocardial infarction, stroke, and revascularization. Subgroup analyses were performed based on PUFA components, dosage, follow-up duration, and risk status. Results Twelve RCTs involving 99,830 participants were included. The mean age of participants ranged from 59.4 to 74.0 years, with a follow-up period varying from 1 to 6.2 years. Compared with placebo and statins, PUFA prescription medication was associated with a reduced risk of cardiovascular events (8 RCTs, n = 75,929, RR, 0.88 [95% CI, 0.81–0.95]; P = 0.0007; I2 = 45%), cardiac death (10 RCTs, n = 95,440, RR, 0.91 [95% CI, 0.84–0.99]; P = 0.02; I2 = 23%), myocardial infarction (9 RCTs, n = 94,877, RR, 0.84 [95% CI, 0.73–0.96]; P = 0.009; I2 = 62%), and revascularization (9 RCTs, n = 91,242, RR, 0.91 [95% CI, 0.84–0.99]; P = 0.02; I2 = 63%). Conclusions and relevance PUFA prescription medication could lower the risks of cardiovascular events, cardiac death, myocardial infarction and revascularization. This research provides insight into the efficacy of PUFA prescription medications in CVD prevention and contributes to the ongoing debate on the role of PUFA products in cardiovascular outcomes.

Abstract Background As two of the most impactful abiotic stresses, salt and drought strongly affect tomato growth and development, especially at the seedling stage. However, dissection of the genetic basis underlying salt/drought tolerance at seedling stage in tomato remains limited in scope. Results Here, we reported an analysis of major quantitative trait locus (QTL) and potential causal genetic variations in seedling stage salt/drought tolerance in recombinant inbred lines (n = 201) of S. pimpinellifolium and S. lycopersicum parents by whole genome resequencing. A total of 5 QTLs on chromosome 1, 3, 5, 7 and 12 for salt tolerance (ST) and 15 QTLs on chromosome 1, 3, 4, 8, 9, 10, 12 for drought tolerance (DT) were identified by linkage mapping. The proportion of phenotypic variation explained (PVE%) by these QTLs ranged from 4.91 to 15.86. Two major QTLs qST7 and qDT1-3 were detected in both two years, for which two candidate genes (methionine sulfoxide reductase SlMSRB1 and brassinosteroid insensitive 1-like receptor SlBRL1) and the potential functional variations were further analyzed. Taking advantage of the tomato population resequencing data, the frequency changes of the potential favorable QTL allele for seedling stage ST/DT during tomato breeding were explored. Conclusions These results will be beneficial for the exploration of salt/drought tolerance genes at seedling stages, laying a foundation for marker-assisted breeding for seedling stage salt/drought tolerance.

Abstract Background Nurses’ positive expectations of patients in medical interactions constitute an important component of nurse-patient trust and can foster good nurse-patient relationships; therefore, it is critical to investigate factors that influence nurses’ expectations. This study aims to examine the relationship between nurses’ institutional trust, nurse-patient communication, and nurses’ expectations of patients before and after the outbreak of the COVID-19 pandemic. Methods Self-reported questionnaires were administered to 1752 nurses (M age = 32.14 years, SD = 7.62) before the COVID-19 outbreak and 768 nurses (M age = 29.48 years, SD = 5.51) after the COVID-19 outbreak to assess their medical institutional trust, communication skills, and expectations of patients. Mediational models were constructed to examine the relationship between these variables. Results Before the outbreak of the COVID-19 pandemic, there was a significant positive correlation between nurses’ medical institutional trust and their expectations of patients, with nurse-patient communication serving as a mediator. During the COVID-19 pandemic, the association between nurses’ medical institutional trust and expectations of patients was nonsignificant; however, a significant mediating effect of nurse-patient communication remained between nurses’ medical institutional trust and expectations of patients. Conclusions Improving nurses’ trust in medical institutions may enhance their positive expectations of patients. Healthcare managers should make efforts to foster nurses’ trust in healthcare institutions. Furthermore, nurse-patient communication plays a critical mediating role between nurses’ medical institutional trust and their expectations of patients, highlighting the importance of interventions and training programs that improve nurses’ communication skills, especially when encountering high-risk circumstances.

Abstract Background Accumulation of coumarins plays key roles in response to immune and abiotic stress in plants, but the genetic adaptation basis of controlling coumarins in perennial woody plants remain unclear. Results We detected 792 SNPs within 334 genes that were significantly associated with the phenotypic variations of 15 single-metabolic traits and multiple comprehensive index, such as principal components (PCs) of coumarins metabolites. Expression quantitative trait locus mapping uncovered that 337 eQTLs associated with the expression levels of 132 associated genes. Selective sweep revealed 55 candidate genes have potential selective signature among three geographical populations, highlighting that the coumarins biosynthesis have been encountered forceful local adaptation. Furthermore, we constructed a genetic network of seven candidate genes that coordinately regulate coumarins biosynthesis, revealing the multiple regulatory patterns affecting coumarins accumulation in Populus tomentosa. Validation of candidate gene variations in a drought-tolerated population and DUF538 heterologous transformation experiments verified the function of candidate genes and their roles in adapting to the different geographical conditions in poplar. Conclusions Our study uncovered the genetic regulation of the coumarins metabolic biosynthesis of Populus, and offered potential clues for drought-tolerance evaluation and regional improvement in woody plants.

Abstract Background A significant proportion of cardiomyopathy patients remain genetically unsolved. Our aim was to use the large genomes cohort of the 100,000 genomes project (100KGP) to explore the proportion of potentially causal mitochondrial (mtDNA) variants in cardiomyopathy patients, particularly in genotype-elusive participants. The homoplasmic MT-TI 4300A>G is unusual in that it typically presents with a cardiac-only phenotype, but MT-TI is currently not part of the genes analysed for non-syndromic cardiomyopathies. Results We analysed 1363 cardiomyopathy genomes from the 100KGP project (of which only 172 had been previously solved) to detect disease causing mtDNA variants. MitoHPC was used to call variants. For controls, 1329 random subjects not recruited for a cardiomyopathy diagnosis and not related to any participant in the cardiomyopathy cohort were selected. We have additionally compared the frequency of detected variants with published UK Biobank data. Pathogenicity annotations were assigned based on MitoMap. Four patients, all with a diagnosis of hypertrophic cardiomyopathy (HCM) and without a previously identified genetic cause from the 100KGP clinical-standard analysis, were found to harbour the pathogenic MT-TI m.4300A>G variant (0.6% of HCM cases without a diagnosis). Conclusion These data support the inclusion of MT-TI in the initial genetic testing panel for (non-syndromic) HCM.

Abstract Background/aims Mesenchymal stem cells (MSCs) have shown promising therapeutic potential in treating liver diseases, such as non-alcoholic fatty liver disease (NAFLD). Genetic modification has been employed to enhance the characteristics of MSCs for more effective disease treatment. Here, we present findings on human adipose-derived MSCs with Atg5 deficiency, investigating their therapeutic impact and the associated mechanisms in NAFLD. Methods In vitro, lentiviral transduction was employed to downregulate Atg5 or HGF in human adipose-derived MSCs using short hairpin RNA (shRNA). Subsequently, experiments were conducted to evaluate cell senescence, proliferation, cell cycle, apoptosis, and other pertinent aspects. In vivo, a non-alcoholic fatty liver mouse model was established by feeding them a high-fat diet (HFD), and the effects of MSCs transplantation were assessed through serological, biochemical, and pathological analyses. Results Our research findings indicate that Atg5-deficient MSCs display heightened proliferative activity. Subsequent co-culturing of MSCs with hepatocytes and the transplantation of Atg5-deficient MSCs into NAFLD mouse models demonstrated their ability to effectively reduce lipid accumulation in the NAFLD disease model by modulating the AMPKα/mTOR/S6K/Srebp1 pathway. Furthermore, we observed that Atg5 deficiency enhances the secretion of hepatocyte growth factor (HGF) by promoting recycling endosome (RE) production. Lastly, our study revealed that 3-MA-primed MSCs can improve the characteristics of NAFLD by boosting the secretion of HGF. Conclusions Our research findings suggest that Atg5-deficient MSCs protect against NAFLD by accelerating HGF secretion. This indicates that Atg5 gene-modified MSCs may represent a promising strategy for treating NAFLD.

Abstract Background Granulosa cell (GC) apoptosis, ferroptosis, and other programmed cell death processes are markers of follicular aging. Quercetin has been shown to reduce ferroptosis, however, its effects on ferroptosis in poultry remains unexplored. Our preliminary study identified ferroptosis in aging ovaries. Therefore, in the present study, 540-day-old Mountain Plum-blossom chickens were fed with quercetin supplementation at varying doses (0.2, 0.4, and 0.6 g/kg), and examined its molecular effects on GC ferroptosis using an in vitro Erastin-induced model. Results The results showed that quercetin supplementation significantly increased egg production, which confirmed its potential to alleviate ferroptosis in chicken ovarian tissue. The in vitro experiment revealed that quercetin and Fer-1 (positive control) mitigated Erastin-induced ferroptosis in GCs. Further, transcriptome analysis revealed that quercetin modulated key genes such as acyl-CoA synthetase long-chain family member 4 (ACSL4), solute carrier family 7 member 11 (SLC7A11), and transferrin receptor (TFRC), involved in ferroptosis regulation. The results further showed that quercetin also reduced Erastin-induced apoptosis and inflammation by modulating the expression of genes and proteins related to apoptosis and inflammatory factors (NF-κB, TNF-α, IL-6, and IL-10). Conclusion Taken together, the results showed that quercetin improves egg production performance in chickens and mitigates ovarian ferroptosis in aging hens, and inhibits Erastin-induced ferroptosis, inflammation, and apoptosis in GCs. These findings revealed the protective role of quercetin in poultry ovarian tissue and its cellular mechanisms against detrimental factors in poultry production. Graphical Abstract

Abstract Background Sulfotransferase family 2B member 1 (SULT2B1) is involved in regulating cell proliferation, migration and metabolism. However, there is still dispute regarding whether SULT2B1 acts as an oncogene or a suppressor, and the intrinsic mechanisms in modulating tumor progression need to be further elucidated. Methods This work aims to reveal the relationship among SULT2B1, AKT, PKM2 signaling and glycolytic pathways, and provided a theoretical basis for SULT2B1 as a potential therapeutic target for CRC.Bioinformatics methods, immunohistochemistry (IHC) and immunoblotting assays were performed to analyze the correlation between SULT2B1 and colorectal cancer (CRC). The effect of SULT2B1 on cell proliferation and migration were investigated by several phenotypic experiments in vitro and animal studies. The SULT2B1 interacting proteins were determined by immunofluorescence, immunoprecipitation and GST-pull down assays. Immunoblotting and mCherry-GFP-LC3 assays were performed to analysis autophagy. Chromatin immunoprecipitation (CHIP) assay was utilized to detect the effect of SULT2B1 in regulating transcription. Small molecule agonist/antagonist was used to modify protein activity and therefore analyze the mutual relationships. Results SULT2B1 is a predictive biomarker that is abnormally overexpressed in CRC tissues. Overexpression of SULT2B1 promoted cell proliferation and migration, while its knockout suppressed these processes. Furthermore, SULT2B1 could directly interact with the oncogene AKT and thereby enhance the activity of AKT-mTORC1 signaling. Furthermore, PKM2 was found to bind with SULT2B1, and regulated by SULT2B1 at both transcription and degradation levels. Moreover, blocking glycolysis attenuated the promoting effect of OE-SULT2B1. Conclusion SULT2B1 acts as an oncogene in CRC via modulating the AKT/PKM2 axis, therefore making it a promising diagnostic and therapeutic target for CRC.

Abstract Background The incidence of Non-alcoholic fatty liver disease (NAFLD) in China and USA is extremely high and rising. TikTok has become a popular channel for medical information dissemination and we aimed to evaluate the quality and reliability of NAFLD related videos on TikTok, in both its USA and Chinese versions. Methods We analyzed the top 100 NAFLD videos on both the USA version and Chinese version of TikTok, a total of 200 videos, from which keywords were extracted and scored using the Global Quality Scale (GQS), modified DISCERN (mDISCERN), and Medical Quality Video Evaluation Tool (MQ-VET). Exploring the relationship between video quality and audience related factors, as well as ranking, through Spearman correlation analysis. Results The mDISCERN scores of videos on the USA version of TikTok is higher than that on the Chinese version (P

Abstract Objective Ductal carcinoma in situ (DCIS) of the breast has a wide disease spectrum with risks of progression to invasive cancer linked to pathological factors. High-grade histology, large tumor volume, and comedonecrosis are adverse prognostic factors. This study explores the correlation between conventional ultrasound (Con-US) and shears wave elastography (SWE) features with DCIS prognostic factors and evaluates their predictive efficacy. Methods A retrospective analysis was conducted on clinical data, Con-US, and SWE imaging features of 83 DCIS patients who underwent surgical resection between June 2018 and December 2022. Binary logistic regression analysis was performed to explore the relationship between sonogram indices and pathological prognostic factors. Results The results revealed that microcalcification observed on Con-US was an independent risk factor for high-grade DCIS and comedonecrosis [odds ratio (OR): 5.316 and 4.512]. In SWE analysis, the Emax value was significantly different between the non-high-grade and high-grade DCIS groups(P = 0.006), with an Emax value greater than 75.03 kPa identified as an independent risk factor for high-grade DCIS [OR:1.022, the area under the curve (AUC): 0.682, 95% confidence interval (CI): 0.555–0.808]. Additionally, the Ecolor, Emax, Emean, and Emean SD values were statistically different between the groups with and without comedonecrosis (P = 0.049, 0.006, 0.012, 0.022), with an Emean value exceeding 30.45 kPa identified as an independent risk factor for comedonecrosis (OR:1.025, AUC:0.708, 95% CI:0.562–0.854). Furthermore, combining microcalcification on Con-US with specific SWE indicators demonstrated an improved predictive specificity for high-grade DCIS and comedonecrosis (0.902 and 0.889, respectively). No significant difference was found in other indexes on SWE. Conclusions The microcalcification signs on Con-US, Emax and Emean values on SWE analysis are associated with the high nuclear grade and comedonecrosis of DCIS, the combination of Con-US and SWE can improve the predictive specificity of DCIS-related prognostic factors.

Abstract Objective A digital classification system based on AO classification was adopted to study and summarize different types of floating knee injuries. Methods One hundred cases with a floating knee injury from March 2005 to December 2020 were collected, including 74 males and 26 females with an average age of 43.74 years. The distribution of the affected limbs in there were 51 cases (51.0%) on the left and 46 cases (46.0%) on the right, as well as 3 cases (3.0%) that got bilaterally affected limbs. The femora and tibiae in this system were divided into three parts separately based on the AO classification, which was finally composed of six types after pairwise combination. The images in this study would be analyzed by using the classification to summarize the distribution rules of the classification in a floating knee injury. Results The proportion of I-VI type injury was 42.7%(44/103) in type I, 18.4%(19/103) in type II, 9.7%(10/103) in type III, 10.7%(11/103) in type IV, 11.7%(12/103) in type V, and 6.8%(7/103) in type VI. Conclusions The digital classification system of floating knee injury based on AO classification could classify most cases of floating knee injury and cases with open injury, which referred to a reference effectively for the selection of surgical treatment plan, and would be conducive to the future clinical classification.

Abstract Background Tubular anastomosis is commonly used in proximal gastrectomy; however, its use in stage II esophagogastric conjugate cancer is currently unclear. In this study, we investigated the short- and long-term clinical outcomes of Siewert II/III adenocarcinoma of the esophagogastric junction after modified proximal gastrectomy with tubular esophagogastric anastomosis compared with total gastrectomy with Roux-en-Y reconstruction. Methods We collected the clinical data of patients who underwent proximal gastrectomy tubular esophagogastric anastomosis (PG-TEA) and total gastrectomy Roux-en-Y reconstruction (TG-RY) from October 2015 to October 2018. The clinical characteristics, postoperative quality of life, nutritional status, and long-term survival outcomes of the two groups were compared. Results There were 43 patients in the PG-TEA group and 80 patients in the TG-RY group, and there was no significant difference between the baseline data of the groups. The operation time of the PG-TEA group was shorter, there was less intraoperative bleeding, and the feeding time was earlier, which was conducive to postoperative recovery. Reflux esophagitis was more evident in the PG-TEA group than in the TG-RY group, and there was no significant difference in the incidence of anastomotic ulcers or other complications. Three months after surgery, the nutritional status of the PG-TEA group was better than the TG-RY group. By the 6th postoperative month, there was no significant difference between the two groups. Regarding quality of life, the PG-TEA group was superior to the TG-RY group in terms of diarrhea and dumping syndrome. In addition, the PG-TEA group had higher satisfaction with daily life and higher-quality meals. There was no significant difference in overall survival between the two groups. Conclusions Proximal gastrectomy tubular gastroesophageal anastomosis is a surgical procedure for stage II Siewert type II and III AEG. It achieves similar clinical outcomes to those after total gastrectomy and can be further applied in the clinic.

Abstract Background Current guidelines recommend maintaining a resting heart rate below 100–110 beats per minute (bpm) for patients with atrial fibrillation (AF). However, there is a lack of research on various treatment approaches for patients with both atrial fibrillation and coronary heart disease (AF&CHD). We have discussed the primary therapeutic options for controlling resting heart rate in patients with AF&CHD. Methods We conducted a post hoc analysis of the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) trial. Our study included 3986(98.2%) participants with AF, of which 1522 had AF&CHD. The primary outcome was all-cause mortality. We utilized the chi-squared test to identify significant differences in categorical variables. Multivariate Cox regression analysis was performed to compare the risk of death by standard deviation of heart rate visit to visit variability quartile. Results Compared to the AF group, a higher proportion of patients in the AF&CHD group had histories of smoking, hypertension, diabetes, heart failure, cardiomyopathy, valvular heart disease, peripheral vascular disease, bradycardia, hepatic or renal disease, pulmonary disease, and stroke (all P

Abstract Background Microvascular obstruction (MVO) develops in approximately 50% of patients with ST-segment elevation myocardial infarction (STEMI) after undergoing percutaneous coronary intervention (PCI). MVO is strongly linked to inflammation, myocardial fibrosis, and adverse clinical outcomes. Soluble suppression of tumorigenicity 2 (sST2) serves as a biomarker for inflammation and myocardial fibrosis. Yet, the correlation between sST2 and MVO in STEMI patients has not been fully elucidated. This study attempts to evaluate the association between sST2 levels and MVO in STEMI patients following pPCI. Methods In this retrospective study, 315 STEMI patients who underwent pPCI at the Affiliated Hospital of Xuzhou Medical University between June 2018 and August 2023 were included. Cardiac magnetic resonance imaging (CMR) was used to assess the characteristics of myocardial infarction and microvascular obstruction (MVO), while sST2 levels were measured upon admission. Results The median time for completion of CMR after hospitalization was 5 (4, 6) days. Multivariate regression analysis showed that sST2 (OR 1.01, 95% CI 1.01–1.02, p

Abstract Background As neuropeptide Y is associated with endothelial dysfunction, this study explored the relationship between neuropeptide Y and acute myocardial infarction. Methods We included 128 acute myocardial infarction cases and 62 controls. Using the SYNTAX scoring system, the acute myocardial infarction group was sub-grouped into “SYNTAX ≤ 22,” “SYNTAX = 23–32,” and “SYNTAX ≥ 33.” Plasma neuropeptide Y, endothelin, endothelial nitric oxide synthase, and thromboxane A2 levels were measured. Results The acute myocardial infarction group had higher plasma neuropeptide Y, endothelin, and thromboxane A2 levels than controls ([58.76 ± 17.63 vs. 37.48 ± 11.36 ng/ml, P = 0.000], [36.16 ± 10.04 vs. 27.80 ± 7.18 pg/ml, P = 0.000], and [27.69 ± 6.91 vs. 24.32 ± 7.28 pg/ml, P = 0.002], respectively). The acute myocardial infarction group also had lower plasma endothelial nitric oxide synthase levels than controls (3.00 ± 0.94 vs. 4.05 ± 1.44 ng/ml, P = 0.000). Additionally, the receiver operating characteristic curve analysis showed that a neuropeptide Y value of 49.94 ng/ml could help diagnose acute myocardial infarction (sensitivity: 70.9%; specificity: 91.9%). The SYNTAX scores, smoking, plasma endothelin, thromboxane A2, and neuropeptide Y levels were positively correlated, whereas plasma endothelial nitric oxide synthase and neuropeptide Y levels were negatively correlated. Lastly, plasma neuropeptide Y levels were different among subgroups (P

Abstract Background Allergic rhinitis (AR) subjects might have their microenvironment changed due to pathogenesis and living environment. Whether the nasal microbe in AR children differs from healthy subjects and how it interplays with dermal, oral and indoor dust microbe needs to be elucidated. Methods In this case–control study, we analyzed and compared the bacterial characterization and associations in nasal, dermal, oral swab samples and dust samples in 62 children with physician-diagnosed AR(cases) and 51 age- and gender-matched healthy ones with no history of allergic diseases(controls). Full-length 16S rRNA sequencing(swabs) and shotgun metagenomics(dust) were applied. Bacterial diversity, composition, abundance difference characteristics and fast expectation–maximization for microbial source tracking(FEAST) analysis were performed and compared between cases and controls. Results The α-diversity of dust microorganisms in AR was lower than that in control group (P = 0.034), and the β-diversity indices of microorganisms in nasal cavity (P = 0.020), skin (P = 0.001) and dust (P = 0.004) were significantly different from those in control group. At species levels, a total of 10, 15, 12, and 15 bacterial species were differentially enriched in either cases or controls in nasal, dermal, oral, and dust samples, respectively(Linear Discriminant Analysis(LDA) score > 2, P

Abstract Background To assess and compare the therapeutic outcomes of 0.05% Cyclosporine A (CsA) ophthalmic solution versus 0.1% Fluorometholone (FML) eyedrops in Chinese patients with mild dry eye disease (DED) unresponsive to conventional artificial tears (AT). Methods A total of 43 patients with mild DED, who have failed to respond to conventional AT therapy for over 3 months, were randomly assigned to receive either 0.05% CsA or 0.1% FML twice daily for 6-months. In addition, all the patients were instructed to use 0.1% SH 4 times a day as supplementary therapy. Dry eye examination, including Ocular Surface Disease Index (OSDI) questionnaire, non-invasive tear break-up time (NIBUT), Schirmer scores, corneal fluorescein staining (CFS) scores, and conjunctival goblet cell (CGC) density, intraocular pressure (IOP), Best corrected visual acuity (BCVA) was conducted at baseline and then evaluated at 1, 3, and 6 months after treatment. Corneal endothelial cell density, corneal dendritic cells (DCs) and nerves were assessed by in vivo confocal microscopy at baseline and 6 months after treatment. Results At 3 and 6 months after treatment, OSDI scores in the 0.05% CsA group showed more improvement than those in the 0.1% FML group. CFS was significantly lower and Schirmer scores were significantly higher in 0.05% CsA group compared with 0.1% FML group. NIBUT improved significantly in both groups, with greater improvement in the 0.05% CsA group at the 1-, 3-, and 6-month visits. Throughout the duration of the study, the 0.1% FML group exhibited no notable enhancement in CGC density. Conversely, a substantial elevation in CGC density was observed in the 0.05% CsA group. After 6 months of treatment, significantly reduced corneal DC density and area were obtained in 0.05% CsA group as compared to 0.1% FML group, while there were no significant changes in cornea nerve fiber density, cornea nerve fiber length and cornea nerve fiber width in both groups. Additionally, after 6 months of treatment, neither group showed any statistically significant changes in IOP, BCVA or in corneal endothelial cell density. Conclusion The administration of 0.05% CsA proved effective in managing mild DED, offering a supplementary advantage in improving Schirmer scores, restoring CGC density and reducing corneal DC density compared to 0.1% FML eyedrops. Consequently, 0.05% CsA eyedrops are recommended as a safe and efficacious therapeutic alternative for patients with mild DED who fail to respond to conventional tear substitutes therapy. Clinical trial registration number Chinese Clinical Trial Registry, ChiCTR2200066441, Registered 06 December 2022-Retrospectively registered.

Abstract Aims To examine the association of disaster literacy with collectivism, social support, psychological resilience and self-efficacy among nurses and analyze the influencing mechanisms among these factors. Background Nurses’ disaster literacy is important for future preparation. However, there is a paucity of research in this field. Methods From January to August 2023, we recruited 1573 nurses in 15 hospitals in Zhejiang province, China using convenient sampling. Based on Social-Ecological Model, questionnaires regarding collectivism, social support, psychological resilience, self-efficacy and disaster literacy were distributed via online platform. Data were analyzed using structural equation model to examine the relationships between the study variables. Results Nurses had a medium level of disaster literacy with the lowest score in critical literacy. Nurses’ collectivism not only had positive direct effect on disaster literacy, but also had indirect pathways from social support, psychological resilience and self-efficacy to influence the level of disaster literacy. Conclusions Multilevel factors including collectivism, social support, psychological resilience and self-efficacy were associated with disaster literacy. Understanding the influencing mechanism would inform effective interventions. Implications for nursing management Our findings illustrate the importance for nurse managers, administrators and authorities to work together to develop and implement effective nursing curriculum and training programs to improve nurses’ disaster literacy for future preparation.

Abstract Background Aneuploidy in plants commonly presents as large variations in morphology, physiology, biochemistry, and genetic effects owing to its karyotypic imbalance. Results In this study, the trait variations of 393 offspring obtained by pollinating Populus alla × Populus glandulosa ‘YXY 7’ (2n = 2x = 38) with Populus ‘Beilinxiongzhu 1#’ (2n = 3x = 57) were explored. The results showed several morphological variations in the cotyledons, including two (69.68%), three (24.07%), and four cotyledons (6.25%). Additionally, the progeny exhibited extensive segregation of ploidy levels, ranging from 38 to 74. Furthermore, seedlings with different chromosome numbers varied in growth traits and physiological activities during growth and development. The backcross progeny with 51–60 chromosomes had a significantly larger basal diameter and seedling height than those with other chromosome numbers. The phenotypic correlations between the traits indicated that the dose effect of the chromosomes significantly affected the basal diameter, petiole length, and leaf length, particularly with stomatal length and stomatal density. Weak and negative estimated correlations were observed between the physiological traits associated with photosynthesis and most of the studied traits. Conclusions This study provides new genetic material with different chromosome compositions, which will contribute to analyzing chromosomal function and integrate the variations in chromosomal dosage into Populus breeding programs.

Abstract Background Equity and efficiency are two fundamental principles for the sound development of health systems, as advocated by the World Health Organization (WHO). Despite the notable progress made by the Association of Southeast Asian Nations (ASEAN) in advancing their health systems, gaps persist in achieving global health goals. This paper examines the efficiency of health system stages and the fairness of health resource distribution in ASEAN countries, analyzes the underlying causes of the existing gaps, and suggests potential solutions to bridge them. Methods Data spanning 2011 to 2019, sourced from the WHO Global Health Observatory and the World Bank Database, form the foundation of this study. This study employs an enhanced two-stage data envelopment analysis (DEA) to assess the efficiency of health system stages in ASEAN countries. Equity in health resource distribution is evaluated using health resource agglomeration degree and concentration curves across demographic, geographic, and economic aspects. Furthermore, the Entropy-Weighted TOPSIS method is utilized to integrate equity across these dimensions, measuring the overall fairness in health resource allocation across different countries. Finally, rankings of health system fairness and efficiency are compared to assess the overall development level of health systems. Results The overall efficiency of the ASEAN health systems from 2011 to 2019 averaged 0.231, with an upward trend in the first stage efficiency at 0.559 and a downward trend in the second stage at 0.502. The health resource agglomeration degree indicated that Singapore, Brunei, and Malaysia had HRAD and HRPD values significantly greater than 1, and Cambodia, Myanmar, and Laos predominantly had indices significantly less than 1. The concentration curve for hospital beds was the closest to the line of absolute equity. During the study period, the health resource concentration curve increasingly approached absolute equity, shifting from above to below the concentration curve. Singapore, Brunei, and Malaysia consistently remained in the first quadrant of the quadrant plot, and Myanmar and Cambodia were consistently in the third quadrant. Conclusion ASEAN countries face two key challenges in their healthcare systems: first, while many nations such as Indonesia, Thailand, and Vietnam have improved resource allocation efficiency, this hasn’t yet translated into better health services. To address this, establishing national health sector steering committees, focusing on workforce training and retention, and implementing centralized monitoring systems are crucial. Second, there is a growing disparity in healthcare development across ASEAN. Promoting balanced resource distribution and leveraging ASEAN’s economic integration for regional collaboration will help bridge these gaps and foster more equitable healthcare systems.

Abstract Background The tumor microenvironment (TME) plays a crucial role in tumorigenesis and tumor progression. This study aimed to identify novel TME-related biomarkers and develop a prognostic model for patients with non-small-cell lung cancer (NSCLC). Methods After downloading and preprocessing data from The Cancer Genome Atlas (TCGA) data portal and Gene Expression Omnibus (GEO) datasets, we classified the molecular subtypes using the “NMF” R package. We performed survival analysis and quantified immune scores between clusters. A Cox proportional hazards model was then constructed, and its formula was produced. We assessed model performance and clinical utility. A prediction nomogram was also constructed and validated. Additionally, we explored the potential regulatory mechanisms of our TME gene signature using Gene Set Enrichment Analysis (GSEA). Results From data processing and univariate Cox regression analysis, 57 TME-related prognostic genes were identified, and two significantly distinct clusters were established. Using Cox regression and Lasso regression, an 18-gene TME-related prognostic model was developed. Patients were stratified into high- and low-risk groups based on the risk score, with survival analysis showing that the low-risk group had significantly better outcomes than the high-risk group (P

Abstract Background Cancer survivors face many challenges in long-term health management, including malnutrition, systemic inflammation, and sleep issues, which significantly affect their survival and quality of life. Methods A prospective cohort study was derived from the National Health and Nutrition Examination Survey from 2005–2018 harboring 1,908 cancer survivors (weighted population, 11,453,293), of whom 688 deaths (220 from cancer mortality, 468 from non-cancer mortality). The Advanced Lung Cancer Inflammation Index (ALI) was used as a measure of nutritional status and systemic inflammation in cancer patients. Weighted multivariable Cox proportional hazards regression models were utilized to explore the independent and combined effects of ALI and sleep quality on mortality outcomes. Results The participants with a high ALI were more likely to be female, aged 40 to 64 years, non-Hispanic white, and have a higher BMI. We observed that elevated ALI levels were associated with decreased risks of all-cause mortality (Hazard ratio [HR] = 0.601, 95% Confidence interval [CI] = 0.521–0.695, P

Abstract Background Evidence has shown that oxidative stress induced by high glucose microenvironment in placenta of gestational diabetes mellitus (GDM) is indispensable to the progression of this condition. Adipokine chemerin was linked with GDM, yet the roles of chemerin in placental oxidative stress and its underlying effects on GDM in vivo remain elusive. Methods We firstly analyzed the disparities of oxidative stress levels in placenta between GDM and normoglycaemic pregnant women, and then added recombinant active chemerin to the high-glucose treated human trophoblastic cells to investigate effects of chemerin on reactive oxygen species (ROS), total antioxidant capacity (T-AOC) and intake of glucose. Finally, a GDM animal model induced by high-fat diet (HFD) was established and the impacts of chemerin on oxidative stress of placenta and fetal growth of GDM were explored. Results Analysis of human samples showed that the extent of lipid peroxidation in placenta was significantly elevated in GDM patients compared with their normoglycaemic counterparts. In the high glucose cell model, active chemerin lessened the content of ROS, heightened the index of T-AOC and stimulated glucose uptake in a concentration-dependent manner. Importantly, we successfully constructed a GDM mouse model through HFD. The treatment of chemerin was found to alleviate the high blood glucose levels in these HFD-fed pregnant mice and attenuate the excessive growth of their offspring. Our data also revealed that chemerin might counteract placental oxidative stress in HFD mice by improving the activity of superoxide dismutase. Conclusions The present study further elucidated the molecular biology of chemerin, which plays a pivotal role in ameliorating oxidative stress and hyperglycemia, resulting in improved fetal overgrowth in GDM. Graphical abstract

Abstract Background Impoverished students constitute a group that cannot be overlooked in higher education. It is crucial for pharmaceutical universities worldwide to implement financial assistance programs that promote the development and success of students from poor families. Chinese universities have carried out active exploration of subsidized education, and made important achievements, but there are also problems, which are worth learning from. This study proposed a strategy to improve the core literacy of impoverished pharmaceutical students under the development-oriented funding system. Methods The study centers on clinical pharmacy students from a pharmaceutical college as the research subjects. A sequential explanatory mixed-methods approach was employed, with quantitative data collected through a survey questionnaire, supplemented by qualitative data collected through in-depth interviews. Data gathered from these two levels were integrated and subjected to statistical analysis. Results The quantitative survey yielded a total of 397 valid samples, most of whom were females (73.8%), mainly at undergraduate level (89.67%), and from non-urban area (73.81%). Five of them participated in further qualitative interviews. The combined data identified: (a) financial aid—most students were highly satisfied with the financial support; (b) psychological support—most of the students interviewed reported that the scholarship significantly improved their self-confidence and motivation; (c) academic guidance—funded students had clear expectations for career development and academic guidance, demonstrating a strong need for further professional study; and (d) employment assistance—most students wanted career guidance and career planning support. Conclusions The financial assistance in pharmaceutical colleges and universities should be enriched to resolve the worries of impoverished clinical pharmacy students through economic assistance, improve the moral cultivation with psychological assistance, strengthen their cultural and scientific literacy, and improve their knowledge and practical ability through academic assistance. Through the integration of pharmacy education, the vocational competence of clinical pharmacy students can be improved by employment assistance, and the reform of higher pharmacy education can be further promoted to improve the training quality of pharmaceutical talents.

Abstract Background Preoperative templating is an important step for total knee arthroplasty (TKA), facilitating hospital personnel in the anticipation and preparation of necessary surgical resources. Despite its importance, this process currently lacks automation. This study aimed to develop an artificial intelligence (AI) model to automate implant size prediction. Methods A total of 13,281 (2938 anteroposterior, 10,343 lateral) knee radiographs obtained from the authors’ institute were utilized for model training, with 2302 (1034 anteroposterior, 1268 lateral) images set apart for validation and testing. The templating AI model integrates a pipeline composed of multiple steps for automated implant size estimation. To predict implant size, anterioposterior (AP) and lateral radiograph predictions were merged, selecting the smaller of the predicted sizes to prevent implant overhang. The model’s size predictions were validated with 81 real TKA data set apart from the training data, and its accuracy was compared to that of manual templating by an orthopedic specialist. Predictions matching the actual implanted sizes were labeled “exact” and those within one size, “accurate.” The influence of patient characteristics on the model’s prediction accuracy was also analyzed. The measurement time elapsed for implant sizing was recorded for both the AI model and the orthopedic specialist. Implant position predicted by the model was validated by comparing insert locations with postoperative images. Results Compared with data from 81 actual TKA procedures, the model provided exact predictions for 39.5% of femoral and 43.2% of tibial components. Allowing a one-size margin of error, 88.9% of predictions were deemed “accurate” for both components. Interobserver reliability (Cohen’s kappa) were 0.60 and 0.70 for femoral and tibial implants, respectively, both classified as “substantial.” The orthopedic specialist produced results accurate within one-size margin of error in 95.1% and 100% of cases for femoral and tibial components, respectively. Interobserver reliability between the orthopedic specialist and ground truth was 0.76 and 0.8 for femoral and tibial components, respectively. The measurement time per case was 48.7 s for the AI model, compared with 97.5 s for the orthopedic specialist. Compared with postoperative radiographs, predicted implant position had an error of less than 4 mm on average. Conclusions An AI-based templating tool for TKA was successfully developed, demonstrating satisfactory accuracy and efficiency. Its application could significantly reduce the clinical workload in TKA preparation.

Abstract Objective Schools play an essential role in providing mental health care for adolescents. School closures during COVID-19, as well as re-opening to remote-only instruction in Fall 2020, may indirectly affect the utilization of emergency psychiatric care. We examine COVID-19-related changes in emergency psychiatric care among youth during the school closure and after school reopening (with remote instruction). Methods We use Box-Jenkins interrupted time series methods to analyze psychiatric emergency department (ED) visits among patients 10–19 years at LAC + USC Medical Center (LAC + USC) between January 5th, 2018, and December 31st, 2020. We control for the 1st societal shutdown in LA County (i.e., the nine weeks from March 13 to May 14, 2020) when analyzing the potential “return to remote school” shock. Results Youth psychiatric ED visits fell by 15.3 per week during the Spring 2020 school closure (p

Abstract Porcine parvovirus (PPV) infection induces germ cell death, leading to reproductive disorders in first-pregnant sows. Porcine placental trophoblast cells (PTCs) are the major target of PPV, and we have previously found that PPV infection leads to the death of PTCs by a non-apoptotic process, which may be related to PPV pathogenicity. The Z-nucleic acid-binding protein 1 (ZBP1) is often activated after virus invasion and mediates subsequent cell death. Here, we found that PPV infection induced ZBP1-mediated necroptosis of porcine PTCs in the presence of the apoptosis inhibitor, AC-DEVD-CHO. ZBP1 expression was upregulated during PPV infection, and ZBP1 knockout or RNA interference significantly reduced its expression along with the PPV-induced necroptosis. We discovered that RIPK3 and MLKL, but not Caspase-8, were involved in downstream signaling of ZBP1 during PPV infection; the phosphorylation levels of RIPK3 and MLKL were enhanced, but Caspase-8 was not significantly cleaved. The knockout of RIPK3 and MLKL significantly reduced the PPV infection-induced necroptosis of porcine PTCs. RIPK3 knockout did not affect the PPV infection-induced upregulation of ZBP1 expression, but blocked the activation of MLKL. MLKL knockout did not affect the upregulation of ZBP1 expression and RIPK3 phosphorylation during PPV infection. UV-inactivated PPV induced significantly less necroptosis of porcine PTCs than non-irradiated PPV. A PPV strain with a mutation in the translation initiation codon was still able to induce necroptosis of PTCs through the ZBP1/RIPK3/MLKL pathway. These results provide new insights into the pathogenic mechanism of PPV infection and suggest that PPV infection of porcine PTCs induces necroptosis through the viral DNA-dependent ZBP1/RIPK3/MLKL pathway.

Abstract Background The gut microbiota of venous thromboembolism (VTE) patients exhibited significant alterations. However, the causal relationship between gut microbiota and VTE has not been fully understood. This study aimed to assess the causal relationship between gut microbiota and the risk of VTE using a two-sample Mendelian Randomization (MR) study. Methods The gut microbiota and VTE genetic data were collected from the MiBioGen consortium and the UK biobank, respectively. The potential causal relationship between gut microbiota and VTE was investigated using a two-sample MR analysis, including inverse variance weighted (IVW), weighted median, MR-Egger, simple mode, and weighted mode methods. Cochran’s Q-test, MR-PRESSO, and MR-Egger regression intercept analysis were utilized to perform sensitivity analysis. Results At the genus level, the results of MR analysis found that Coprococcus1 (OR: 1.0029, 95% CI: 1.0005–1.0054, p = 0.0202) was suggestively linked with an increased risk of VTE, while Slackia (odds ratio (OR): 0.9977, 95% confidence interval (CI): 0.9957–0.9998, p = 0.0298), Butyricicoccus (OR: 0.9971, 95% CI: 0.9945–0.9997, p = 0.0309), Eubacterium coprostanoligenes group (OR: 0.9972, 95% CI: 0.9946–0.9999, p = 0.0445), and Bacteroides (OR: 0.9964, 95% CI: 0.9932–0.9995, p = 0.0234) were suggestively associated with a reduced risk of VTE. No heterogeneity and horizontal pleiotropy was detected. Conclusion This study found that there were potential causal relationships between five gut microbiota and VTE. Our findings may provide new insights into the mechanisms of VTE.

Abstract Background Blood-brain barrier (BBB) disruption after stroke is closely associated with brain tissue edema and neuronal injury, which requires accurate assessment. However, there is a lack of appropriate BBB imaging modality in vivo. As albumin in the blood could cross the damaged BBB into brain tissue after stroke, it serves as a biomarker for BBB disruption. Therefore, we aimed to develop an albumin-seeking near-infrared (NIR) probe to assess BBB disruption in stroke. Results We proposed a chemoselective strategy for seeking albumin with NIR dyes and identified an optimal probe to evaluate BBB disruption in stroke. The probe combined a NIR fluorescent dye with inherent albumin-targeting moieties and exhibited high affinity and selectivity for binding to albumin. Using a mouse stroke model, the probe displayed a high-resolution visualization of the location and extent of BBB disruption in vivo and correlated well with BBB leakage measured by Evans blue ex vivo. A dual-channel NIR-II imaging was successfully used to simultaneously assess BBB disruption and cerebral perfusion after stroke. Furthermore, we applied this method to dynamically evaluate the BBB disruption process and reperfusion of thrombolytic therapy in a stroke model in real time, which showed excellent application value. Conclusions We developed an albumin-seeking NIR probe that accurately evaluated BBB disruption in a safe, non-invasive and real-time manner in various stroke models, and has a great potential guiding stroke treatment in a real-time manner. Graphical Abstract

Abstract Background Enteral nutrition for stroke patients in China presents major shortcomings. This aspect of care involves multiple components, and poor implementation of any one of them may affect the patients’ enteral nutrition. Most current studies only confirm the effectiveness of the application of single interventions and lack any scientific evaluation of the overall ensemble of enteral nutrition interventions in stroke patients. This study focuses on evaluating the overall effectiveness of a care bundles for the management of enteral nutrition in stroke patients by targeting multiple simultaneous interventions. Methods This study is to be conducted over 10 periods in the stroke patient wards of eight hospitals across China. As the trial progresses, each hospital begins by receiving the control group care and then shifts to the intervention group care. The point at which each hospital shifts care is randomised. During this time, the control group implements its usual care, while the intervention group implements an evidence-based care bundles for enteral nutrition management in stroke patients. The primary indicator in this study is feeding intolerance; indicators for the evaluation of nutritional status, gastrointestinal complications, and disease prognosis are also included. Discussion We anticipate that the care bundles developed by pooling this evidence will be manifestly more beneficial than harmful and will be worthy of replication. Hence, we chose a stepped wedge cluster randomised trial to validate the application of these interventions. This study will provide experience and reference on how to promote the clinical translation of evidence-based evidence and standardise enteral nutrition care management in stroke patients. Trial registration ChiCTR2300067930. Registered on January 31, 2023.

Abstract Background Influenza vaccination confers broad benefits in the elderly and certain high-risk populations, but its effectiveness in patients with acute heart failure (HF) is uncertain. Rates of influenza vaccination are low in China due to poor awareness, cultural misunderstandings, and cost. Aims To determine the effectiveness of influenza vaccination in patients with acute HF admitted to hospitals in China. Methods The second Population Assessment of Influenza and Disease Activity (PANDA II) study is a two-arm, parallel-group, county-level hospital-based, cluster randomized controlled trial to determine the benefits and risks of full access to routine free influenza vaccination before hospital discharge, compared to routine limited use of influenza vaccination, on the primary endpoint of death or hospital readmission. Consecutive hospitalized patients at each site are enrolled to a target of 50 participants in each autumn–winter influenza outbreak period (October to March) over 3 consecutive years to reach the required sample size. Patients are centrally followed up at 1, 3, 6, and 12 months after hospital discharge (or death if earlier). Site numbers varied across year according to predicted influenza activity and logistical reasons. Conclusions This study offers a unique chance to clarify uncertainties surrounding the effectiveness of influenza vaccination in patients with HF and to lay the groundwork for future prevention strategies. Trial registration This trial was registered with the acronym PANDA II (Population Assessment of Influenza and Disease Activity) at ChiCTR.org.cn (ChiCTR2100053264). Registered on 17 November 2021.

Abstract Background Cancer navigation programs aim to support, educate, and empower patients and families, addressing barriers to diagnostics, treatment, and care. Navigators engage with people to ensure timely access to services and resources. While promising for older people with cancer, these programs are scarce in Europe, and research on their effectiveness and implementation is limited. We describe the protocol of the EU NAVIGATE randomized controlled trial, aimed to evaluate (1) effectiveness and cost-effectiveness of NavCare-EU, an intervention that aims to support older people with cancer throughout their illness trajectory, spanning the continuum of supportive, palliative, and end-of-life care, and (2) the intervention’s implementation processes and feasibility of its integration into different health care systems in Europe, contextual barriers and facilitators for effective and sustainable implementation, and mechanisms involved in reaching the outcomes. Methods We will conduct a multisite pragmatic fast-track randomized controlled trial with embedded convergent mixed-method process evaluation in Belgium, Ireland, Italy, Netherlands, Poland, and Portugal. The study targets people with cancer and declining health, 70 years or older, and their close family caregivers. The trial compares the NavCare-EU intervention plus standard care with standard care alone. We will perform a baseline measurement prior to randomization and follow-up measurements at 12 weeks, 24 weeks, and 48 weeks in intervention and control group, and an additional measurement at 72 weeks in the control group. Primary outcomes, measured at 24 weeks are (1) the older person’s global health status/quality of life, a 2-item subscale from EORTC-QLQ-C30 (revised) measuring health-related quality of life, (2) level of social support measured with Medical Outcomes Study Social Support Survey (MOS-SSS scale). The study will include at least 246 older persons with completed global health status/quality of life at 24 weeks. Discussion The EU NAVIGATE trial will cross-nationally test the effectiveness and cost-effectiveness of a navigation intervention for older people with cancer and their family caregivers, and its implementation in different health care systems in Europe. As continuity and access to health, social, and community care is a priority for patients and caregivers, the trial is timely and critically needed. Trial registration Clinicaltrials.gov: identifier NCT06110312 (2023/10/31).

Abstract Background Cancer-associated fibroblasts (CAFs), a predominant stromal cell type in the tumor microenvironment, significantly affect the progression of oral squamous cell carcinoma (OSCC). Results The specific mechanisms through which CAFs influence the cancer stem cell phenotype in OSCC are not fully understood. This study explored the effects of lactic acid produced by CAFs on the cancer stem cells (CSCs) phenotype of OSCC cells. Our results demonstrated that CAFs exhibit increased glycolysis and lactic acid production. Lactic acid treatment enhances CSCs-related markers expression, sphere formation, and clonogenic ability of OSCC cells. RNA sequencing revealed that lactic acid treatment elevates Discs Large Homolog 5 (DLG5) expression and markedly affects the Hippo pathway. Further investigation revealed that DLG5 mediates the effects of lactic acid on the CSCs phenotype. DLG5 knockdown results in elevated expression of E3 ubiquitin ligase Cullin 3, which can promote the ubiquitination and degradation of MST1, but the expression of phosphorylated MST1 remains unchanged. This leads to enhanced binding of phosphorylated MST1 to YAP1, increasing YAP1 phosphorylation and activating the Hippo pathway. Conclusion Collectively, our findings suggest that lactic acid from CAFs promotes the CSCs phenotype in OSCC through the DLG5/CUL3/MST1 axis. Therefore, targeting lactic acid exchange between CAFs and tumor cells may provide a novel therapeutic approach to suppress the CSCs phenotype in OSCC.

Abstract Background Workplace may not only increase the risk of heat-related illnesses and injuries but also compromise work efficiency, particularly in a warming climate. This study aimed to utilize machine learning (ML) and deep learning (DL) algorithms to quantify the impact of temperature discomfort on productivity loss among petrochemical workers and to identify key influencing factors. Methods A cross-sectional face-to-face questionnaire survey was conducted among petrochemical workers between May and September 2023 in Fujian Province, China. Initial feature selection was performed using Lasso regression. The dataset was divided into training (70%), validation (20%), and testing (10%) sets. Six predictive models were evaluated: support vector machine (SVM), random forest (RF), extreme gradient boosting (XGBoost), Gaussian Naive Bayes (GNB), multilayer perceptron (MLP), and logistic regression (LR). The most effective model was further analyzed with SHapley Additive exPlanations (SHAP). Results Among the 2393 workers surveyed, 58.4% (1,747) reported productivity loss when working in high temperatures. Lasso regression identified twenty-seven predictive factors such as educational level and smoking. All six models displayed strong prediction accuracy (SVM = 0.775, RF = 0.760, XGBoost = 0.727, GNB = 0.863, MLP = 0.738, LR = 0.680). GNB model showed the best performance, with a cutoff of 0.869, accuracy of 0.863, precision of 0.897, sensitivity of 0.918, specificity of 0.715, and an F1-score of 0.642, indicating its efficacy as a predictive tool. SHAP analysis showed that occupational health training (SHAP value: -3.56), protective measures (-2.61), and less physically demanding jobs (-1.75) were negatively associated with heat-attributed productivity loss, whereas lack of air conditioning (1.92), noise (2.64), vibration (1.15), and dust (0.95) increased the risk of heat-induced productivity loss. Conclusions Temperature discomfort significantly undermined labor productivity in the petrochemical sector, and this impact may worsen in a warming climate if adaptation and prevention measures are insufficient. To effectively reduce heat-related productivity loss, there is a need to strengthen occupational health training and implement strict controls for occupational hazards, minimizing the potential combined effects of heat with other exposures.

Abstract Drought, a prevalent abiotic stressor, significantly impacts plant yield and quality. Melatonin (MT), a potent and economical growth regulator, plays a pivotal role in augmenting crop resilience against stress. This study investigated the efficacy of exogenous MT on drought-stressed celery seedlings by comprehensively analyzing phenotypic, physiological, and molecular attributes. The results revealed that exogenous MT mitigated celery seedling damage under drought stress, lowered malondialdehyde (MDA) concentrations, elevated oxidase activities, osmolyte levels, chlorophyll content, and augmented light energy conversion efficiency. Transcriptomic analysis demonstrated that MT could regulate chlorophyll synthesis genes (AgPORA1 and AgDVR2), contributing to heightened photosynthetic potential and increased drought tolerance in celery. Moreover, MT was found to modulate glycolytic pathways, upregulate pyruvate synthesis genes (AgPEP1 and AgPK3), and downregulate degradation genes (AgPDC2 and AgPDHA2), thereby promoting pyruvate accumulation and enhancing peroxidase activity and drought tolerance. The RNA-seq and qRT-PCR analyses demonstrated similar results, showing the same general expression trends. The study elucidates the physiological and molecular mechanisms underlying MT’s stress-alleviating effects in celery seedlings, offering insights into MT-based strategies in plant cultivation and breeding for arid environments.

Abstract Saccharomyces boulardii (S. boulardii) is a fungal probiotic used to treat digestive disorders. However, the mechanism(s) by which S. boulardii affects the small intestine remains unclear. Here, we aimed to explore the effects of S. boulardii on the small intestine and the underlying mechanisms in mice with loperamide-induced constipation. While S. boulardii administration did not fully reverse the alterations in loperamide-induced defecation parameters, it altered the small intestinal floral composition toward a community conducive to alleviate constipation. Moreover, S. boulardii up-regulated the expression of tyrosine-protein kinase Kit (c-Kit), aquaporin 3 (AQP3), interleukin (IL)-10, myosin light chain kinase (MLCK), and phosphorylated myosin light chain 20 (P-MLC20), while concurrently down-regulating the expression levels of inducible nitric oxide synthase (iNOS), p65, and IL-17 A. These alterations indicate a discernible effect of small intestinal water reabsorption, inflammatory factor levels, and smooth muscle contraction. Saccharomyces boulardii also positively regulated small intestinal metabolite levels, such as fructose 6-phosphate, dihomo-alpha-linolenic acid, and 3-(4-hydroxyphenyl) lactate, and participated in metabolic pathways such as arginine biosynthesis, linoleic acid metabolism, and protein digestion and absorption. While not fully reversing defecation changes, Saccharomyces boulardii alters intestinal flora, up-regulates key proteins affecting water reabsorption and inflammation, and positively influences metabolic pathways. Our study provides serves as a basis for further studies on the application of S. boulardii in the treatment of intestinal disorders.

Abstract Background Many studies have shown that seed traits, which are among the most important plant traits, can be inherited stably, a finding which is of great value for the improvement of seed germination, seed propagation, seedling establishment, plant breeding, and ecological restoration. The differences in phenotype and nutritional traits and their interactions in Zanthoxylum planispinum var. dingtanensis were ascertained, and the nutrient input rule and the strategy of resource balancing were analyzed in order to provide a scientific basis for the screening of improved variants of the test plant. Results The nutrient distribution with in the tissues of Z. planispinum var. dingtanensis fruit was that the pericarp had adequate concentrations of N and P concentrations and the seed was also sufficient in P, but low in N concentration. Inorganic nutrients were particularly invested in the pericarp, while organic nutrients are more likely to be stored in the seed. In the economic spectrum of seed traits, the large leaf Zanthoxylum variant represented the low-investment economic type, the tufted leaf Zanthoxylum variant represented the high-investment luxury type, and the safflower Zanthoxylum and acutifoliate leaf Zanthoxylum variants represented transitional types. Conclusions Inorganic nutrients were more invested in the pericarp to produce secondary metabolites, while organic nutrients are more likely to be stored in the seed to ensure seed germination and seedling establishment in order to achieve inheritance. The variants of Z. planispinum var. dingtanensis differ in terms of resource allocation and balance, which could be further exploited through combining characters in breeding programs.

Abstract Background Zinc finger proteins (ZFPs) are important regulators in abiotic and biotic stress tolerance in plants. However, the role of the ZFPs in wheat responding to pathogen infection is poorly understood. Results In this study, we found TaZFP8-5B was down-regulated by Puccinia striiformis f. sp. tritici (Pst) infection. TaZFP8-5B possesses a single C2H2-type zinc finger domain with a plant-specific QALGGH motif, and an EAR motif (LxLxL) at the C-terminus. The EAR motif represses the trans-activation ability of TaZFP8-5B. Knocking down the expression of TaZFP8 by virus-induced gene silencing increased wheat resistance to Pst, whereas TaZFP8-5B-overexpressing reduced wheat resistance to stripe rust and rice resistance to Magnaporthe oryzae, suggesting that TaZFP8-5B plays a negative role in the modulation of plant immunity. Using bimolecular fluorescence complementation, split-luciferase, and yeast two-hybrid assays, we showed that TaZFP8-5B interacted with a wheat calmodulin-like protein TaCML21. Knock-down of TaCML21 reduced wheat resistance to Pst. Conclusions This study characterized the function of TaZFP8-5B and its interacting protein TaCML21. Our findings provide a new perspective on a regulatory module made up of TaCML21-TaZFP8-5B in plant immunity.

Abstract Background Activation of pericytes leads to renal interstitial fibrosis, but the regulatory mechanism of pericytes in the progression from AKI to CKD remains poorly understood. CD36 activation plays a role in the progression of CKD. However, the significance of CD36 during AKI-CKD, especially in pericyte, remains to be fully defined. Methods GEO and DISCO database were used to analyze the expression of CD36 in pericyte during AKI-CKD; IRI to conduct AKI-CKD mouse model; Hypoxia/Reoxygenation (H/R) to induce the cell model; RT-qPCR and Western blotting to detect gene expression; IP and confocal-IF to determine the core fucosylation (CF) level of CD36. Flow cytometry (AV/PI staining) to detect the cell apoptosis and JC-1 staining to react to the change of mitochondrial membrane potential. Results During AKI to CKD progression, CD36 expression in pericytes is higher and may be influenced by CF. Moreover, we confirmed the positive association of CD36 expression with pericyte-myofibroblast transition and the progression of AKI-CKD in an IRI mouse model and hypoxia/reoxygenation (H/R) pericytes. Notably, we discovered that FUT8 upregulates both CD36 expression and its CF level, contributing to the activation of the mitochondrial-dependent apoptosis signaling pathway in pericytes, ultimately leading to the progression of AKI-CKD. Conclusion These results further identify FUT8 and CD36 as potential targets for the treatment in the progression of AKI-CKD.

Abstract Background Spaghetti knotting technology is an emerging technique that can reduce the visual field restriction of the operator in laparo-endoscopic single site (LESS) surgery. Multi-directional stitching technology has been proved to improve the accuracy of suturing in clinical application of LESS surgery. Therefore, we conducted a study to evaluate the teaching efficacy and the operation workload of spaghetti knotting technology and conventional knotting technology in LESS suture teaching based on the multi-directional stitching technology. Methods We selected forty junior residents to learn the skill of knot tying with single-hole laparoscopic simulators. The forty students were randomly and equally divided into control group and experimental group. The control group was trained by the conventional knotting method, and the experimental group was trained by the spaghetti knotting technology. The grades were calculated before and after the training program, including operation score of suturing time, trhead length, needle insertion accuracy, knotting stability, tissue integrity, tissue tightness and the cognitive workload score of mental, physical and temporal demands, performance, effort and frustration. Results There was no significant difference between two groups before training. After training, knotting skills and workload were significantly improved. There were significant differences between the two groups in knotting time (p = 0.001), thread length (p = 0.01), and tissue integrity(p = 0.003). The experiment group took less time, left longer thread and had higher tissue integrity. The workload of the experiment group was also accurately reduced. However, there was no significant difference between the two groups in needle insertion accuracy(p = 0.560), knotting stability(p = 0.059), and tissue tightness(p = 0.731). Conclusion In LESS suture teaching based on the multi-directional stitching technology, the training of spaghetti knotting techniques significantly improved students’ learning efficacy and reduced their workload compared to training conventional knotting techniques. It suggested the combination of spaghetti knotting and multi-directional stitching technology could be a practicable method for laparoscopic skills teaching and a feasible clinical application value on spaghetti knotting technology in LESS surgery.

Abstract Background Rapid innovation and new regulations lead to an increased need for post-marketing surveillance of implantable devices. However, complex multi-level confounding related not only to patient-level but also to surgeon or hospital covariates hampers observational studies of risks and benefits. We conducted parametric and plasmode simulations to compare the performance of cardinality matching (CM) vs propensity score matching (PSM) to reduce confounding bias in the presence of cluster-level confounding. Methods Two Monte Carlo simulation studies were carried out: 1) Parametric simulations (1,000 iterations) with patients nested in clusters (ratio 10:1, 50:1, 100:1, 200:1, 500:1) and sample size n = 10,000 were conducted with patient and cluster level confounders; 2) Plasmode simulations generated from a cohort of 9981 patients admitted for pancreatectomy between 2015 to 2019 from a US hospital database. CM with 0.1 standardised mean different constraint threshold (SMD) for confounders and PSM were used to balance the confounders for within-cluster and cross-cluster matching. Treatment effects were then estimated using logistic regression as the outcome model on the obtained matched sample. Results CM yielded higher sample retention but more bias than PSM for cross-cluster matching in most scenarios. For instance, with ratio of 100:1, sample retention and relative bias were 97.1% and 26.5% for CM, compared to 82.5% and 12.2% for PSM. The results for plasmode simulation were similar. Conclusions CM offered better sample retention but higher bias in most scenarios compared to PSM. More research is needed to guide the use of CM particularly in constraint setting for confounders for medical device and surgical epidemiology.

Abstract Background Glycated albumin (GA) has been demonstrated to be associated with adverse outcomes in patients with acute coronary syndrome (ACS). However, as a specific subgroup of ACS, a significant proportion of patients with ACS without standard modifiable cardiovascular risk factors (SMuRFs) are currently being identified. The prognostic value of serum GA for adverse events in such patients remains unexplored. This study aims to evaluate the prognostic value of GA in predicting adverse outcomes in patients with ACS without SMuRFs. Methods This retrospective study involved 1,140 consecutive patients who were diagnosed with ACS without SMuRFs at the Beijing Anzhen Hospital between May 2018 and December 2020 and underwent coronary angiography. Each patient was followed up for a period of 35–66 months after discharge. The primary endpoint of this study was major adverse cardiovascular and cerebrovascular events (MACCEs) that included all-cause mortality, non-fatal myocardial infarction, non-fatal ischemic stroke, and ischemia-driven revascularization. Results The average age of the study participants was 59.55 ± 10.98 years, and men accounted for 61.8%. The average GA level was 14.37 ± 2.42. The median follow-up duration was 48.3 months, during which 220 cases (19.3%) experienced MACCEs. In the fully adjusted model, with GA as a continuous variable, the hazard ratio (HR) for MACCEs in the high GA group was 1.069 (95% confidence interval (CI): 1.008, 1.133), the HR for ischemia-driven revascularization was 1.095 (95% CI: 1.021, 1.175), and the HR for all-cause mortality was 1.155 (95% CI: 1.021, 1.306), all with P values less than 0.05. Similarly, when GA was considered as a categorical variable, in the fully adjusted model, GA was associated with MACCEs, ischemia-driven revascularization, and all-cause mortality, with P values all less than 0.05. The restricted cubic spline curve showed that the relationship between GA and MACCEs was linear (p for non-linear = 0.079; p for overall association = 0.026). Furthermore, GA levels were correlated with poor prognosis in the subgroups of patients. Conclusion Serum GA might be an independent predictor of all-cause death and ischemia-driven revascularization in patients with ACS without SMuRFs.