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Abstract Background Metabolic regulation of various amino acids have been proven to be effective in preventing cardiovascular disease (CVD). The impact of tryptophan, an essential amino acid, on the risk of developing CVD has not been fully elucidated. Aims The aim of this meta-analysis was to systematically review evidence of the effects of tryptophan on CVD risk. Methods The PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases were searched to collect relevant trials from inception to August 2024. The means and hazard ratios (HRs) were extracted and pooled. Subgroup analysis was performed to identify pooled effect estimates, and sensitivity analysis was conducted to assess the robustness of the pooled estimates. Results Data were collected from 34,370 people under follow-up for CVD events in 13 studies, including cohort studies and case-control studies. They were categorized into three groups on the basis of sample type and indicators: the plasma tryptophan level group, the plasma tryptophan CVD hazard group, and the urinary tryptophan CVD hazard group. The CVD included in this study were coronary artery disease, heart failure, and peripheral artery disease. Twelve studies on plasma tryptophan were meta-analyzed. The plasma tryptophan levels in CVD patients were generally lower than those in individuals without CVD (SMD = -8.57, 95%CI (-15.77, -1.37), P = 0.02). Decreased circulating tryptophan levels are associated with cardiovascular disease risk (HR = 0.85, 95%CI (0.78, 0.92), P

Abstract Background Acute myeloid leukaemia (AML) comprises a group of heterogeneous and aggressive haematological malignancies with unsatisfactory prognoses and limited treatment options. Treatments targeting B-cell lymphoma-2 (BCL-2) with venetoclax have been approved for patients with AML, and venetoclax-based drug combinations are becoming the standard of care for older patients unfit for intensive chemotherapy. However, the therapeutic duration of either single or combination strategies is limited, and the development of resistance seems inevitable. Therefore, more effective combination regimens are urgently needed. Methods The efficacy of combination therapy with NL101, a SAHA-bendamustine hybrid, and venetoclax was evaluated in preclinical models of AML including established cell lines, primary blasts from patients, and animal models. RNA-sequencing and immunoblotting were used to explore the underlying mechanism. Results NL101 significantly potentiated the activity of venetoclax in AML cell lines, as evidenced by the enhanced decrease in viability and induction of apoptosis. Mechanistically, the addition of NL101 to venetoclax decreased the stability of the antiapoptotic protein myeloid cell leukaemia-1 (MCL-1) by inhibiting ERK, thereby facilitating the release of BIM and triggering mitochondrial apoptosis. Moreover, the strong synergy between NL101 and venetoclax also relied on the downregulation of c-Myc via PI3K/Akt/GSK3β signalling. The combination of NL101 and venetoclax synergistically eliminated primary blasts from 10 AML patients and reduced the leukaemia burden in an MV4-11 cell-derived xenograft model. Conclusions Our results encourage the pursuit of clinical trials of combined treatment with NL101 and venetoclax and provide a novel venetoclax-incorporating therapeutic strategy for AML.

Abstract Abnormal expression of circRNAs has been observed in different types of carcinomas, and they play significant roles in the biology of these cancers. Nevertheless, the clinical relevance and functional mechanisms of the majority of circRNAs implicated in breast cancer progression remain unclear. The primary objective of our investigation is to uncover new circRNAs in breast cancer and elucidate the underlying mechanisms by which they exert their effects. The circRNA expression profile data for breast cancer and RNA-sequencing data were acquired from distinct public databases. Differentially expressed circRNAs and mRNA were identified through fold change filtering. The establishment of the competing endogenous RNAs (ceRNAs) network relied on the interplay between circular RNAs, miRNAs, and mRNAs. The hub genes were identified from the protein–protein interaction (PPI) regulatory network using the CytoHubba plugin in Cytoscape. Moreover, the expression levels and prognostic value of these hub genes in the PPI network were assessed using the GEPIA and Kaplan–Meier plotter databases. Fluorescence in situ hybridization (FISH) was used to identified the expression and intracellular localization of hsa_circ_0059665 by using the tissue microarray. Transwell analysis and CCK-8 analysis were performed to assess the invasion, migration, and proliferation abilities of breast cancer cells. Additionally, we investigated the interactions between hsa_circ_0059665 and miR-602 through various methods, including FISH, RNA-binding protein immunoprecipitation (RIP), and luciferase reporter assay. Rescue experiments were conducted to determine the potential regulatory role of hsa_circ_0059665 in breast cancer progression. A total of 252 differentially expressed circRNAs were identified. Among them, 246 circRNAs were up-regulated, while 6 circRNAs were down-regulated. Based on prediction and screening of circRNA-miRNA and miRNA-mRNA binding sites, we constructed a network consisting of circRNA-miRNA-mRNA interactions. In addition, we constructed a Protein–Protein Interaction (PPI) network and identified six hub genes. Moreover, the expression levels of these six hub genes in breast cancer tissues were found to be significantly lower. Furthermore, the survival analysis results revealed a significant correlation between low expression levels of KIT, FGF2, NTRK2, CAV1, LEP and poorer prognosis in breast cancer patients. The FISH experiment results indicated that hsa_circ_0059665 exhibits significant downregulation in breast cancer, and its decreased expression is linked to poor prognosis in breast cancer patients. Functional in vitro experiments revealed that overexpression of hsa_circ_0059665 can inhibit proliferation, migration and invasion abilities of breast cancer cells. Further molecular mechanism studies showed that hsa_circ_0059665 exerts its anticancer gene role by acting as a molecular sponge for miR-602. In our study, we constructed and analyzed a circRNA-related ceRNA regulatory network and found that hsa_circ_0059665 can act as a sponge for miR-602 and inhibit the proliferation, invasion and migration of breast cancer cells.

Abstract Background Intestinal obstruction represents a severe intestinal disease associated with higher mortality rates. However, the determinants of mortality in patients with intestinal obstruction remain inadequately understood. This study sought to elucidate the potential risk factors associated with mortality in the context of intestinal obstruction during the COVID-19 pandemic. Methods A retrospective analysis was performed on a cohort of 227 patients diagnosed with intestinal obstruction at the First Hospital of Hebei Medical University, spanning the period from September 7, 2022, to January 7, 2023. The primary endpoint of the study was mortality within four weeks following discharge. Univariate and multivariable logistic regression models were utilized to evaluate the risk factors associated with mortality outcomes. Results A cohort of 227 patients diagnosed with intestinal obstruction (median age, 59.02 years [IQR, 48.95–70.85 years]) was included in our study. Malignant bowel obstruction (MBO) and COVID-19 were identified as independent risk factors for mortality among these patients. Notably, the mortality rate increased significantly to 38.46% when MBO was concomitant with COVID-19. Furthermore, postoperative pulmonary complications (PPC) (OR, 54.21 [death]; 95% CI, 3.17-926.31), gastric cancer (OR, 9.71 [death]; 95% CI, 1.38–68.18), VTE (Caprini Score ≥ 5) (OR, 7.64 [death]; 95% CI, 1.37–42.51), and COVID-19 (OR, 5.72 [death]; 95% CI, 1.01–32.29) were all determined to be independent risk factors for postoperative mortality. Additionally, gastric cancer could have emerged as one of the most severe risk factors for mortality in individuals with intestinal obstruction within the cohort of cancer patients, of which gastric cancer exhibited higher mortality rates compared to individuals with other forms of cancer. Conclusion The study identifies MBO, gastric cancer, COVID-19, PPC, and VTE as potential risk factors for mortality in cases of intestinal obstruction. These findings highlight the necessity for continuous monitoring of indicators related to these mortality risk factors and their associated complications, thereby offering valuable insights for the management and treatment of intestinal obstruction.

Abstract Introduction Deep sternal wound infection (DSWI) after midline sternotomy of cardiac surgery is a challenging complication that affects the outcome of surgery. This study aims to assess the clinical effectiveness of the antibiotic-loaded bone cement fixation technique combined with bilateral pectoralis major muscle flaps tension-free management in the treatment of DSWI. Methods We retrospectively analyzed 5 patients with DSWI who underwent antibiotic-loaded bone cement combined with bilateral pectoralis major muscle flaps for chest wall reconstruction after sternotomy for cardiac surgery in a tertiary hospital in China from January 2020 to December 2021. The clinical and follow-up data were retrospectively analyzed. Results All patients had no perioperative mortalities, no postoperative complications, 100% wound healing, and an average hospital stay length of 24 days. The follow-up periods were from 6 to 35 months (mean 19.6 months). None of the cases showed wound problems after initial reconstruction using antibiotic-loaded bone cement combined with bilateral pectoralis major muscle flaps. Conclusions We report our successful treatment of DSWI, using antibiotic-loaded bone cement fixation technique combined with bilateral pectoralis major muscle flaps tension-free management. The clinical and follow-up results are favorable.

Abstract. Background:. While type 2 diabetes mellitus (T2DM) is considered a putative causal risk factor for coronary artery disease (CAD), the intrinsic link underlying T2DM and CAD is not fully understood. We aimed to highlight the importance of integrated care targeting both diseases by investigating the phenotypic and genetic relationships between T2DM and CAD. Methods:. We evaluated phenotypic associations using data from the United Kingdom Biobank (N = 472,050). We investigated genetic relationships by leveraging genomic data conducted in European ancestry for T2DM, with and without adjustment for body mass index (BMI) (T2DM: Ncase/Ncontrol = 74,124/824,006; T2DM adjusted for BMI [T2DMadjBMI]: Ncase/Ncontrol = 50,409/523,897) and for CAD (Ncase/Ncontrol = 181,522/984,168). We performed additional analyses using genomic data conducted in multiancestry individuals for T2DM (Ncase/Ncontrol = 180,834/1,159,055). Results:. Observational analysis suggested a bidirectional relationship between T2DM and CAD (T2DM→CAD: hazard ratio [HR] = 2.12, 95% confidence interval [CI]: 2.01–2.24; CAD→T2DM: HR = 1.72, 95% CI: 1.63–1.81). A positive overall genetic correlation between T2DM and CAD was observed (rg = 0.39, P = 1.43 × 10–75), which was largely independent of BMI (T2DMadjBMI–CAD: rg = 0.31, P = 1.20 × 10–36). This was corroborated by six local signals, among which 9p21.3 showed the strongest genetic correlation. Cross-trait meta-analysis replicated 101 previously reported loci and discovered six novel pleiotropic loci. Mendelian randomization analysis supported a bidirectional causal relationship (T2DM→CAD: odds ratio [OR] = 1.13, 95% CI: 1.11–1.16; CAD→T2DM: OR = 1.12, 95% CI: 1.07–1.18), which was confirmed in multiancestry individuals (T2DM→CAD: OR = 1.13, 95% CI: 1.10–1.16; CAD→T2DM: OR = 1.08, 95% CI: 1.04–1.13). This bidirectional relationship was significantly mediated by systolic blood pressure and intake of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, with mediation proportions of 54.1% (95% CI: 24.9–83.4%) and 90.4% (95% CI: 29.3–151.5%), respectively. Conclusion:. Our observational and genetic analyses demonstrated an intrinsic bidirectional relationship between T2DM and CAD and clarified the biological mechanisms underlying this relationship.

Background Pneumoconiosis mostly combines pulmonary and cardiovascular diseases, among which pulmonary heart disease (PHD) is of major concern due to its significant impact on the survival of pneumoconiosis patients. White cell count (WCC), red cell distribution width (RDW) and platelet parameters are thought to affect inflammatory responses and may be predictors of various cardiovascular diseases. However, very few studies have focused on PHD.Objectives To examine the relationship between baseline complete blood count parameters (WCC, RDW, platelet parameters) and the risk of incident PHD in pneumoconiosis patients.Design A retrospective cohort study.Setting This was a single-centre, retrospective cohort study that used data from an Occupational Disease Hospital, Chengdu, Sichuan.Participants A total of 946 pneumoconiosis patients from January 2012 to November 2021 were included in the study. Female patients and patients who had PHD, coronary heart disease, hypertensive heart disease, cardiomyopathy, heart failure, oncological disease, multiple organ dysfunction, AIDS at baseline and follow-up time of less than 6 months were also excluded.Outcome measures We identified PHD according to the patient’s discharge diagnosis. We constructed Cox proportional hazard regression models to assess the HR of incident PHD in pneumoconiosis, as well as 95% CIs.Results In the multiple Cox proportional hazard regression analysis, platelet count (PLT) and plateletcrit (PCT) above the median at baseline were associated with an increased risk of PHD in pneumoconiosis with adjusted HR of 1.52 (95% CI 1.09 to 2.12) and 1.42 (95% CI 1.02 to 1.99), respectively.Conclusion Higher baseline PLT and PCT are associated with a higher risk of PHD in pneumoconiosis.

Aims: The xanthone dimer 12-O-deacetyl-phomoxanthone A (12-ODPXA) was extracted from the secondary metabolites of the endophytic fungus Diaporthe goulteri. The 12-ODPXA compound exhibited anticancer properties in murine lymphoma; however, the anti-ovarian cancer (OC) mechanism has not yet been explored. Therefore, the present study evaluated whether 12-ODPXA reduces OC cell proliferation, metastasis, and invasion by downregulating pyruvate dehydrogenase kinase (PDK)4 expression. Methods: Cell counting kit-8, colony formation, flow cytometry, wound healing, and transwell assays were performed to examine the effects of 12-ODPXA on OC cell proliferation, apoptosis, migration, and invasion. Transcriptome analysis was used to predict the changes in gene expression. Protein expression was determined using western blotting. Glucose, lactate, and adenosine triphosphate (ATP) test kits were used to measure glucose consumption and lactate and ATP production, respectively. Zebrafish xenograft models were constructed to elucidate the anti-OC effects of 12-ODPXA. Results: The 12-ODPXA compound inhibited OC cell proliferation, migration, invasion, and glycolysis while inducing cell apoptosis via downregulation of PDK4. In vivo experiments showed that 12-ODPXA suppressed tumor growth and migration in zebrafish. Conclusion: Our data demonstrate that 12-ODPXA inhibits ovarian tumor growth and metastasis by downregulating PDK4, revealing the underlying mechanisms of action of 12-ODPXA in OC.

Sweetpotatoes are a great source of carotenoids, which are important for human health and have attracted increasing attention. This study examined the impact of the steaming method on the contents of carotenoids, starch, soluble sugar, volatile organic compounds, and pasting properties of nine table-stock sweetpotatoes with different carotenoids content (from 3.21 to 233.46 μg/g). After steaming, carotenoids content was significantly decreased, among which G79 and P32 had the highest levels of 88.20 μg/g and 94.27 μg/g, respectively. The starch content of G42 decreased the most (20 %) with the highest peak viscosity (1764.33 cP), while the amylose content of P32 increased the most (12.59 %) with the lowest peak viscosity (441.33 cP). The contents of total starch and amylose were significantly correlated with sensory evaluation. G79 presented the best sensory evaluation and a sweet, delicious, and soft texture. A total of 57 volatile organic compounds were detected, among which benzene, a few aldehydes, and terpenoids contributed to the aroma of steamed sweetpotatoes. These results provide a theoretical foundation for future sweetpotato processing.

Purple-fleshed sweetpotatoes (PFSPs) are rich in anthocyanins and are one of the health foods of interest. In this study, the effects of steaming on the anthocyanin, starch, soluble sugar, volatile organic compounds (VOCs) and pasting properties of nine PFSPs from China were investigated. The anthocyanin content of raw PFSP ranged from 9 to 185 mg/100 g. The total starch content decreased and soluble sugar content increased in all purple potatoes after steaming. Among the nine PFSPs varieties, Guangshu20 showed the greatest decrease in starch content (30.61%) and the greatest increase in soluble sugar content (31.12%). The pasting properties affected the taste of the PFSPs, with Shuangpihuang having the lowest peak viscosity (720.33 cP) and Guangzishu12 having the highest peak viscosity (2501.67 cP). Correlation studies showed that the anthocyanin content and pasting properties were negatively correlated with most of the sensory indicators, whereas the soluble sugar content of steamed PFSPs was significantly positively correlated with sweetness. A total of 54 VOCs were identified in this study, and aldehydes and terpenoids were the major VOCs in PFSPs. This study provides a theoretical basis for the processing of different PFSP varieties.

The nuclear-encoded mitochondrial protein Tu translation elongation factor, mitochondrial (TUFM) is well-known for its role in mitochondrial protein translation. Originally discovered in yeast, TUFM demonstrates significant evolutionary conservation from prokaryotes to eukaryotes. Dysregulation of TUFM has been associated with mitochondrial disorders. Although early hypothesis suggests that TUFM is localized within mitochondria, recent studies identify its presence in the cytoplasm, with this subcellular distribution being linked to distinct functions of TUFM. Significantly, in addition to its established function in mitochondrial protein quality control, recent research indicates a broader involvement of TUFM in the regulation of programmed cell death processes (e.g., autophagy, apoptosis, necroptosis, and pyroptosis) and its diverse roles in viral infection, cancer, and other disease conditions. This review seeks to offer a current summary of TUFM’s biological functions and its complex regulatory mechanisms in human health and disease. Insight into these intricate pathways controlled by TUFM may lead to the potential development of targeted therapies for a range of human diseases.

Under climate change, the ability of water bodies to maintain ecology and human activities becomes more fragile, leading to water shortages. The change in the carrying capacity of the water environment further intensifies the management difficulties of the resource-environment-economic system. This study aims to establish a comprehensive framework that integrates an interval fuzzy program and water environmental carrying capacity assessment model to obtain the optimal state of the energy-water-carbon coupling system by promoting industrial structure adjustment. It is demonstrated that a 10 % reduction in carbon emissions leads to a 15 % increase in the water environmental carrying capacity of the Huangshui watershed. Under the influence of climate change, total energy consumption and carbon emissions show a downward trend. Water consumption per unit of output, energy consumption and carbon emission management policies are highly related and are the main control points for policymakers. The developed model simultaneously considers industrial structure optimization and water environment carrying capacity, and assists in formulating the energy-water-carbon balanced management policies to promote the sustainability of the regional environ-economic system.

Age at first sexual intercourse (AFS) and lifetime number of sexual partners (NSP) may influence the pathogenesis of uterine leiomyoma (UL) through their associations with hormonal concentrations and uterine infections. Leveraging summary statistics from large-scale genome-wide association studies conducted in European ancestry for each trait (NAFS = 214,547; NNSP = 370,711; NUL = 302,979), we observed a significant negative genomic correlation for UL with AFS (rg = -0.11, P = 7.83×10-4), but not with NSP (rg = 0.01, P = 0.62). Four specific genomic regions were identified as contributing significant local genetic correlations to AFS and UL, including one genomic region further identified for NSP and UL. Partitioning SNP-heritability with cell-type-specific annotations, a close clustering of UL with both AFS and NSP was identified in immune and blood-related components. Cross-trait meta-analysis revealed 15 loci shared between AFS/NSP and UL, including 7 novel SNPs. Univariable two-sample Mendelian randomization (MR) analysis suggested no evidence for a causal association between genetically predicted AFS/NSP and risk of UL, nor vice versa. Multivariable MR adjusting for age at menarche or/and age at natural menopause revealed a significant causal effect of genetically predicted higher AFS on a lower risk of UL. Such effect attenuated to null when age at first birth was further included. Utilizing participant-level data from the UK Biobank, one-sample MR based on genetic risk scores yielded consistent null findings among both pre-menopausal and post-menopausal females. From a genetic perspective, our study demonstrates an intrinsic link underlying sexual factors (AFS and NSP) and UL, highlighting shared biological mechanisms rather than direct causal effects. Future studies are needed to elucidate the specific mechanisms involved in the shared genetic influences and their potential impact on UL development.

Based on the water-rock-gas coupling test system, the work combined the scanning electron microscope and XTDIC 3D full-field strain measurement system. The Brazilian splitting test was performed on four groups of sandy mudstone specimens under contrast (CO), mash-gas soaking (MS), water-mash gas soaking (WM), and water-soaking (WS) conditions. The tensile strength, deformation failure, and microscopic characteristics of fractures were studied to reveal the deterioration mechanism of the tensile properties of sandy mudstone under water-gas coupling. The results showed that the uniaxial tensile strength of sandy mudstone specimens under the three soaking conditions was less than that of the contrast conditions. Compared with specimens in the CO group, the tensile strength of specimens in MS-WS groups was reduced; the WS group decreased the most. Specimens changed from brittle failure to plastic failure after soaking. The decrease rate in strength after the peak was consistent with the change trend in tensile strength. It led to a larger localized deformation zone of specimens and more obvious displacement. The deformation localization zone of the WS group was the broadest, with the most intense displacement. Besides, stress concentration first occurred in the submerged part of the WM group. Fractures expanded in the direction of maximum principal strain. The internal pore structure of sandy mudstone specimens in each group changed after soaking. The average porosity, maximum pore area, and probability entropy of specimens in WS-MS groups increased compared to the CO group. The WS group had the largest reduction and the MS group had the smallest. The pre-peak energy storage capacity of sandy mudstone specimens was gradually weakened. Compared with the CO group, that in the WS-MS groups was reduced. The WS group had the greatest reduction, and the MS group had the smallest. The deterioration effect of water on the interior of sandy mudstone was stronger than that of gas. The work is of great significance for understanding the stability of coal and rocks in closed-pit high-gas mines.

Abstract Objective To summarize the clinical characteristics and imaging manifestations of patients with nonketotic hyperglycemic hemichorea (NH‐HC) and to explore the possible pathogenesis, diagnosis. and treatment of the disease in order to improve the understanding of this disease and avoid misdiagnosis. Methods Retrospective analysis was performed on the case data of five patients with NH‐HC admitted to our hospital in recent years. The patients were treated in the department of endocrinology, department of neurology, and department of neurosurgery in our hospital, respectively. Meanwhile, relevant literatures were consulted for further learning. Results NH‐HC is usually presented as a triad of nonketotic hyperglycemia, lateral chorea, and typical imaging manifestations of head magnetic resonance imaging or computed tomography, but the clinical manifestations are not the same, and imaging features may also be different, presenting a diversified trend in clinical practice. All five patients were given glucose‐lowering drugs and improved with or without combination of drugs to control symptoms of chorea. Conclusion NH‐HC is a rare complication of diabetes, characterized by hyperglycemia and hemichorea. How to identify the extreme situation and make fast judgment is a top priority. Timely and correct control of blood glucose is the key to the treatment, and when necessary, application of dopamine receptor antagonists in patients with combination therapy can accelerate improvement of the clinical symptoms. The prognosis of NH‐HC is good, the clinician should strengthen comprehensive understanding of this disease to avoid missed diagnosis or misdiagnosis and enable patients to get more timely and effective treatment.

This study investigated the conditions and modes of interaction between nutrients and heavy metals within river and lake environments under multivariate conditions. Nitrogen and phosphorus nutrients were categorized into dissolved phosphorus, inorganic phosphorus, dissolved nitrogen, ammonium nitrogen, and nitrate nitrogen based on their chemical composition. Their correlations with heavy metal elements were scrutinized utilizing Bayesian models. The results revealed the following: (1) A robust interrelationship was observed between sediment metals and soluble metals within lake sediments and water bodies. (2) In lake environments, the competition between metals was relatively weak, and the influence of environmental factors was variable, without discernible patterns. This phenomenon may be attributed to the low concentration of soluble metals in the overlying water in the absence of external inputs. (3) Competition between metals in river sediment was weaker than that in lakes. This may be attributed to the flow dynamics and velocity of rivers, coupled with their strong self-purification ability. (4) Dissolved phosphorus (DP) exhibited greater control over the direction of metal adsorption and desorption compared to inorganic phosphorus (IP). (5) Similarly, dissolved total nitrogen (DTN) exhibited greater control over the direction of metal adsorption and desorption in river sediments compared to total nitrogen (TN). (6) Nitrate (NO3–-N) and ammonium (NH4+-N) simultaneously controlled the adsorption and desorption directions of metals such as Cr, Mn, Ni, Zn, and Pb in river sediment, with the direction of metal action dependent on soil adsorption capacity. These findings provide valuable insights into the complex interactions shaping nutrient-metal dynamics in aquatic systems, offering potential avenues for enhanced environmental management and remediation strategies.

BackgroundTo investigate the causal associations of serum urate (SUA) with stroke risk and prognosis using Mendelian randomization (MR) and the potential mediating role of stroke risk factors in the causal pathways.MethodsWe used the random-effects inverse variance weighting (IVW) as our primary method. We initially performed two-sample univariable MR (UVMR) to identify the causal associations of SUA (n = 437,354) with any stroke (AS, FinnGen: n = 311,635; MEGASTROKE: n = 446,696), ischemic stroke (IS, FinnGen: n = 212,774; MEGASTROKE: n = 440,328), intracranial hemorrhage (ICH, FinnGen: n = 343,663; ISGC: n = 3,026), functional outcome after ischemic stroke at 90d (n = 4,363), and motor recovery within 24 months after stroke (n = 488), and then multivariable MR (MVMR) to estimate the direct causal effects of SUA on these outcomes, adjusting for potential confounders. Finally, we further conducted a two-step MR to investigate the potential mediating role of body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), and estimated glomerular filtration rate (eGFR) in the identified causal pathways.ResultsGenetically predicted elevated SUA levels were significantly associated with increased risk of AS (meta-analysis: OR = 1.09, 95% CI [1.04–1.13], p = 3.69e-05) and IS (meta-analysis: OR = 1.10, 95% CI [1.01–1.19], p = 0.021) and with improved poor functional outcome after ischemic stroke at 90d (OR = 0.81, 95% CI [0.72–0.90], p = 1.79e-04) and motor recovery within 24 months after stroke (OR = 1.42, 95% CI [1.23–1.64], p = 2.15e-06). In MVMR, SBP and DBP significantly attenuated the causal effects of SUA on AS, IS, and functional outcome after ischemic stroke at 90d and motor recovery within 24 months after stroke. Further mediation analyses showed that SBP mediated 52.4 and 34.5% of the effects of SUA on AS and IS, while DBP mediated 28.5 and 23.4% of the causal effects, respectively.ConclusionThis study supports the dual role of genetically predicted SUA in increasing stroke risk, especially ischemic stroke risk, and in improving functional outcome and motor recovery. SBP and DBP are key mediators lying on the causal pathways of SUA with AS and IS.

BackgroundThe incidence of prostate cancer is increasing in older males globally. Age, ethnicity, and family history are identified as the well-known risk factors for prostate cancer, but few modifiable factors have been firmly established. The objective of this study was to identify and evaluate various factors modifying the risk of prostate cancer reported in meta-analyses of prospective observational studies and mendelian randomization (MR) analyses.Methods and findingsWe searched PubMed, Embase, and Web of Science from the inception to January 10, 2022, updated on September 9, 2023, to identify meta-analyses and MR studies on prostate cancer. Eligibility criteria for meta-analyses were (1) meta-analyses including prospective observational studies or studies that declared outcome-free at baseline; (2) evaluating the factors of any category associated with prostate cancer incidence; and (3) providing effect estimates for further data synthesis. Similar criteria were applied to MR studies. Meta-analysis was repeated using the random-effects inverse-variance model with DerSimonian-Laird method. Quality assessment was then conducted for included meta-analyses using AMSTAR-2 tool and for MR studies using STROBE-MR and assumption evaluation. Subsequent evidence grading criteria for significant associations in meta-analyses contained sample size, P values and 95% confidence intervals, 95% prediction intervals, heterogeneity, and publication bias, assigning 4 evidence grades (convincing, highly suggestive, suggestive, or weak). Significant associations in MR studies were graded as robust, probable, suggestive, or insufficient considering P values and concordance of effect directions. Finally, 92 selected from 411 meta-analyses and 64 selected from 118 MR studies were included after excluding the overlapping and outdated studies which were published earlier and contained fewer participants or fewer instrument variables for the same exposure. In total, 123 observational associations (45 significant and 78 null) and 145 causal associations (55 significant and 90 null) were categorized into lifestyle; diet and nutrition; anthropometric indices; biomarkers; clinical variables, diseases, and treatments; and environmental factors. Concerning evidence grading on significant associations, there were 5 highly suggestive, 36 suggestive, and 4 weak associations in meta-analyses, and 10 robust, 24 probable, 4 suggestive, and 17 insufficient causal associations in MR studies. Twenty-six overlapping factors between meta-analyses and MR studies were identified, with consistent significant effects found for physical activity (PA) (occupational PA in meta: OR = 0.87, 95% CI: 0.80, 0.94; accelerator-measured PA in MR: OR = 0.49, 95% CI: 0.33, 0.72), height (meta: OR = 1.09, 95% CI: 1.06, 1.12; MR: OR = 1.07, 95% CI: 1.01, 1.15, for aggressive prostate cancer), and smoking (current smoking in meta: OR = 0.74, 95% CI: 0.68, 0.80; smoking initiation in MR: OR = 0.91, 95% CI: 0.86, 0.97). Methodological limitation is that the evidence grading criteria could be expanded by considering more indices.ConclusionsIn this large-scale study, we summarized the associations of various factors with prostate cancer risk and provided comparisons between observational associations by meta-analysis and genetically estimated causality by MR analyses. In the absence of convincing overlapping evidence based on the existing literature, no robust associations were identified, but some effects were observed for height, physical activity, and smoking.

Background: Exercise has been reported to be associated with a reduced risk of nonalcoholic fatty liver disease (NAFLD), but there is no consensus on the role of weight changes in this association. This study aims to investigate whether the impact of exercise on NAFLD is mainly dependent on weight changes or is inherent to exercise itself.Methods: The study recruited 1671 Chinese NAFLD-free adults in 2019, and collected their exercise habits as well as 3 years of medical examination data including anthropometric measurements, blood biochemistry parameters, and liver ultrasound results. Univariate and multivariate logistic regression models were employed to examine the impact of exercise habits on NAFLD risk, with mediation analysis utilized to estimate the magnitude of the role of weight maintenance in the association between exercise and NAFLD.Results: After adjusting for confounders, moderate to high-intensity exercisers were 1.56 times (95% CIs = 1.09–2.22) more likely to successfully control their body weight, and therefore the weight-controlled group had a lower NAFLD risk of 34.9% (95% CIs = 21.8%–56.0%) compared to the weight-gain group. Mediation analysis reveals that exercise can significantly reduce the risk of NAFLD both through weight maintenance (37.1%) and independent of weight maintenance (62.9%).Conclusion: It might be more crucial to emphasize the adoption of regular moderate to high-intensity exercise for preventing NAFLD in the general population, rather than solely focusing on weight maintenance.

Colorectal cancer (CRC), one of the most common malignancies in the world, urgently requires more treatment strategies. Although there has been much research on probiotics, limited research has been done in treating cancer. The purpose of this study was to investigate the role of Bifidobacterium longum (B. longum) in the prevention and treatment of CRC. Through Cell Counting Kit-8 and Colony Formation Assays, 8 h and a B. longum count of 1 × 108 CFU/ml were chosen as the best cocultivation conditions with CRC cells. The role of B. longum in inhibiting the progression of CRC cells was verified by a series of functional and immunofluorescence assays. For instance, in vivo assays have verified that B. longum could alleviate CRC progression. In addition, according to the results of in vivo assays and clinical statistical analysis, B. longum could reduce diarrhea symptoms. Mechanistically, by 16S and RNA sequencing, it was found that B. longum could affect the development of CRC by regulating the composition of gut microbes and enhancing immune function. The B. longum might inhibit the occurrence and development of CRC and relieve diarrhea symptoms by regulating intestinal microbes and immune function.

BackgroundGeneral obesity is a well-established risk factor for gallstone disease (GSD), but whether central obesity contributes additional independent risk remains controversial. We aimed to comprehensively clarify the effect of body fat distribution on GSD.MethodsWe first investigated the observational association of central adiposity, characterized by waist-to-hip ratio (WHR), with GSD risk using data from UK Biobank (N=472,050). We then explored the genetic relationship using summary statistics from the largest genome-wide association study of GSD (ncase=43,639, ncontrol=506,798) as well as WHR, with and without adjusting for body mass index (BMI) (WHR: n=697,734; WHRadjBMI: n=694,649).ResultsObservational analysis demonstrated an increased risk of GSD with one unit increase in WHR (HR=1.18, 95%CI=1.14-1.21). A positive WHR-GSD genetic correlation (rg =0.41, P=1.42×10-52) was observed, driven by yet independent of BMI (WHRadjBMI: rg =0.19, P=6.89×10-16). Cross-trait meta-analysis identified four novel pleiotropic loci underlying WHR and GSD with biological mechanisms outside of BMI. Mendelian randomization confirmed a robust WHR-GSD causal relationship (OR=1.50, 95%CI=1.35-1.65) which attenuated yet remained significant after adjusting for BMI (OR=1.17, 95%CI=1.09-1.26). Furthermore, observational analysis confirmed a positive association between general obesity and GSD, corroborated by a shared genetic basis (rg =0.40, P=2.16×10-43), multiple novel pleiotropic loci (N=11) and a causal relationship (OR=1.67, 95%CI=1.56-1.78).ConclusionBoth observational and genetic analyses consistently provide evidence on an association of central obesity with an increased risk of GSD, independent of general obesity. Our work highlights the need of considering both general and central obesity in the clinical management of GSD.

Organophosphorus flame retardants (OPFRs) have been frequently detected with relatively high concentrations in various environmental media and are considered emerging environmental pollutants. However, their biological effect and underlying mechanism is still unclear, and whether chlorinated OPFRs (Cl-OPFRs) cause adverse outcomes with the same molecular initial events or share the same key events (KEs) remains unknown. In this study, in vitro bioassays were conducted to analyze the cytotoxicity, mitochondrial impairment, DNA damage and molecular mechanisms of two Cl-OPFRs. The results showed that these two Cl-OPFRs, which have similar structures, induced severe cellular and molecular damages via different underlying mechanisms. Both tris(2-chloroethyl) phosphate (TCEP) and tris(1-chloro-2-propyl) (TCPP) induced oxidative stress-mediated mitochondrial impairment and DNA damage, as shown by the overproduction of intracellular reactive oxygen species (ROS) and mitochondrial superoxide. Furthermore, the DNA damage caused by TCPP resulted in p53/p21-mediated cell cycle arrest, as evidenced by flow cytometry and real-time PCR. At the cellular and molecular levels, TCPP increased the sub-G1 apoptotic peak and upregulated the p53/Bax apoptosis pathway, possibly resulted in apoptosis associated with its stronger cytotoxicity. Although structurally similar to TCPP, TCEP did not induce mitochondrial impairment and DNA damage by the same KEs. These results provide insight into the toxicity of Cl-OPFRs with similar structures but different mechanisms, which is of great significance for constructing adverse outcome pathways or determining intermediate KEs.

Abstract Background This study aims to comprehensively investigate the phenotypic and genetic relationships between four common lipids (high-density lipoprotein cholesterol, HDL-C; low-density lipoprotein cholesterol, LDL-C; total cholesterol, TC; and triglycerides, TG), chronic kidney disease (CKD), and estimated glomerular filtration rate (eGFR). Methods We first investigated the observational association of lipids (exposures) with CKD (primary outcome) and eGFR (secondary outcome) using data from UK Biobank. We then explored the genetic relationship using summary statistics from the largest genome-wide association study of four lipids (N = 1,320,016), CKD (Ncase = 41,395, Ncontrol = 439,303), and eGFR(N = 567,460). Results There were significant phenotypic associations (HDL-C: hazard ratio (HR) = 0.76, 95%CI = 0.60–0.95; TG: HR = 1.08, 95%CI = 1.02–1.13) and global genetic correlations (HDL-C: $${r}_{g}$$ r g = − 0.132, P = 1.00 × 10–4; TG: $${r}_{g}$$ r g = 0.176; P = 2.66 × 10–5) between HDL-C, TG, and CKD risk. Partitioning the whole genome into 2353 LD-independent regions, twelve significant regions were observed for four lipids and CKD. The shared genetic basis was largely explained by 29 pleiotropic loci and 36 shared gene-tissue pairs. Mendelian randomization revealed an independent causal relationship of genetically predicted HDL-C (odds ratio = 0.91, 95%CI = 0.85–0.98), but not for LDL-C, TC, or TG, with the risk of CKD. Regarding eGFR, a similar pattern of correlation and pleiotropy was observed. Conclusions Our work demonstrates a putative causal role of HDL-C in CKD and a significant biological pleiotropy underlying lipids and CKD in populations of European ancestry. Management of low HDL-C levels could potentially benefit in reducing the long-term risk of CKD. Graphical Abstract

Abstract Background Despite epidemiological evidence associating gallstone disease (GSD) with cardiovascular disease (CVD), a dilemma remains on the role of cholecystectomy in modifying the risk of CVD. We aimed to characterize the phenotypic and genetic relationships between GSD and two CVD events – stroke and coronary artery disease (CAD). Methods We first performed a meta-analysis of cohort studies to quantify an overall phenotypic association between GSD and CVD. We then investigated the genetic relationship leveraging the largest genome-wide genetic summary statistics. We finally examined the phenotypic association using the comprehensive data from UK Biobank (UKB). Results An overall significant effect of GSD on CVD was found in meta-analysis (relative risk [RR] = 1.26, 95% confidence interval [CI] = 1.19–1.34). Genetically, a positive shared genetic basis was observed for GSD with stroke ( $${r}_{g}$$ r g =0.16, P = 6.00 × 10–4) and CAD ( $${r}_{g}$$ r g =0.27, P = 2.27 × 10–15), corroborated by local signals. The shared genetic architecture was largely explained by the multiple pleiotropic loci identified in cross-phenotype association study and the shared gene-tissue pairs detected by transcriptome-wide association study, but not a causal relationship (GSD to CVD) examined through Mendelian randomization (MR) (GSD-stroke: odds ratio [OR] = 1.00, 95%CI = 0.97–1.03; GSD-CAD: OR = 1.01, 95%CI = 0.98–1.04). After a careful adjustment of confounders or considering lag time using UKB data, no significant phenotypic effect of GSD on CVD was detected (GSD-stroke: hazard ratio [HR] = 0.95, 95%CI = 0.83–1.09; GSD-CAD: HR = 0.98, 95%CI = 0.91–1.06), further supporting MR findings. Conclusions Our work demonstrates a phenotypic and genetic relationship between GSD and CVD, highlighting a shared biological mechanism rather than a direct causal effect. These findings may provide insight into clinical and public health applications.

The Xiaoxinganling Mountains–Sanjiang Plain region represents a crucial ecological security barrier for the Northeast China Plain and serves as a vital region for national grain production. Over the past two decades, the region has undergone numerous ecological restoration projects. Nevertheless, the combined impact of enhanced vegetation greening and global climate change on the regional hydrological cycle remains inadequately understood. This study employed the distributed hydrological model ESSI-3, reanalysis datasets, and multi-source satellite remote sensing data to quantitatively evaluate the influences of climate change and vegetation dynamics on regional hydrological processes. The study period spans from 2000 to 2020, during which there were significant increases in regional precipitation and leaf area index (p < 0.05). The hydrological simulation results exhibited strong agreement with observed river discharge, evapotranspiration, and terrestrial water storage anomalies, thereby affirming the ESSI-3 model’s reliability in hydrological change assessment. By employing both a constant scenario that solely considered climate change and a dynamic scenario that integrated vegetation dynamics, the findings reveal that: (1) Regionally, climate change driven by increased precipitation significantly augmented runoff fluxes (0.4 mm/year) and water storage components (2.57 mm/year), while evapotranspiration trends downward, attributed primarily to reductions in solar radiation and wind speed; (2) Vegetation greening reversed the decreasing trend in evapotranspiration to an increasing trend, thus exerting a negative impact on runoff and water storage. However, long-term simulations demonstrated that regional runoff fluxes (0.38 mm/year) and water storage components (2.21 mm/year) continue to increase, mainly due to precipitation increments surpassing those of evapotranspiration; (3) Spatially, vegetation greening altered the surface soil moisture content trend in the eastern forested areas from an increase to a decrease. These findings suggested that sub-regional ecological restoration initiatives, such as afforestation, significantly influence the hydrological cycle, especially in areas with higher vegetation greening. Nevertheless, persistent increases in precipitation could effectively mitigate the moisture deficits induced by vegetation greening. The study’s outcomes provide a basis for alleviating concerns regarding potential water consumption risks associated with future ecological restoration and extensive vegetation greening projects, thereby offering scientific guidance for sustainable water resource management.

Adult neurogenesis involves the generation of functional neurons from neural progenitor cells, which have the potential to complement and restore damaged neurons and neural circuits. Therefore, the development of drugs that stimulate neurogenesis represents a promising strategy in stem cell therapy and neural regeneration, greatly facilitating the reconstruction of neural circuits in cases of neurodegeneration and brain injury. Our study reveals that compound A5, previously designed and synthesized by our team, exhibits remarkable neuritogenic activities, effectively inducing neurogenesis in neural stem/progenitor cells (NSPCs). Subsequently, transcriptome analysis using high-throughput Illumina RNA-seq technology was performed to further elucidate the underlying molecular mechanisms by which Compound A5 promotes neurogenesis. Notably, comparative transcriptome analysis showed that the up-regulated genes were mainly associated with neurogenesis, and the down-regulated genes were mainly concerned with cell cycle progression. Furthermore, we confirmed that Compound A5 significantly affected the expression of transcription factors related to neurogenesis and cell cycle regulatory proteins. Collectively, these findings identify a new compound with neurogenic activity and may provide insights into drug discovery for neural repair and regeneration.

Abstract Background Our study aims to investigate an intrinsic link underlying sex hormone-binding globulin (SHBG) and rheumatoid arthritis (RA), which remains inconclusive in observational settings. Methods Summary statistics were collected from the largest GWAS(s) on SHBG adjusted for BMI (SHBGadjBMI; N overall = 368,929; N men = 180,094; N women = 188,908), crude SHBG (N overall = 370,125; N men = 180,726; N women = 189,473), and RA (N case = 22,350; N control = 74,823). A genome-wide cross-trait design was performed to quantify global and local genetic correlation, identify pleiotropic loci, and infer a causal relationship. Results Among the overall population, a significant global genetic correlation was observed for SHBGadjBMI and RA ( $$r_{{\text{g}}}$$ r g = 0.11, P = 1.0 × 10−4) which was further supported by local signal (1q25.2). A total of 18 independent pleiotropic SNPs were identified, of which three were highly likely causal variants and four were found to have effects on both traits through gene expression mediation. A putative causal association of SHBGadjBMI on RA was demonstrated (OR = 1.20, 95% CI = 1.01–1.43) without evidence of reverse causality (OR = 0.999, 95% CI = 0.997–1.000). Sex-specific analyses revealed distinct shared genetic regions (men: 1q32.1-q32.2 and 5p13.1; women: 1q25.2 and 22q11.21-q11.22) and diverse pleiotropic SNPs (16 in men and 18 in women, nearly half were sex-specific) underlying SHBGadjBMI and RA, demonstrating biological disparities between sexes. Replacing SHBGadjBMI with crude SHBG, a largely similar yet less significant pattern of results was observed. Conclusion Our cross-trait analysis suggests an intrinsic, as well as a sex-specific, link underlying SHBG and RA, providing novel insights into disease etiology.

Abstract Bacterial infections can significantly impede wound healing and pose a serious threat to the patient’s life. The excessive use of antibiotics to combat bacterial infections has led to the emergence of multi-drug-resistant bacteria. Therefore, there is a pressing need for alternative approaches, such as photothermal therapy (PTT), to address this issue. In this study, for the first time, CuS NPs with photothermal properties were synthesized using sericin as a biological template, named CuS@Ser NPs. This method is simple, green, and does not produce toxic and harmful by-products. These nanoparticles were incorporated into a mixture (XK) of xanthan gum and konjac glucomannan (KGM) to obtain XK/CuS NPs composite hydrogel, which could overcome the limitations of current wound dressings. The composite hydrogel exhibited excellent mechanical flexibility, photothermal response, and biocompatibility. It also demonstrated potent antibacterial properties against both Gram-positive and negative bacteria via antibacterial experiments and accelerated wound healing in animal models. Additionally, it is proved that the hydrogel promoted tissue regeneration by stimulating collagen deposition, angiogenesis, and reducing inflammation. In summary, the XK/CuS NPs composite hydrogel presents a promising alternative for the clinical management of infected wounds, offering a new approach to promote infected wound healing.

Abstract Prospective inter-relationships among biomarkers were unexplored, which may provide mechanistic insights into diseases. We investigated the longitudinal associations of BMI change with trajectories of biomarkers related to cardiometabolic or breast cancer risk. A longitudinal study was conducted among 444 healthy women between 2019 to 2021. Cross‑lagged path analysis was used to examine the temporal relationships among BMI, cardiometabolic risk score (CRS), and obesity‑related proteins score (OPS) of breast cancer. Linear mixed-effect models were applied to investigate associations of time-varying BMI with biomarker-based risk score trajectories. Baseline BMI was associated with subsequent change of breast cancer predictors (P = 0.03), and baseline CRS were positively associated with OPS change (P

BackgroundThe relationship between type 2 diabetes mellitus (T2DM) and gallstone disease (GSD) have been incompletely understood. We aimed to investigate their phenotypic and genetic associations and evaluate the biological mechanisms underlying these associations.MethodsWe first evaluated the phenotypic association between T2DM and GSD using data from the UK Biobank (n>450,000) using a prospective observational design. We then conducted genetic analyses using summary statistics from a meta-analysis of genome-wide association studies of T2DM, with and without adjusting for body mass index (BMI) (Ncase=74,124, Ncontrol=824,006; T2DMadjBMI: Ncase=50,409, Ncontrol=523,897) and GSD (Ncase=43,639, Ncontrol=506,798).ResultsA unidirectional phenotypic association was observed, where individuals with T2DM exhibited a higher GSD risk (hazard ratio (HR)=1.39, P

IntroductionVitamin K deficiency may elevate the incidence of musculoskeletal disorders (MSD), whereas it lacks validation for pediatric populations and has uncertain dose recommendations. In this context, we hypothesized that serum vitamin K levels are associated with MSD in preschool children, and the widely used vitamin A and vitamin D supplements may mediate these associations based on potential mechanisms, which expects to provide guidance for future practice.MethodsA cross-sectional study was conducted in Sichuan province in southwestern China, from January 2021 to May 2022. Serum levels of vitamin K1/K2 and 25(OH)D were determined using the high-performance liquid chromatography method, and the diagnosis of MSD was executed by clinicians. Overall and stratified logistic regression analysis based on categorized 25(OH)D levels were conducted to assess association between serum vitamin K levels and MSD prevalence after adjusting for confounders. Mediation analysis was further performed and vitamin A and D supplementation was regressed as the mediator.ResultsA total of 6,368 children aged 0–6 years old were enrolled. MSD was identified in 1179 (18.51%) of the children, while 5,189 (81.49%) of them did not present such disorder. After adjusting confounders, a significant difference was found in serum vitamin K1 level between children in MSD and Non-MSD group (OR = 0.802, 95%CI 0.745–0.864). No significant difference was found in serum vitamin K2 level between the two groups (OR = 0.975, 95%CI 0.753–1.261). The association between vitamin K1 level and MSD prevalence was partly (36.8%) mediated by vitamin A and D supplementation.ConclusionsA low serum vitamin K1 level is connected with an increased risk of MSD among children, highlighting that vitamin A and D supplementation is a helpful intervention to prevent MSD in children with vitamin K deficiency.

Colorectal cancer (CRC) is the third most common cancer in the world, with increasing morbidity and mortality. The current diagnosis and treatment plan rely on early detection and comprehensive treatment based on surgery. Still, most patients are in the middle and advanced stage at the time of diagnosis, and the therapeutic effect is very limited. Immunotherapy is a new cancer treatment method. The most commonly used are immune checkpoint inhibitors, specifically anti PD-1/PD-L1 interaction. However, immunotherapy has limitations, with its therapeutic effect closely related to the immune response in the tumor microenvironment. In recent years, the effect of arginine metabolism disorder on the occurrence and development of cancer and tumor immune regulation has attracted wide attention. Studies have confirmed that cancer cells cannot survive without arginine and arginine metabolites. In addition, arginine is essential for the proliferation, differentiation, and survival of tumor-infiltrating lymphocytes. High arginine levels can promote the anti-tumor immune response, thus increasing the effect of tumor immunotherapy. In this paper, the molecular mechanisms of arginine metabolism in the development and immune regulation of CRC are reviewed, with the authors hoping to provide potential evidence for the development of immunotherapy for CRC. Abbreviation CRC = Colorectal cancer, dMMR = Mismatch repair deficient, MSI-H = Microsatellite highly Instability, MSS = Microsatellite stability, TME = Tumor microenvironment, MHC = Major histocompatibility complex, pMMR = Mismatch repair proficient, NOS = Nitric Oxide synthase, NO = Nitric oxide, ASS-1 = Arginine succinate synthetase 1, ASL = Argininosuccinate lyase, ARG = arginase, CAT = Cationic amino acid transporter, AGAT = Arginine-glycine amidinotransferase, ADC = Arginine decarboxylase, ADI = Arginine deiminase, ODC = Ornithine decarboxylase, GCN2 = General control non-depressible 2, mTOR = Mammalian target of rapamycin, HIF-1 = Hypoxia-inducible factor 1, VEGF = Vascular endothelial growth factor, ICI = Immune checkpoint inhibitor, ORR = Objective response rate, DCR = Disease control rate, OS = Overall survival, PFS = Progress free survival, TIL = Tumor-infiltrating lymphocyte, TCM = Central memory T cell

Abstract Background Both depression and breast cancer (BC) contribute to a substantial global burden of morbidity and mortality among women, and previous studies have observed a potential depression-BC link. We aimed to comprehensively characterize the phenotypic and genetic relationships between depression and BC. Methods We first evaluated phenotypic association using longitudinal follow-up data from the UK Biobank (N = 250,294). We then investigated genetic relationships leveraging summary statistics from the hitherto largest genome-wide association study of European individuals conducted for depression (N = 500,199), BC (N = 247,173), and its subtypes based on the status of estrogen receptor (ER + : N = 175,475; ER − : N = 127,442). Results Observational analysis suggested an increased hazard of BC in depression patients (HR = 1.10, 95%CIs = 0.95–1.26). A positive genetic correlation between depression and overall BC was observed ( $${r}_{g}$$ r g = 0.08, P = 3.00 × 10–4), consistent across ER + ( $${r}_{g}$$ r g = 0.06, P = 6.30 × 10–3) and ER − subtypes ( $${r}_{g}$$ r g = 0.08, P = 7.20 × 10–3). Several specific genomic regions showed evidence of local genetic correlation, including one locus at 9q31.2, and four loci at, or close, to 6p22.1. Cross-trait meta-analysis identified 17 pleiotropic loci shared between depression and BC. TWAS analysis revealed five shared genes. Bi-directional Mendelian randomization suggested risk of depression was causally associated with risk of overall BC (OR = 1.12, 95%Cis = 1.04–1.19), but risk of BC was not causally associated with risk of depression. Conclusions Our work demonstrates a shared genetic basis, pleiotropic loci, and a putative causal relationship between depression and BC, highlighting a biological link underlying the observed phenotypic relationship; these findings may provide important implications for future studies aimed reducing BC risk.

Abstract Background and aims Currently, surgical resection is the most commonly performed and effective treatment for intrahepatic cholangiocarcinoma (ICC) worldwide. However, the prognosis of ICC is unsatisfactory. This study aimed to compare the efficacy and safety of neoadjuvant chemotherapy followed by surgery and upfront surgery in treating intrahepatic cholangiocarcinoma (ICC). The study also intends to explore whether chemotherapy should be introduced before surgery and which populations should be considered for neoadjuvant chemotherapy. Method Four databases, including PubMed, EMBASE, Cochrane Library, and Web of Science, were searched from their inception dates to January 2022 for relevant articles. The statistical analysis was performed using the Review Manager Software (version5.3). The non-randomized interventions (ROBINS-I) was used to assess the methodological quality of included studies and the overall quality of evidence was assessed through the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool. Moreover, the primary outcomes included 1-year, 3-year and 5-year overall survival (OS), while the secondary outcomes were R0 resection, 1-year, 3-year and 5-year recurrence-free survival (RFS), postoperative complications and ninety-day postoperative mortality. Results Five studies involving 2412 patients were included in this meta-analysis. There was no significant difference in 1-year OS, 3-year OS, 1-year, 3-year and 5-year RFS, postoperative complications and ninety-day postoperative mortality between the two groups. However, the meta-analysis showed that the neoadjuvant chemotherapy group had a better 5-year OS benefit in ICC patients than the upfront surgery group (OR = 1.27, 95% CI: 1.02–1.58), while the R0 resection rate was lower in neoadjuvant chemotherapy group than that in the upfront surgery group (OR = 0.49, 95% CI: 0.26–0.91). Conclusion Compared with the upfront surgery, neoadjuvant chemotherapy followed by surgery could prolong the 5-year OS without increasing the risk of postoperative complications in ICC patients. Considering that the patients in the neoadjuvant chemotherapy followed by surgery group had more advanced ICC cases, the benefits of neoadjuvant chemotherapy may be more significant in patients with more advanced ICC.

Abstract Background No studies have assessed the association between sleep duration and obesity in Chinese ethnic minorities. Whether the relationship between sleep duration and obesity is different between Chinese Han people and Chinese ethnic minorities remains unclear. The study aimed to explore the relationship between sleep duration and obesity among Chinese Han people and Chinese ethnic minorities. Methods We applied data from the Guizhou Population Health Cohort Study (GPHCS), which 9,280 participants were recruited in the baseline survey from 2010 to 2012, and 8,163 completed the follow-up survey from 2016 to 2020. A total of 5,096 participants (3,188 Han Chinese and 1,908 ethnic minorities) were included in the ultimate analysis. Information on sleep duration (total 24-hour sleep time), body mass index (BMI), and waist circumference (WC) was collected at the baseline and follow-up survey, respectively. Cross-lagged panel analyses were conducted to explore the temporal relationship between sleep duration and obesity for Han people and ethnic minorities. Results For Han people, the results from cross-lagged panel analyses indicated that baseline sleep duration was significantly associated with follow-up BMI (βBMI = -0.041, 95% CIBMI: -0.072 ~ -0.009) and follow-up WC (βWC = -0.070, 95%CIWC: -0.103 ~ -0.038), but baseline BMI (βBMI = -0.016, 95% CIBMI: -0.050 ~ 0.018) and baseline WC (βWC = -0.019, 95% CIWC: -0.053 ~ 0.016) were not associated with follow-up sleep duration. In addition, the relationship between baseline sleep duration and follow-up BMI was gender-specific and significant only in the Han people female (βBMI = -0.047, 95% CIBMI: -0.090 ~ -0.003) but not in the Han people male (βBMI = -0.029, 95% CIBMI: -0.075 ~ 0.016). For ethnic minorities, the results indicated that there was no relationship between sleep duration and obesity at all, either from sleep duration to obesity (βBMI = 0.028, 95%CIBMI: -0.012 ~ 0.068; βWC = 0.020, 95%CIWC: -0.022 ~ 0.062), or from obesity to sleep duration (βBMI = -0.022, 95%CIBMI: -0.067 ~ 0.022; βWC = -0.042, 95%CIWC: -0.087 ~ 0.003). Conclusion The relationship pattern between sleep duration and obesity across Han people and ethnic minorities is different. Future sleep-aimed overweight and obesity intervention should be conducted according to population characteristics.

This study details the rational design and synthesis of Cu2ZnSnS4 (CZTS)-doped anatase (A) heterostructures, utilizing earth-abundant elements to enhance the efficiency of solar-driven water splitting. A one-step hydrothermal method was employed to fabricate a series of CZTS–A heterojunctions. As the concentration of titanium dioxide (TiO2) varied, the morphology of CZTS shifted from floral patterns to sheet-like structures. The resulting CZTS–A heterostructures underwent comprehensive characterization through photoelectrochemical response assessments, optical measurements, and electrochemical impedance spectroscopy analyses. Detailed photoelectrochemical (PEC) investigations demonstrated notable enhancements in photocurrent density and incident photon-to-electron conversion efficiency (IPCE). Compared to pure anatase electrodes, the optimized CZTS–A heterostructures exhibited a seven-fold increase in photocurrent density and reached a hydrogen production efficiency of 1.1%. Additionally, the maximum H2 production rate from these heterostructures was 11-times greater than that of pure anatase and 250-times higher than the original CZTS after 2 h of irradiation. These results underscore the enhanced PEC performance of CZTS–A heterostructures, highlighting their potential as highly efficient materials for solar water splitting. Integrating Cu2ZnSnS4 nanoparticles (NPs) within TiO2 (anatase) heterostructures implied new avenues for developing earth-abundant and cost-effective photocatalytic systems for renewable energy applications.

BackgroundDue to the lower reliability of laboratory tests, skin diseases are more suitable for diagnosis with AI models. There are limited AI dermatology diagnostic models combining images and text; few of these are for Asian populations, and few cover the most common types of diseases.MethodsLeveraging a dataset sourced from Asia comprising over 200,000 images and 220,000 medical records, we explored a deep learning-based system for Dual-channel images and extracted text for the diagnosis of skin diseases model DIET-AI to diagnose 31 skin diseases, which covers the majority of common skin diseases. From 1 September to 1 December 2021, we prospectively collected images from 6,043 cases and medical records from 15 hospitals in seven provinces in China. Then the performance of DIET-AI was compared with that of six doctors of different seniorities in the clinical dataset.ResultsThe average performance of DIET-AI in 31 diseases was not less than that of all the doctors of different seniorities. By comparing the area under the curve, sensitivity, and specificity, we demonstrate that the DIET-AI model is effective in clinical scenarios. In addition, medical records affect the performance of DIET-AI and physicians to varying degrees.ConclusionThis is the largest dermatological dataset for the Chinese demographic. For the first time, we built a Dual-channel image classification model on a non-cancer dermatitis dataset with both images and medical records and achieved comparable diagnostic performance to senior doctors about common skin diseases. It provides references for exploring the feasibility and performance evaluation of DIET-AI in clinical use afterward.

Summary: Little is known regarding the long-term adverse effects of COVID-19 on female-specific cancers, nor the shared genetic influences underlying these conditions. We performed a comprehensive genome-wide cross-trait analysis to investigate the shared genetic architecture between COVID-19 (infection, hospitalization, and critical illness) with three female-specific cancers (breast cancer (BC), epithelial ovarian cancer (EOC), and endometrial cancer (EC)). We identified significant genome-wide genetic correlations with EC for both hospitalization (rg = 0.19, p = 0.01) and critical illness (rg = 0.29, p = 3.00 × 10−4). Mendelian randomization demonstrated no valid association of COVID-19 with any cancer of interest, except for suggestive associations of genetically predicted hospitalization (ORIVW = 1.09, p = 0.04) and critical illness (ORIVW = 1.06, p = 0.04) with EC risk, none withstanding multiple correction. Cross-trait meta-analysis identified 20 SNPs shared between COVID-19 with BC, 15 with EOC, and 5 with EC; and transcriptome-wide association studies revealed multiple shared genes. Findings support intrinsic links underlying these complex traits, highlighting shared mechanisms rather than causal associations.

Abstract Purpose The primary objective of this study was to evaluate knowledge and behavior of medication use among guardians of left-behind children (LBC) and non-left-behind children (NLBC). Methods A cross-sectional study was conducted in Chengdu, the major city of southwestern China from May 2020 to August 2020. A logistic regression model was conducted to assess medication-related knowledge and behavior of guardians between the LBC group and NLBC group, adjusted for confounders. Stratified analysis was further performed. Results The overall mean scores for knowledge and for behavior were 20.22 (standard deviation = 4.472) and 15.77 (standard deviation = 3.604), respectively. No significant difference was found in medication-related knowledge and behavior scores between LBC and NLBC guardians (P > 0.05). A significant difference was only observed after adjusting for past medical history and history of present illness (HPI). Conclusion There was no significant difference in the awareness and behavior of medication use between guardians of LBC and NLBC in this study, having more contact with the doctor was an effective method of health education that could possibly improve their health literacy.

Abstract Background Previous studies have reported that the tumor heterogeneity and complex oncogenic mechanisms of proximal and distal colon cancer (CRC) are divergent. Therefore, we aim to analyze the differences between left-sided CRC (L_cancer) and right-sided CRC (R_cancer), as well as constructing respective nomograms. Methods We enrolled 335 colon cancer patients (146 L_cancer patients and 189 R_cancer patients) from The Cancer Genome Atlas (TCGA) data sets, and 102 pairs of color cancer tissue and adjacent normal tissue (51 L_cancer patients and 51 R_cancer patients) from our hospital. Firstly, we analyzed the differences between the L_cancer patients and R_cancer patients, and then established the L_cancer and R_cancer prognostic models using LASSO Cox. Results R_cancer patients had lower survival than L_cancer patients. R_cancer patients had higher ESTIMATE and immune scores and lower tumor purity. These patterns of expression of immune checkpoint-related genes and TMB level were higher in R_cancer than in L_cancer patients. Finally, we using Lasso Cox regression analyses established a prognostic model for L_cancer patients and a prognostic model for R_cancer patients. The AUC values of the risk score for OS in L_cancer were 0.862 in the training set and 0.914 in the testing set, while those in R_cancer were 0.835 in the training set and 0.857 in the testing set. The AUC values in fivefold cross-validation were between 0.727 and 0.978, proving that the two prognostic models have great stability. The nomogram of L_cancer included prognostic genes, age, pathological M, pathological stage, and gender, the AUC values of which were 0.800 in the training set and 0.905 in the testing set. Meanwhile, the nomogram of R_cancer comprised prognostic genes, pathological N, pathological T, and age, the AUC values of which were 0.836 in the training set and 0.850 in the testing set. In the R_cancer patients, high-risk patients had a lower proportion of ‘B cells memory’, ‘Dendritic cells resting’, immune score, ESTIMATE score, immune checkpoint-related genes, and HLA-family genes, and a higher proportion of ‘T cells follicular helper’, ‘Dendritic cells activated’, and ‘Mast cells activated’. Conclusions We found significant differences between L_cancer and R_cancer patients and established a clinical predictive nomogram for L_cancer patients and a nomogram for R_cancer patients. Additionally, R_cancer patients in low-risk groups may be more beneficial from immunotherapy.

Abstract Background Palbociclib was the only available cyclin‐dependent kinase 4/6 inhibitor in China until very recently, and its effect has not been systemically evaluated among Chinese patients. This study aims to assess the efficacy, safety and patient‐reported outcomes (PROs) of palbociclib plus endocrine therapy (ET) in real‐world China. Methods An ambispective cohort study was conducted on patients with advanced HR+HER2− breast cancer who received palbociclib between July 2018, and November 2020 and were enrolled from 12 hospitals. Treatment patterns, survival outcomes, and safety events were documented, and PROs (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire‐Core 30 items [EORTC QLQ‐C30] and EuroQoL 5 dimensions [EQ‐5D]) were analyzed. The Kaplan–Meier method was used to visualize and estimate the median progression‐free survival (mPFS). Log‐rank tests, Cox regressions, t tests, and chi‐square tests were performed for comparison. Results A total of 190 patients (median follow‐up of 18.0 months) were enrolled. Palbociclib was mostly combined with aromatase inhibitors (66.3%), fulvestrant (32.6%), and tamoxifen (1.1%). The mPFS values were 21.0, 14.0, and 7.0 months with palbociclib administered in first‐ (n = 83), second‐ (n = 41) and subsequent‐line settings (n = 66), respectively. Endocrine sensitivity was significantly associated with patient prognosis (mPFS: 23.0, 12.0, and 6.0 months for endocrine naïve, acquired, and primary resistant patients, respectively, p

Abstract Background Breast parenchymal texture features, including grayscale variation (V), capture the patterns of texture variation on a mammogram and are associated with breast cancer risk, independent of mammographic density (MD). However, our knowledge on the genetic basis of these texture features is limited. Methods We conducted a genome-wide association study of V in 7040 European-ancestry women. V assessments were generated from digitized film mammograms. We used linear regression to test the single-nucleotide polymorphism (SNP)-phenotype associations adjusting for age, body mass index (BMI), MD phenotypes, and the top four genetic principal components. We further calculated genetic correlations and performed SNP-set tests of V with MD, breast cancer risk, and other breast cancer risk factors. Results We identified three genome-wide significant loci associated with V: rs138141444 (6q24.1) in ECT2L, rs79670367 (8q24.22) in LINC01591, and rs113174754 (12q22) near PGAM1P5. 6q24.1 and 8q24.22 have not previously been associated with MD phenotypes or breast cancer risk, while 12q22 is a known locus for both MD and breast cancer risk. Among known MD and breast cancer risk SNPs, we identified four variants that were associated with V at the Bonferroni-corrected thresholds accounting for the number of SNPs tested: rs335189 (5q23.2) in PRDM6, rs13256025 (8p21.2) in EBF2, rs11836164 (12p12.1) near SSPN, and rs17817449 (16q12.2) in FTO. We observed significant genetic correlations between V and mammographic dense area (r g = 0.79, P = 5.91 × 10−5), percent density (r g = 0.73, P = 1.00 × 10−4), and adult BMI (r g = − 0.36, P = 3.88 × 10−7). Additional significant relationships were observed for non-dense area (z = − 4.14, P = 3.42 × 10−5), estrogen receptor-positive breast cancer (z = 3.41, P = 6.41 × 10−4), and childhood body fatness (z = − 4.91, P = 9.05 × 10−7) from the SNP-set tests. Conclusions These findings provide new insights into the genetic basis of mammographic texture variation and their associations with MD, breast cancer risk, and other breast cancer risk factors.

Balancing the tradeoff between economy, energy, environment, water resources and carbon emissions has become the major challenge for sustainable development. In this study, a fuzzy multi-objective method is developed by integrating multi-objective programming, fuzzy linear programming and multiple scenarios. The developed approach can tackle multiple uncertainties and complexities existing in economy–energy–environment system, random carbon dioxide emission and water consumption control policies mix. Results disclose that (1) policy orientation and carbon emission control policy can achieve both carbon and water resource control goals, and water resource control policies are relatively unnecessary; (2) the tertiary sector will become the leading industry, accounting for more than three quarters of the total output value, the construction industry will also overgrow, and the proportion of the manufacturing industry will drop significantly; (3) coal still dominates in the energy production and total quantity consumed, and petroleum consumption will fall, coal accounts for about 75 percent of total energy consumption and electricity for about 15 percent; (4) according to different sources, carbon dioxide emissions are mainly from coal and electricity utilization. Coal’s contribution gradually rose to 65 percent, while electricity dropped from 35 percent to 30 percent. For each industry, the mining industry, the electricity industry and the tertiary sector are the primary sources. (5) the sulfur dioxide control policy and carbon dioxide control policy has a strong correlation, and nitrogen oxide control policies have a specific correlation with them. The water resource control policy and particulate matter control policy are relatively independent.

Abstract Background The most common type of cancer of the digestive system is hepatocellular carcinoma. In China, many patients harbour HBV. The lin28B/Let-7c/MYC axis is associated with the occurrence of many cancers. Therefore, we aimed to illuminate the function of the lin28B/Let-7c/MYC axis in hepatocellular carcinoma. We aimed to evaluate the critical involvement of lin28B and Let-7c in the carcinogenesis of human hepatocellular carcinoma (B-HCC). Methods Data from the GEO database were used to analyse differentially expressed genes and IRGs. A protein − protein interaction (PPI) network and Venn diagram were generated to analyse relationships. Real-time RT-PCR, Western blotting, and cell counting kit-8 assays were used to examine the association of lin28B, Let-7c, and MYC with cell proliferation. Results A total of 2552 functionally annotated differentially expressed RNAs were analysed in HBV patients from the GSE135860 database. In addition, 46 let-7c target genes were screened in HBV patients, and the interactions were analysed through PPI network analysis. The results confirmed that Let-7c and its target genes play a key role in HBV-related diseases. Next, we discovered a gradual decrease in Let-7c expression during the progression from HBV-associated chronic hepatitis (B-CH) and HBV-associated liver cirrhosis (B-LC) to B-HCC. We found evidence for a negative association between lin28B expression and Let-7c expression. The expression of MYC was obviously upregulated when Let-7c was inhibited. Conclusion Our results highlight that Let-7c and lin28B participate in the carcinogenesis of HBV-associated diseases through the lin28B/Let-7c/MYC axis.

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has exerted a profound influence on humans. Increasing evidence shows that immune response is crucial in influencing the risk of infection and disease severity. Observational studies suggest an association between COVID‐19 and immunoglobulin G (IgG) N-glycosylation traits, but the causal relevance of these traits in COVID-19 susceptibility and severity remains controversial.MethodsWe conducted a two-sample Mendelian randomization (MR) analysis to explore the causal association between 77 IgG N-glycosylation traits and COVID-19 susceptibility, hospitalization, and severity using summary-level data from genome-wide association studies (GWAS) and applying multiple methods including inverse-variance weighting (IVW), MR Egger, and weighted median. We also used Cochran’s Q statistic and leave-one-out analysis to detect heterogeneity across each single nucleotide polymorphism (SNP). Additionally, we used the MR-Egger intercept test, MR-PRESSO global test, and PhenoScanner tool to detect and remove SNPs with horizontal pleiotropy and to ensure the reliability of our results.ResultsWe found significant causal associations between genetically predicted IgG N-glycosylation traits and COVID-19 susceptibility, hospitalization, and severity. Specifically, we observed reduced risk of COVID-19 with the genetically predicted increased IgG N-glycan trait IGP45 (OR = 0.95, 95% CI = 0.92–0.98; FDR = 0.019). IGP22 and IGP30 were associated with a higher risk of COVID-19 hospitalization and severity. Two (IGP2 and IGP77) and five (IGP10, IGP14, IGP34, IGP36, and IGP50) IgG N-glycosylation traits were causally associated with a decreased risk of COVID-19 hospitalization and severity, respectively. Sensitivity analyses did not identify any horizontal pleiotropy.ConclusionsOur study provides evidence that genetically elevated IgG N-glycosylation traits may have a causal effect on diverse COVID-19 outcomes. Our findings have potential implications for developing targeted interventions to improve COVID-19 outcomes by modulating IgG N-glycosylation levels.

Abstract Background Deep sternal wound infection (DSWI) is a rare but serious complication after median sternotomy, and treatment success depends mainly on surgical experience. Traditional treatment methods for DSWI include complete debridement, vacuum sealing drainage wound therapy and sometimes transposition of muscle flap. This study aimed to evaluate the utility of antibiotic-loaded bone cement combined with vacuum sealing drainage on DSWI and explore the effect of this treatment on lung function. Methods Between January 2018 and December 2019, we treated 12 patients suffering a mediastinitis and open thorax using antibiotic-loaded bone cement combined with vacuum sealing drainage. Subsequently, the blood and local concentration of antibiotic were measured. The patient characteristics, pulmonary function, were retrospectively analyzed. Subjects were followed up for 12 months. Results There were no intraoperative deaths. All patients’ healing wounds were first-stage healing without complications and reoperation, the mean hospital stay was 20.2 ± 3.5 days. Local vancomycin concentrations largely exceeded the ones needed for their efficacy while little antibiotic was found in the blood. Pulmonary function testing was improved 2 weeks after the operation. No infection reoccurred in12-month follow-up. Conclusions The antibiotic-loaded bone cement combined with vacuum sealing drainage might be an effective method for the sternal reconstruction of deep sternal wound infection and it can improve the patient's lung function in a short time.

Objectives: The non-O1/non-O139 Vibrio cholerae caused outbreaks or sporadic cases of gastroenteritis that was rarely seen in good sanitary condition. It was described a case of systemic multiple organ lesions that worsened because of non-O1/non-O139 V. cholerae, suggesting that serogroups have a potential virulence in enhancing pathogenicity with patients with underlying diseases compared with a healthy population. Design or methods: Samples are identified by strain culture, polymerase chain reaction (PCR) virulence identification, and whole genome sequencing. Results: A middle-aged man was diagnosed with cytotoxin-producing and nontoxin V. cholerae non-O1/non-O139 serogroups. Although lacking the CT toxin encoded by ctxAB gene, the pathogenesis of cholera relies on the synergistic action of many other genes, especially virulence genes. Conclusions: This case suggested that the laborers engaging in agricultural production are at potential risk of V. cholerae infection by exposure of open wounds to contaminated water . However, epidemiological investigation should focus on the objective cause of the change of working environment. Furthermore, common diseases can possibly enhance the virulence of non-O1/non-O139 serogroups by attacking the tight junction of small intestinal epithelial cells, further triggering bacteremia, a process that may lead to death within 48–72 hours, which requires great attention.

Employee recognition, an incentive method widely used in management practice, plays an important role in the organization. Although extant studies have confirmed its effectiveness, little attention has been paid to its spillover effect. Based on the Social Cognitive Theory and Affective Events Theory, this study argues that employee recognition encounter can trigger cognitive and behavioral reactions. Through perceived organizational justice and workplace wellbeing, a chain-mediating effect connects witnessing employee recognition to work engagement. This research adopts the empirical research method by asking the participants to do the weekly survey (four times in 1 month), and 258 samples are collected. Using SPSS20.0 and its PROCESS macro module, hypotheses are tested. The results indicate (1) employees who witness leaders’ recognition of colleagues will (a) perceive higher organizational justice and (b) be more engaged in work. (2) Perceived organizational justice will mediate the positive relationship between employee recognition encounters with (a) workplace wellbeing and (b) work engagement. (3) Perceived organizational justice and workplace wellbeing will have a chain-mediating effect in the path of employee recognition encounter and work engagement. The results provide both practical and theoretical contribution to employee recognition.