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Abstract Objective Early identification of modifiable risk factors is crucial for the prevention of constipation. This study systematically investigated the relationship between genetically predicted modifiable risk factors and constipation. Methods The inverse variance weighting (IVW) method was employed as the primary analytical approach. For similar exposure indicators, the multivariate Mendelian randomization (MVMR) method was used to adjust for potential biases in univariate MR analysis. The robustness of the results was further evaluated using the MR-Egger intercept test, Cochran’s Q test, and leave-one-out analysis. Bonferroni correction was applied to reduce the false positive rate in the results. Results The IVW analysis indicated a significant causal association between genetically predicted gastroesophageal reflux disease [OR (95% CI) = 1.192 (1.079–1.315), P = 0.0005], atorvastatin use [OR (95% CI) = 16.995 (3.327–86.816), P = 0.0007], and constipation. Additionally, there was a potential causal association between education level [OR (95% CI) = 0.859 (0.767–0.964), P = 0.009], major depressive disorder [OR (95% CI) = 1.206 (1.041–1.399), P = 0.013], hypothyroidism [OR (95% CI) = 2.299 (1.327–3.985), P = 0.003], and aspirin use [OR (95% CI) = 4.872 (1.174–20.221), P = 0.029] with constipation. No causal associations were found for the other included indicators. Sensitivity analysis demonstrated the absence of evidence for heterogeneity and pleiotropy in any positive results. Conclusion This study identified several risk factors that could be targeted for the prevention of constipation, offering valuable insights for public health policies.

Abstract Background Exposure of the hepatic artery is a fundamental step in many surgeries, during which iatrogenic hepatic artery injury may occur. Although the incidence of hepatic artery haemorrhage is low, its occurrence can lead to life-threatening haemorrhage. It is difficult and dangerous to accumulate clinical experience in laparoscopic hepatic artery repair in actual patients, and simulation training models for laparoscopic hepatic artery repair are currently lacking. In this study, a 3D printed model was designed to simulate the training curriculum for sudden hepatic artery haemorrhage, but whether training with the 3D printed model could yield superior skill improvement for surgeons remained to be determined. Methods A new 3D printed model was designed for this study. Surgeons from the General Surgery Department of Sir Run Run Shaw Hospital participated in this simulation training. The surgical performance of each model was compared, and the authenticity of the model was evaluated and mechanically tested. Results Experienced surgeons performed better on the 3D printed model. After repeated training, inexperienced surgeons showed significant improvement of their laparoscopic hepatic artery repair skills. The authenticity of the model was generally satisfactory, but shortcomings persisted in the mechanical testing of artery wall tearing, necessitating further improvement. Conclusions Few studies have investigated laparoscopic simulation training for sudden hepatic artery haemorrhage. This simulation model distinguishes surgeons with different levels of experience and allows those with less experience to improve their laparoscopic hepatic artery repair skills through training on the model.

Abstract With the increasing demand for exercise, the population of patients with ankle sprain to anterior talofibular ligament injury has the characteristics of a large base and high requirements for returning to sports, and how to promote the repair of damaged ligaments from a microscopic perspective is an urgent problem to be solved. In many studies, human amniotic mesenchymal stem cells have strong differentiation ability, and can be induced to continuously differentiate into ligament cells to achieve the purpose of repairing damaged ligaments. Human amniotic stem cells were extracted and cultured from human amniotic tissues, evaluated by cell identification and other techniques, and evaluated into ligament differentiation by toluidine blue, alizarin red, oil red O staining and detection of ligament cell differentiation, protein detection by Western blot, mRNA level by qPCR, and finally, the targeted binding relationship between miR-16a-5p and mRNA FGF2 was verified by double luciferase reporter assay. The expression of collagen type 1 (COL 1), collagen type 3 (COL3), SCX and MKX was increased by overexpression of mRNA FGF2, respectively, and miR-16a-5p had a targeted effect on FGF2 and regulated the ligamentous differentiation of human amniotic mesenchymal stem cells. We found that the regulatory effect of overexpressed mRNA FGF2 on mesenchymal stem cells could be inhibited by up-regulation of miR-16a-5p, while the knockdown of FGF2 could reverse the regulatory effect of miR-16a-5p inhibition on ligament-forming differentiation of human amniotic mesenchymal stem cells. In this study, we discovered the existence of the miR-16a-5p–FGF2 axis in human amniotic mesenchymal stem cells, and the differentiation of human amniotic mesenchymal stem cells into ligamentous cells can be regulated by regulating various links in this axis.

Abstract Objective Empathy is crucial for patient health. The Balint group is a commonly used method for empathy training. However, the impact of Balint groups on empathy remains unclear. This systematic review and meta-analysis of randomized controlled trials (RCTs) aims to assess the impact of Balint groups on empathy training among medical and nursing students, as well as doctors and nurses. Methods This review involved searching multiple databases for relevant articles. Rigorous eligibility criteria were applied during the screening of titles and abstracts, and during the selection of records. Following a full-text eligibility evaluation, two reviewers independently extracted data from the final selection of studies, and a meta-analysis was conducted. The standardized mean difference (SMD) was calculated to assess the systematic outcomes. Results A total of 11 studies were included in this systematic review and meta-analysis. Participants in Balint groups demonstrated a significant increase in empathy than those in the control group (SMD = 1.46, 95% confidence interval [CI] 0.86–2.06; p

Implant-associated Staphylococcus aureus (S. aureus) osteomyelitis is a severe challenge in orthopedics. While antibiotic-loaded bone cement is a standardized therapeutic approach for S. aureus osteomyelitis, it falls short in eradicating Staphylococcus abscess communities (SACs) and bacteria within osteocyte-lacuna canalicular network (OLCN) and repairing bone defects. To address limitations, we developed a borosilicate bioactive glass (BSG) combined with ferroferric oxide (Fe3O4) magnetic scaffold to enhance antibacterial efficacy and bone repair capabilities. We conducted comprehensive assessments of the osteoinductive, immunomodulatory, antibacterial properties, and thermal response of this scaffold, with or without an alternating magnetic field (AMF). Utilizing a well-established implant-related S. aureus tibial infection rabbit model, we evaluated its antibacterial performance in vivo. RNA transcriptome sequencing demonstrated that BSG + 5%Fe3O4 enhanced the immune response to bacteria and promoted osteogenic differentiation and mineralization of MSCs. Notably, BSG + 5%Fe3O4 upregulated gene expression of NOD-like receptor and TNF pathway in MSCs, alongside increased the expression of osteogenic factors (RUNX2, ALP and OCN) in vitro. Flow cytometry on macrophage exhibited a polarization effect towards M2, accompanied by upregulation of anti-inflammatory genes (TGF-β1 and IL-1Ra) and downregulation of pro-inflammatory genes (IL-6 and IL-1β) among macrophages. In vivo CT imaging revealed the absence of osteolysis and periosteal response in rabbits treated with BSG + 5%Fe3O4 + AMF at 42 days. Histological analysis indicated complete controls of SACs and bacteria within OLCN by day 42, along with new bone formation, signifying effective control of S. aureus osteomyelitis. Further investigations will focus on the in vivo biosafety and biological mechanism of this scaffold within infectious microenvironment.

Abstract Background Exposure to cadmium (Cd) is associated with a reduction in lung function among patients with chronic obstructive pulmonary disease (COPD). The longitudinal relationship and mechanism underlying the link between Cd exposure and lung function changes among COPD patients are yet unknown. Methods The cohort study included 259 eligible patients who underwent regular professional follow-ups. Blood Cd levels and serum 8-iso-prostaglandin F2 alpha (8-iso-PGF2α) levels were assessed. Lung function was determined at baseline and follow-up research. The associations between changes in lung function and blood Cd concentration were analysed using multivariate linear and logistic regression models. Results Each 1-ppb elevation in blood Cd content resulted in a 0.420 L decrease in forced vital capacity (FVC), a 0.424 L decrease in forced expiratory volume in 1 s (FEV1), a 4.341% decrease in FEV1/FVC%, and a 8.418% decrease in FEV1% predicted in patients with COPD. Blood Cd concentration showed a positive correlation with serum 8-iso-PGF2α levels in a specific range. The relative contribution of increased serum levels of 8-iso-PGF2α to Cd-induced declines in FEV1, predicted FEV1%, and FEV1/FVC% were 2.08%, 8.08%, and 13.19%, respectively. Conclusion Blood Cd levels are associated with lung function changes in COPD patients. Oxidative stress is thought to be an important mediator in Cd-induced reduction of pulmonary function.

Abstract Background Elderly patients undergoing recovery from general anesthesia face a heightened risk of critical respiratory events (CREs). Despite this, there is a notable absence of effective predictive tools tailored to this specific demographic. This study aims to develop and validate a predictive model (nomogram) to address this gap. CREs pose significant risks to elderly patients during the recovery phase from general anesthesia, making it an important issue in perioperative care. With the increasing aging population and the complexity of surgical procedures, it is crucial to develop effective predictive tools to improve patient outcomes and ensure patient safety during post-anesthesia care unit (PACU) recovery. Methods A total of 324 elderly patients who underwent elective general anesthesia in a grade A tertiary hospital from January 2023 to June 2023 were enrolled. Risk factors were identified using least absolute shrinkage and selection operator (LASSO) regression. A multivariate logistic regression model was constructed and represented as a nomogram. Internal validation of the model was performed using Bootstrapping. This study followed the TRIPOD checklist for reporting. Results The indicators included in the nomogram were frailty, snoring, patient-controlled intravenous analgesia (PCIA), emergency delirium and cough intensity at extubation. The diagnostic performance of the nomogram model was satisfactory, with AUC values of 0.990 and 0.981 for the training set and internal validation set, respectively. The optimal cutoff value was determined to be 0.22, based on a Youden index of 0.911. The F1-score was 0.927, and the MCC was 0.896. The calibration curve, Brier score (0.046), and HL test demonstrated acceptable consistency between the predicted and actual results. DCA revealed high net benefits of the nomogram prediction across all threshold probabilities. Conclusions This study developed and validated a nomogram to identify elderly patients in the PACU who are at higher risk of CREs. The identified predictive factors included frailty condition, snoring syndrome, PCIA, emergency delirium, and cough intensity at extubation. By identifying patients at higher risk of CREs early on, medical professionals can implement targeted strategies to mitigate the occurrence of complications and provide better postoperative care for elderly patients recovering from general anesthesia.

Abstract Background Different hormone receptor (HR) expression patterns have significant biological and therapeutic implications in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, the distinction between HR-positive /HER2-positive (HR+/HER2+) and HR-negative/HER2-positive (HR-/HER2+) subtypes remains unclear. Methods This retrospective study analyzed 828 patients with HER2-positive breast cancer at the First Affiliated Hospital of Xi’an Jiaotong University from 2012 to 2022. Baseline characteristics were compared by chi-square test. Survival outcomes were estimated by Kaplan-Meier method. Results In total, 56.3% (n = 466) had HR-positive and 43.7% (n = 362) had HR-negative disease. Comparatively, HR+/HER2 + breast cancers presented favorable clinicopathological features. At a median follow-up of 49 months, 199 disease-free survival (DFS) events and 99 deaths were observed. HR+/HER2 + patients had significantly better survival outcomes than HR-/HER2 + patients. HR-positive status was an independent protective factor for overall survival (OS) [P = 0.032; hazard ratio, 0.61; 95% confidence interval (CI), 0.39–0.96] and DFS (P = 0.001; hazard ratio, 0.61; 95% CI, 0.46–0.81). HR+/HER2 + patients were significantly less sensitive to neoadjuvant therapy than HR-/HER2 + patients. In the first-line treatment for HR+/HER2 + advanced breast cancer, receiving endocrine therapy significantly improved advanced-OS (P

Lithium ion batteries are widely used in chemical energy storage systems. However, due to their inherent heat generation characteristics, thermal runaway has become a major safety hazard for chemical energy storage power plants. Therefore, optimizing the design of a battery thermal management system to effectively avoid thermal runaway is crucial for the safe operation of chemical energy storage systems. A new type of parallel serpentine flow channel liquid cooling plate with both series turn back and parallel branch structures is designed. Through simulation experiments, the effects of the flow channel structure of the liquid cooling plate, the layout of the liquid cooling system, and the inlet flow velocity of the coolant on the maximum temperature, temperature uniformity, and inlet and outlet pressure drop are studied to optimize the liquid cooling system. The results show that, under the same coolant inlet flow rate, the maximum temperature of the new channel is reduced by 0.284 9 K, and the temperature difference within the module is reduced by 0.466 3 K compared with the traditional parallel flow channel. The inlet and outlet pressure drop is reduced by 40.18% compared with the traditional serpentine flow channel. Based on the parallel serpentine flow channel liquid cooling plate, the optimal layout scheme for the liquid cooling system is the injection of coolant at the two split ports and the staggered arrangement of the liquid cooling plate. Different liquid cooling plates have different flow velocity settings. The inlet flow velocity of the two liquid cooling plates is set to 0.1 m/s, and the inlet flow velocity of the central liquid cooling plate is set to 0.2 m/s. Compared with the same flow velocity of 0.2 m/s for the four plates, the temperature difference within the battery module group is reduced by 13.62%, the inter column temperature difference is reduced by 82.59%, and the energy consumption is reduced by 44.87%, achieving an optimization effect of 'cost reduction and efficiency enhancement'. A reasonable flow channel structure, staggered cold plate layout, and differentiated inlet flow rate design can optimize the liquid cooling system of battery modules and increase the safety of battery module operation.

The high-temperature molten salt pump is the core equipment in the small modular molten salt reactor with media temperatures up to 700 °C. The cantilever ratio of the molten salt pump is usually large. Excessively large cantilever ratios cause increased deformations and rotational amplitudes at the impeller, thus affecting the operational stability of the main pump; small cantilever ratios cause heavy temperature gradients, thus affecting the structural integrity evaluation. This paper used numerical simulation methods to calculate and analyze the temperature field, stress, and structural integrity, optimized the pump shaft cantilever length of the original scheme based on structural integrity using the dichotomy method, and analyzed the rotor dynamics of the optimization results. The results of this study show that the thermal expansion load caused by the temperature difference has a significant mechanical effect on the structure; the first-order critical speed of the rotor system of the optimized schemes has been improved, and the amplitude of the unbalanced response has been significantly reduced, which not only improves the operational stability of the rotor, also contributes to the compact design of the main pump of a small modular molten salt reactor.

Background: Influenza is an acute respiratory infectious disease with a significant global disease burden. Additionally, the coronavirus disease 2019 pandemic and its related non-pharmaceutical interventions (NPIs) have introduced uncertainty to the spread of influenza. However, comparative studies on the performance of innovative models and approaches used for influenza prediction are limited. Therefore, this study aimed to predict the trend of influenza-like illness (ILI) in settings with diverse climate characteristics in China based on sentinel surveillance data using three approaches and evaluate and compare their predictive performance. Methods: The generalized additive model (GAM), deep learning hybrid model based on Gate Recurrent Unit (GRU), and autoregressive moving average-generalized autoregressive conditional heteroscedasticity (ARMA—GARCH) model were established to predict the trends of ILI 1-, 2-, 3-, and 4-week-ahead in Beijing, Tianjin, Shanxi, Hubei, Chongqing, Guangdong, Hainan, and the Hong Kong Special Administrative Region in China, based on sentinel surveillance data from 2011 to 2019. Three relevant metrics, namely, Mean Absolute Percentage Error (MAPE), Root Mean Squared Error (RMSE), and R squared, were calculated to evaluate and compare the goodness of fit and robustness of the three models. Results: Considering the MAPE, RMSE, and R squared values, the ARMA—GARCH model performed best, while the GRU-based deep learning hybrid model exhibited moderate performance and GAM made predictions with the least accuracy in the eight settings in China. Additionally, the models’ predictive performance declined as the weeks ahead increased. Furthermore, blocked cross-validation indicated that all models were robust to changes in data and had low risks of overfitting. Conclusions: Our study suggested that the ARMA—GARCH model exhibited the best accuracy in predicting ILI trends in China compared to the GAM and GRU-based deep learning hybrid model. Therefore, in the future, the ARMA—GARCH model may be used to predict ILI trends in public health practice across diverse climatic zones, thereby contributing to influenza control and prevention efforts.

Abstract Objective This study aims to conduct an extensive analysis of autoimmune bullous diseases, particularly pemphigus vulgaris and bullous pemphigoid, in Shanghai, China, from 2016 to 2023. It seeks to understand the demographic profiles, comorbidities, mortality rates, risk factors, and socioeconomic impacts associated with autoimmune bullous disease. Methods A cross-sectional study design was employed, enrolling 1,072 patients. Diagnostic measures included clinical manifestations, histopathology, direct immunofluorescence, and serologic tests. The study also involved a detailed socioeconomic analysis and evaluation of occupational risks. Results The findings highlight a significant occupational risk in industries requiring enhanced safety measures, with a notable prevalence of autoimmune bullous disease among workers in these sectors. A considerable portion of the patients were from low-income backgrounds with limited literacy, indicating the economic burden of autoimmune bullous disease. A key discovery of the study is the potential pathological link between autoimmune bullous disease and interstitial lung disease. Conclusion This research, one of the first comprehensive studies on autoimmune bullous disease in China, underscores the need for targeted healthcare strategies and further investigation into autoimmune bullous disease, particularly its relationship with interstitial lung disease.

Aiming at the difficult problem of gas drainage in low permeability outburst coal seam in China, taking the transportation lane of coal mining face in K15 coal seam of Maizigou Coal Mine in Guizhou Province as the engineering background, through the establishing the multi-field coupling model of gas flow in coal mining face under high temperature field, the gas drainage effect of coal seam boreholes under different heating temperature, borehole diameter and borehole spacing conditions was simulated and studied. The research shows that temperature has a significant impact on the effect of coal seam gas emission. When the heating temperature is 86 ℃, the gas pressure decreases significantly; the borehole diameter has a great influence on the effect of coal seam gas emission. When the borehole diameter is 113 mm, the maximum gas pressure between boreholes is 0.36 MPa, the maximum gas pressure decreases by 14.28% year on year, and the gas emission from boreholes increases by 27.27%. The effect of borehole spacing on coal seam gas pressure and discharge effect is also very obvious. When the borehole spacing is 1 m, the maximum gas pressure between boreholes is 0.45 MPa, and the influence range is 5.72 m. The decrease range of gas pressure increased by 37.8% compared with the hole spacing of 1.5 m and the influence range increased by 18.18% compared with the hole spacing of 1.5 m. The comprehensive gas discharge effect was the best. Comparing the simulation results of different schemes, the numerical simulation scheme 9 has the best gas emission effect.

Abstract Background Atherogenic index of plasma (AIP), a marker of atherosclerosis and cardiovascular disease (CVD). However, few studies have investigated association between AIP and all-cause mortality and specific-mortality in the general population. Methods This study included data from 14,063 American adults. The exposure variable was the AIP, which was defined as log10 (triglycerides/high-density lipoprotein cholesterol). The outcome variables included all-cause mortality and specific-mortality. Survey-weighted cox regressions were performed to evaluate the relation between AIP and all-cause mortality and specific-mortality. Weighted restricted cubic spline was conducted to examin the non-linear relationship. Results During 10 years of follow-up, we documented 2,077, 262, 854, and 476 cases of all-cause mortality, diabetes mortality, CVD mortality and cancer mortality, respectively. After adjustment for potential confounders, we found that atherogenic index of plasma (AIP) was significantly associated with an increased risk of diabetes mortality when comparing the highest to the lowest quantile of AIP in female (p for trend = 0.001) or participants older than 65 years (p for trend = 0.002). AIP was not significantly associated with all-cause mortality, CVD mortality and cancer mortality (p > 0.05). Moreover, a non-linear association was observed between AIP and all-cause mortality in a U-shape (p for non-linear = 0.0011), while a linear relationship was observed with diabetes mortality and non-diabetes mortality (p for linear

Abstract Pumped storage plants (PSPs) play an important role in renewable energy consumption in power systems. Variable‐speed technology is a new and critical direction for the development of PSPs. In pump mode, variable‐speed pumped storage units (VSPSUs) have wider power regulation ranges and more flexible power responses than fixed‐speed pumped storage units (FSPSUs); however, the corresponding quantification study of VSPSUs is rare. Therefore, this study aims to quantify the static and dynamic power regulation characteristics of VSPSU in pump mode. First, the modeling of the fast speed control strategy of VSPSU in pump mode is improved. Then, the power regulation range of the VSPSU is explored. The factors (i.e., power command, governor, and converter) affecting the power response rapidity are quantified through the engineering case of a variable‐speed PSP adopting the doubly fed induction machine. Accordingly, suggestions on the settings of the parameters are provided. Quantification results show that parameter tuning based on this study effectively solves the problem of low regulation rate caused by great power fluctuations under typical power regulation cases in pump mode. This VSPSU has the fastest regulation rate of 13.75%/s when adjusting 40% power. This study could provide technical support to the practical operation of VSPSU.

Abstract Diabetes mellitus (DM) and arginine vasopressin deficiency (AVP‐D) are characterized by polyuria. Marfan syndrome is an autosomal dominant disorder caused by pathogenetic variants in FBN1. Here, we report a patient with type 2 diabetes mellitus, AVP‐D, and Marfan syndrome. Although the coexistence of type 2 diabetes mellitus and AVP‐D is rare, for those patients with type 2 diabetes mellitus, the existence of AVP‐D should be considered when polyuria is not in accordance with the blood glucose levels, especially for those with a low urine specific gravity. Specific symptoms or signs help to identify Marfan syndrome early, and genetic testing of the FBN1 pathogenetic variant helps to make a definitive diagnosis.

Introduction: Lipid metabolism dysfunction is widely involved in the pathological process of acute ischemic stroke (AIS). The coordination of lipid metabolism between neurons and astrocytes is of great significance. However, the full scope of lipid dynamic changes and the function of key lipids during AIS remain unknown. Hence, identifying lipid alterations and characterizing their key roles in AIS is of great importance. Methods: Untargeted and targeted lipidomic analyses were applied to profile lipid changes in the ischemic penumbra and peripheral blood of transient middle cerebral artery occlusion (tMCAO) mice as well as the peripheral blood of AIS patients. Infarct volume and neurological deficits were assessed after tMCAO. The cell viability and dendritic complexity of primary neurons were evaluated by CCK8 assay and Sholl analysis. Seahorse, MitoTracker Green, tetramethyl rhodamine methyl ester (TMRM), 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) and MitoSOX were used as markers of mitochondrial health. Fluorescent and isotopic free fatty acid (FFA) pulse-chase assays were used to track FFA flux in astrocytes. Results: Long-chain acylcarnitines (LCACs) were the lipids with the most dramatic changes in the ischemic penumbra and peripheral blood of tMCAO mice. LCACs were significantly elevated on admission in AIS patients and associated with poor outcomes in AIS patients. Increasing LCACs through a bolus administration of palmitoylcarnitine amplified stroke injury, while decreasing LCACs by overexpressing carnitine palmitoyltransferase 2 (CPT2) ameliorated stroke injury. Palmitoylcarnitine aggravated astrocytic mitochondrial damage after OGD/R, while CPT2 overexpression in astrocytes ameliorated cocultured neuron viability. Further study revealed that astrocytes stimulated by OGD/R liberated FFAs from lipid droplets into mitochondria to form LCACs, resulting in mitochondrial damage and lowered astrocytic metabolic support and thereby aggravated neuronal damage. Conclusion: LCACs could accumulate and damage neurons by inducing astrocytic mitochondrial dysfunction in AIS. LCACs play a crucial role in the pathology of AIS and are novel promising diagnostic and prognostic biomarkers for AIS.

Abstract Background Monoterpenes are among the most important volatile aromatic compounds contributing to the flavor and aroma of grapes and wine. However, the molecular basis of monoterpene biosynthesis has not yet been fully elucidated. Results In our study, transcriptomics and gas chromatography-mass spectrometry (GC-MS) were used to mine candidate genes and transcription factors involved in monoterpene biosynthesis between high-monoterpene and zero-monoterpene table grape cultivars. We found that monoterpene biosynthesis was positively correlated by the expression of five genes encoding 1-deoxy-D-xylulose-5-phosphate synthase (VvDXSs), one encoding 4-hydroxy-3-methylbut-2-enyl diphosphate reductase (VvHDR), three hydroxy-3-methylglutaryl-CoA synthases (VvHMGSs) and one mevalonate kinase (VvMVK), whereas the expression of one isopentenyl diphosphate isomerase (VvIDI) and one 3-hydroxy-3-methylglutaryl-CoA reductase (VvHMGR) negatively correlated monoterpene biosynthesis. Of these genes, VvIDI was selected to validate its function in monoterpene accumulation through a transient overexpression experiment, and was shown to inhibit the biosynthesis of grape linalool and α-terpineol. Meanwhile, we found that a 64-amino acid extension sequence at the N-terminus can guide the VvIDI protein to target the chloroplast. Conclusions The findings of this study should help to guide future functional analysis of key genes as well as mining the potential regulatory mechanism of monoterpene biosynthesis in grapes and grape products.

Abstract Economic productivity depends on reliable access to electricity, but the extreme shortage events of variable wind-solar systems may be strongly affected by climate change. Here, hourly reanalysis climatological data are leveraged to examine historical trends in defined extreme shortage events worldwide. We find uptrends in extreme shortage events regardless of their frequency, duration, and intensity since 1980. For instance, duration of extreme low-reliability events worldwide has increased by 4.1 hours (0.392 hours per year on average) between 1980–2000 and 2001–2022. However, such ascending trends are unevenly distributed worldwide, with a greater variability in low- and middle-latitude developing countries. This uptrend in extreme shortage events is driven by extremely low wind speed and solar radiation, particularly compound wind and solar drought, which however are strongly disproportionated. Only average 12.5% change in compound extremely low wind speed and solar radiation events may give rise to over 30% variability in extreme shortage events, despite a mere average 1.0% change in average wind speed and solar radiation. Our findings underline that wind-solar systems will probably suffer from weakened power security if such uptrends persist in a warmer future.

Abstract Background Numerous studies have developed or validated prediction models aimed at estimating the likelihood of amputation in diabetic foot (DF) patients. However, the quality and applicability of these models in clinical practice and future research remain uncertain. This study conducts a systematic review and assessment of the risk of bias and applicability of amputation prediction models among individuals with DF. Methods A comprehensive search was conducted across multiple databases, including PubMed, Web of Science, EBSCO CINAHL Plus, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, Chinese Biomedical Literature Database (CBM), and Weipu (VIP) from their inception to December 24, 2023. Two investigators independently screened the literature and extracted data using the checklist for critical appraisal and data extraction for systematic reviews of prediction modeling studies. The Prediction Model Risk of Bias Assessment Tool (PROBAST) checklist was employed to evaluate both the risk of bias and applicability. Results A total of 20 studies were included in this analysis, comprising 17 development studies and three validation studies, encompassing 20 prediction models and 11 classification systems. The incidence of amputation in patients with DF ranged from 5.9 to 58.5%. Machine learning-based methods were employed in more than half of the studies. The reported area under the curve (AUC) varied from 0.560 to 0.939. Independent predictors consistently identified by multivariate models included age, gender, HbA1c, hemoglobin, white blood cell count, low-density lipoprotein cholesterol, diabetes duration, and Wagner’s Classification. All studies were found to exhibit a high risk of bias, primarily attributed to inadequate handling of outcome events and missing data, lack of model performance assessment, and overfitting. Conclusions The assessment using PROBAST revealed a notable risk of bias in the existing prediction models for amputation in patients with DF. It is imperative for future studies to concentrate on enhancing the robustness of current prediction models or constructing new models with stringent methodologies.

Abstract Accumulating studies have shown that E3 ligases play crucial roles in regulating cellular biological processes and signaling pathways during carcinogenesis via ubiquitination. Tripartite-motif (TRIM) ubiquitin E3 ligases consist of over 70 members. However, the clinical significance and their contributions to tumorigenesis remain largely unknown. In this study, we analyzed the RNA-sequencing expression of TRIM E3 ligases in colorectal cancer (CRC) and identified 10 differentially expressed genes, among which TRIM1 expression predicted poor prognosis of CRC patients. We demonstrated that TRIM1 expression is positively associated with CRC pathological stages, and higher expression is positively correlated with infiltrating levels of immune cells and immunotherapy biomarkers. TRIM1 expression promotes the proliferation and migration of colorectal cancer cells in vitro and in vivo. Transcriptional analysis showed that TRIM1 is responsible for metabolism promotion and immune suppression. Mechanistically, we found that TRIM1 binds HIF1α and mediates its K63-linked ubiquitination, which is required for HIF1α nuclear translocation and subsequent activation. Ubiquitination occurs at Lys214 in the loop between the two PAS domains of HIF1α, and mutation of Lys214 severely disturbs the function of HIF1α. Besides, HIF1α ubiquitination enhances its binding with proteins involved in cellular trafficking and nucleocytoplasmic transport pathway. Collectively, our results indicate TRIM1’s role in predicting prognosis and reveal how TRIM1 functions to upregulate HIF1α expression and promote tumor cell proliferation.

Abstract Background Detecting epistatic interactions (EIs) involves the exploration of associations among single nucleotide polymorphisms (SNPs) and complex diseases, which is an important task in genome-wide association studies. The EI detection problem is dependent on epistasis models and corresponding optimization methods. Although various models and methods have been proposed to detect EIs, identifying EIs efficiently and accurately is still a challenge. Results Here, we propose a linear mixed statistical epistasis model (LMSE) and a spherical evolution approach with a feedback mechanism (named SEEI). The LMSE model expands the existing single epistasis models such as LR-Score, K2-Score, Mutual information, and Gini index. The SEEI includes an adaptive spherical search strategy and population updating strategy, which ensures that the algorithm is not easily trapped in local optima. We analyzed the performances of 8 random disease models, 12 disease models with marginal effects, 30 disease models without marginal effects, and 10 high-order disease models. The 60 simulated disease models and a real breast cancer dataset were used to evaluate eight algorithms (SEEI, EACO, EpiACO, FDHEIW, MP-HS-DHSI, NHSA-DHSC, SNPHarvester, CSE). Three evaluation criteria (pow1, pow2, pow3), a T-test, and a Friedman test were used to compare the performances of these algorithms. The results show that the SEEI algorithm (order 1, averages ranks = 13.125) outperformed the other algorithms in detecting EIs. Conclusions Here, we propose an LMSE model and an evolutionary computing method (SEEI) to solve the optimization problem of the LMSE model. The proposed method performed better than the other seven algorithms tested in its ability to identify EIs in genome-wide association datasets. We identified new SNP–SNP combinations in the real breast cancer dataset and verified the results. Our findings provide new insights for the diagnosis and treatment of breast cancer. Availability and implementation: https://github.com/scutdy/SSO/blob/master/SEEI.zip .

Abstract Background The faithful maintenance of DNA methylation homeostasis indispensably requires DNA methyltransferase 1 (DNMT1) in cancer progression. We previously identified DNMT1 as a potential candidate target for oral squamous cell carcinoma (OSCC). However, how the DNMT1- associated global DNA methylation is exploited to regulate OSCC remains unclear. Methods The shRNA-specific DNMT1 knockdown was employed to target DNMT1 on oral cancer cells in vitro, as was the use of DNMT1 inhibitors. A xenografted OSCC mouse model was established to determine the effect on tumor suppression. High-throughput microarrays of DNA methylation, bulk and single-cell RNA sequencing analysis, multiplex immunohistochemistry, functional sphere formation and protein immunoblotting were utilized to explore the molecular mechanism involved. Analysis of human samples revealed associations between DNMT1 expression, global DNA methylation and collaborative molecular signaling with oral malignant transformation. Results We investigated DNMT1 expression boosted steadily during oral malignant transformation in human samples, and its inhibition considerably minimized the tumorigenicity in vitro and in a xenografted OSCC model. DNMT1 overexpression was accompanied by the accumulation of cancer-specific DNA hypomethylation during oral carcinogenesis; conversely, DNMT1 knockdown caused atypically extensive genome-wide DNA hypomethylation in cancer cells and xenografted tumors. This novel DNMT1-remodeled DNA hypomethylation pattern hampered the dual activation of PI3K-AKT and CDK2-Rb and inactivated GSK3β collaboratively. When treating OSCC mice, targeting DNMT1 achieved greater anticancer efficacy than the PI3K inhibitor, and reduced the toxicity of blood glucose changes caused by the PI3K inhibitor or combination of PI3K and CDK inhibitors as well as adverse insulin feedback. Conclusions Targeting DNMT1 remodels a novel global DNA hypomethylation pattern to facilitate anticancer efficacy and minimize potential toxic effects via balanced signaling synergia. Our study suggests DNMT1 is a crucial gatekeeper regarding OSCC destiny and treatment outcome.

Abstract Background Metabolic reprogramming and epigenetic alterations contribute to the aggressiveness of pancreatic ductal adenocarcinoma (PDAC). Lactate-dependent histone modification is a new type of histone mark, which links glycolysis metabolite to the epigenetic process of lactylation. However, the role of histone lactylation in PDAC remains unclear. Methods The level of histone lactylation in PDAC was identified by western blot and immunohistochemistry, and its relationship with the overall survival was evaluated using a Kaplan-Meier survival plot. The participation of histone lactylation in the growth and progression of PDAC was confirmed through inhibition of histone lactylation by glycolysis inhibitors or lactate dehydrogenase A (LDHA) knockdown both in vitro and in vivo. The potential writers and erasers of histone lactylation in PDAC were identified by western blot and functional experiments. The potential target genes of H3K18 lactylation (H3K18la) were screened by CUT&Tag and RNA-seq analyses. The candidate target genes TTK protein kinase (TTK) and BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) were validated through ChIP-qPCR, RT-qPCR and western blot analyses. Next, the effects of these two genes in PDAC were confirmed by knockdown or overexpression. The interaction between TTK and LDHA was identified by Co-IP assay. Results Histone lactylation, especially H3K18la level was elevated in PDAC, and the high level of H3K18la was associated with poor prognosis. The suppression of glycolytic activity by different kinds of inhibitors or LDHA knockdown contributed to the anti-tumor effects of PDAC in vitro and in vivo. E1A binding protein p300 (P300) and histone deacetylase 2 were the potential writer and eraser of histone lactylation in PDAC cells, respectively. H3K18la was enriched at the promoters and activated the transcription of mitotic checkpoint regulators TTK and BUB1B. Interestingly, TTK and BUB1B could elevate the expression of P300 which in turn increased glycolysis. Moreover, TTK phosphorylated LDHA at tyrosine 239 (Y239) and activated LDHA, and subsequently upregulated lactate and H3K18la levels. Conclusions The glycolysis-H3K18la-TTK/BUB1B positive feedback loop exacerbates dysfunction in PDAC. These findings delivered a new exploration and significant inter-relationship between lactate metabolic reprogramming and epigenetic regulation, which might pave the way toward novel lactylation treatment strategies in PDAC therapy.

Sodium-glucose cotransporter 2 inhibitors are a class of glucose-lowering drugs known for robust cardiovascular protective properties. However, the side effects induced by Sodium-glucose cotransporter 2 inhibition limit application in cardiovascular medicine. Our prior research showed that thoughtful structural modifications can dissociate the anti-heart failure activity from glucose-lowering effects. Moreover, we showed that the glyceraldehyde derivative, JX22, developed by scaffold hopping from empagliflozin, exhibits a superior cardiomyocyte protective effect, albeit with increased cytotoxicity compared to empagliflozin. In the current study systematic structural modifications of JX22 were performed to enhance anti-heart failure efficacy and safety, while reducing glucose-lowering activity. Twenty glyceraldehyde-based derivatives were synthesized and compound 12 emerged as an optimal candidate by exhibiting an improved cytoprotective effect compared to JX22. Compound 12 significantly inhibited the activity of NHE1 on the myocardial membrane, thereby maintaining intracellular ion homeostasis. In vivo efficacy results demonstrated that compound 12 at 10 mg/kg significantly ameliorated cardiac dysfunction, myocardial fibrosis, and exercise tolerance in isoproterenol-induced heart failure mice without a glucose-lowering effect. Furthermore, compound 12 exhibited favorable safety profiles in single-dose toxicity and hERG inhibition tests, along with promising pharmacokinetic properties in mice. The current study not only underscores the potential of compound 12 for further investigation but also highlights the effectiveness of the scaffold hopping strategy.

Abstract Contemporary distribution networks can be seen with diverse dispatchable and non‐dispatchable energy resources. The coordinated scheduling of these dispatchable resources with non‐dispatchable resources can provide several techno‐economic and social benefits. Since battery energy storage systems (BESSs) and microturbine units are capital intensive. A thorough investigation of their coordinated scheduling on a purely economic basis will be an interesting and challenging task while considering dynamic electricity price and uncertainty of renewable power generation and load demand. This paper proposes a new methodology for optimal coordinated scheduling of BESSs and microturbine units considering existing renewable energy resources and dynamic electricity price to maximize daily profit function of the utility. In this study, a recently explored modified African buffalo optimization algorithm is employed. The key attributes of the proposed methodology are comprised of mean price‐based adaptive scheduling embedded within a decision mechanism system to maximize arbitrage benefits. Decision mechanism system keeps a track of system states as a‐priori thus guides the artificial intelligence‐based solution technique for sequential optimization. This may also reduce the computational burden of complex real‐life engineering optimization problems. Further, a novel concept of fictitious charges in coordination with BESS management algorithm is proposed to restrict the counterproductive operational management of BESSs. The application results investigated and compared on a benchmark 33‐bus test distribution system highlights the importance of the proposed methodology.

Abstract Object detection in remote sensing images poses great challenges due to the dense distribution, arbitrary orientation, and aspect ratio variations of objects. Most of the existing methods rely on aligned convolutional features, which fail to capture the geometric information of objects effectively and result in the inconsistency between the classification score and localization accuracy. Moreover, densely packed objects suffer from spatial feature aliasing caused by the intersection of reception fields between objects. To address this issue, a deformable convolution‐based method named rotated points is proposed, which consists of two modules: a point set loss module and a high‐quality sample assignment module. The point set loss module can extract geometric features of objects in arbitrary directions with fine‐grained point sets for feature representation and introduce outlier penalties to penalize outlier points. The high‐quality sample assignment module measures the classification and localization ability, orientation quality, and point‐wise correlation of point sets comprehensively to enhance the consistency of classification and regression significantly. Experiments on the DOTA and FAIR1M datasets demonstrate that the proposed method achieves significant improvements over the benchmark model.

IntroductionMigraine is a prevalent neurological disorder characterized by recurrent attacks, leading to a substantial global disease burden. Recent observational studies have reported the onset and worsening of migraine following COVID-19 infection and vaccination. However, traditional observational study designs have limitations in controlling for confounding factors, potentially resulting in biased and inconsistent conclusions. To address this, we applied Mendelian randomization (MR) to investigate the causal relationship between COVID-19 infection and vaccination with migraine.MethodsThis study utilized summary-level genome-wide association study (GWAS) data from the GWAS catalog and FinnGen database to evaluate the effects of varying degrees of COVID-19 infection and vaccination on migraine. We employed inverse variance weighted (IVW) fixed-effect and random-effect models as the primary methods for MR analysis, with MR-Egger and other approaches as complementary methods. Sensitivity analyses, including Cochran's Q test, MR-Egger intercept regression, and MR-PRESSO, were conducted to ensure robustness of the results.ResultsOur MR analysis revealed no significant causal association between COVID-19 infection and migraine. However, a significant causal association was found between COVID-19 vaccination and migraine (beta = 0.071, P = 0.034). The results were confirmed through a series of sensitivity tests, demonstrating the robustness of the findings.DiscussionThis study provides novel evidence of a significant causal link between COVID-19 vaccination and migraine, while no such association was observed with COVID-19 infection. These findings may have important implications for clinical practice, particularly in planning treatment adjustments and optimizing patient care for individuals with migraines in the context of COVID-19 vaccination.

Summary: Background: The phase 2 PERMEATE study has shown the antitumor activity and safety of pyrotinib plus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer and brain metastases. In this report, survival results were updated with extended follow-up. Methods: Between January 29, 2019 and July 10, 2020, adult patients with HER2-positive metastatic breast cancer who had radiotherapy-naïve brain metastases (cohort A, n = 59) or progressive disease after radiotherapy (cohort B, n = 19) were enrolled and received pyrotinib (400 mg once daily) and capecitabine (1000 mg/m2 twice daily on days 1–14 of each 21-day cycle) until disease progression or unacceptable toxicity. Secondary endpoints progression-free survival (PFS) and overall survival (OS) were updated, and post-hoc central nervous system (CNS)-PFS was analyzed. This study is registered with ClinicalTrials.gov (NCT03691051). Findings: As of February 2, 2023, the median follow-up duration was 30.9 months (interquartile range, 16.1–39.8). Median PFS was 10.9 months (95% confidence interval [CI], 7.6–14.6) in cohort A and 5.7 months (95% CI, 3.4–11.5) in cohort B. Median OS was 35.9 months (95% CI, 24.4-not reached) in cohort A and 30.6 months (95% CI, 12.6–33.3) in cohort B. Median CNS-PFS was 13.6 months (95% CI, 9.0–15.8) in cohort A and 5.7 months (95% CI, 3.4–11.5) in cohort B. Median OS was 34.1 months (95% CI, 21.7-not reached) for 14 patients with intracranial progression only in cohort A who restarted pyrotinib plus capecitabine after local radiotherapy. Interpretation: These data support further validation in a randomized controlled trial for the assessment of pyrotinib in combination with capecitabine as systemic therapy for patients with HER2-positive breast cancer and brain metastases. Funding: National Cancer Center Climbing Foundation Key Project of China, Jiangsu Hengrui Pharmaceuticals.

Club cell secretory protein (CC16) is considered a biological marker indicating lung epithelial and lung permeability. The joint effect of polycyclic aromatic hydrocarbons (PAHs) exposure on CC16 levels and the association between CC16 levels and long-term lung function changes lacks epidemiological evidence. To investigate the effect of PAHs exposure on plasma CC16 levels and the association between CC16 levels and long-term lung function changes, this study enrolled 307 coke oven workers in 2014, measured their baseline concentrations of urinary PAHs metabolites and plasma CC16, with follow-up after nine years. Bayesian kernel machine regression (BKMR) was employed to analyze the effect of mixed PAHs metabolites. The dose-effect association between baseline CC16 levels and lung function during 2014–2023 was explored using restricted cubic spline (RCS) models, and stratified analysis investigated the effect modification of PAHs exposure and smoking status on this association. The median age of the participants was 40 years, with 93.81 % male. The results showed that plasma CC16 levels decreased by 2.02 ng/mL (95 % CI: −3.77, −0.27) among all participants and FVC (% predicted) decreased by 2.87 % (95 % CI: −5.59, −0.14) in the low CC16 group with each unit increase in log-transformed 2-OHNAP. The BKMR model revealed a negative association between PAHs metabolites and both plasma CC16 levels and FVC (% predicted). Plasma CC16 decreased by 1.05 units when all PAHs metabolites at P65 compared to those at P50. After 9 years of follow-up, baseline CC16 levels were significantly associated with follow-up FVC (% predicted), FEV1 (% predicted), and small airway dysfunction risk. Furthermore, high PAHs exposure and smoking enhanced the association between CC16 and lung function. In conclusion, PAHs exposure decreases CC16 levels, and coking workers with low baseline CC16 levels may experience more severe future lung function decline.

Lung cancer as a molecularly and histologically high heterogonous disease, there is an urgent need to predict lung cancer patients' responses to anti-cancer treatment, and patient-derived organoids (PDOs) have been recognized as a valuable platform for preclinical drug screening. In this study, we successfully established 26 PDO lines from various subtypes of lung cancers including benign tumor, adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, large-cell carcinoma, and small-cell carcinoma. These PDOs were shown to retain the major genomic and histological characteristics of primary tumors and remain stable during long-term culture. With the help of targeted genomic sequencing, we found that lung cancer that harbors METN375S mutation is selectively sensitive to afatinib, and a combination of afatinib and gemcitabine induced synthetic lethality in PDO and mini-PDX models. In summary, our findings demonstrate the potential of PDO in predicting lung cancer drug response, and reveal a promising strategy for METN375S mutant lung cancer treatment.

BackgroundTotal hip arthroplasty or total knee arthroplasty (THA/TKA) is often associated with varying degrees of pain. In recent years, transdermal buprenorphine (TDB) patch has shown encouraging results for acute postoperative pain control in orthopedic surgery. The aim of our study was to investigate the efficacy and safety of the combination of TDB patch and nonsteroidal anti-inflammatory drugs (NSAIDs) as a multimodal analgesic regimen after THA/TKA.MethodsPatients who underwent THA and TKA between January 2022 and January 2023 were reviewed. Three postoperative analgesic regimens were selected: Group A (flurbiprofen 50 mg and tramadol 37.5 mg/acetaminophen 325 mg), Group B (flurbiprofen 50 mg and TDB 5 mg), and Group C (Parecoxib 40 mg and TDB 5 mg). The primary outcomes were the Wong-Baker face pain scale revision (FPS-R) scores and the rate of sleep disturbances. Secondary outcomes of the study included the proportion of patients with postoperative pain relief rates categorized as 0%, 0.05).ConclusionThis study suggests that the combination of TDB patch and NSAIDs is safe and effective for postoperative analgesia after THA/TKA.

Breast cancer is a malignant tumor that poses a serious threat to women's health, and vasculogenic mimicry (VM) is strongly associated with bad prognosis in breast cancer. However, the relationship between VM and immune infiltration in breast cancer and the underlying mechanisms have not been fully studied. On the basis of the Cancer Genome Atlas (TCGA), Fudan University Shanghai Cancer Center (FUSCC) database, GSCALite database, and gene set enrichment analysis (GSEA) datasets, we investigated the potential involvement of VM-related genes in the development and progression of breast cancer. We analyzed the differential expression, mutation status, methylation status, drug sensitivity, tumor mutation burden (TMB), microsatellite instability (MSI), immune checkpoints, tumor microenvironment (TME), and immune cell infiltration levels associated with VM-related genes in breast cancer. We created two VM subclusters out of breast cancer patients using consensus clustering, and discovered that patients in Cluster 1 had better survival outcomes compared to those in Cluster 2. The infiltration levels of T cells CD4 memory resting and T cells CD8 were higher in Cluster 1, indicating an immune-active state in this cluster. Additionally, we selected three prognostic genes (LAMC2, PIK3CA, and TFPI2) using Lasso, univariate, and multivariate Cox regression and constructed a risk model, which was validated in an external dataset. The prognosis of patients is strongly correlated with aberrant expression of VM-related genes, which advances our knowledge of the tumor immune milieu and enables us to identify previously unidentified breast cancer subtypes. This could direct more potent immunotherapy approaches.

Abstract Human‐induced disturbances such as dam construction and regulation have led to widespread alterations in hydrological processes and thus substantially influence plant characteristics in the hydro‐fluctuation zones (HFZs). To reveal utilization of limited resources and mechanisms of inter‐specific competition and species co‐existence of plant communities based on niche breadth and overlap under the different HFZs of the Three Gorges Reservoir (TGR) in China, we conducted a field investigation with 368 quadrats on the effects of hydrological alterations on plant diversity and niche characteristics. The results showed anti‐seasonal flooding precipitated the gradual disappearance of the original diverse niches, resulting in the reduction of plant species richness and functional diversity and more obvious competition among plant species with similar resource requirements. Annuals, perennials and shrubs accounted for 71.23%, 27.39% and 1.37%, respectively, suggesting that annuals and flood‐tolerant riparian herbs were favored under such novel flooding conditions. A consistent increase in species number, Shannon‐Wiener diversity index and Simpson dominance index with altitude was inconsistent with hump‐shaped diversity–disturbance relationship of the intermediate disturbance hypothesis, while the opposite trend was observed for the Pielou evenness index. This species distribution pattern might be caused by several synergetic attributes (e.g., the submergence depth, plant tolerant capacity to flooding, life form, dispersal mode and inter‐specific competition). Vegetation types shifted from xerophytes to mesophytes and eventually to hygrophytes with the increasing flooding time in the HFZs. Hydrological alterations proved to be the paramount driver of vegetation distribution in the different HFZs. The niche analysis provided the first insights on the mechanisms of resource utilization and inter‐specific competition, of which annuals could germinate quickly after soil drainage to achieve the greatest competitive advantages and occupy a larger niche space than other plants. Vegetation was still in the early stage of primary succession in the novel riparian forests. Therefore, vegetation restoration strategies should be biased towards herbaceous plants, due to annuals with better environmental adaptability, supplemented by shrubs and small trees. To establish a complete reference system for vegetation restoration, natural vegetation monitory plots in the different succession stages should be established in the different HFZs of the TGR, and their environmental conditions, community structures and inter‐specific relationships further analyzed.

Abstract Background The MONALEESA‐7 and ‐2 phase 3 randomized trials demonstrated a statistically significant progression‐free survival (PFS) and overall survival (OS) benefit with initial ribociclib + endocrine therapy (ET) versus placebo + ET in pre‐ and postmenopausal patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC), respectively. Similar trends were observed in Asian subgroup analyses. This phase 2 bridging study of initial ET + ribociclib enrolled pre‐ and postmenopausal patients with HR+/HER2– ABC from China and was conducted to demonstrate consistency of PFS results in a Chinese population relative to the global MONALEESA‐7 and ‐2 studies. Methods Patients were randomized (1:1) to ET (nonsteroidal aromatase inhibitor + goserelin for premenopausal patients; letrozole for postmenopausal patients) + either ribociclib or placebo. The primary endpoint was investigator‐assessed PFS. Results As of April 25, 2022, the median follow‐up was 34.7 months in both cohorts. In the premenopausal cohort, median PFS was 27.6 months in the ribociclib arm (n = 79) versus 14.7 months in the placebo arm (n = 77) (hazard ratio 0.67 [95% CI: 0.45, 1.01]). In the postmenopausal cohort, median PFS was not reached in the ribociclib arm versus 18.5 months in the placebo arm (n = 77 in each arm) (hazard ratio 0.40 [95% CI: 0.26, 0.62]). Data also suggested improvements in secondary efficacy endpoints, although OS data were not mature. The safety profile in this population was consistent with that in global studies. Conclusions These data demonstrate a favorable benefit–risk profile for ribociclib + ET in Chinese patients.

ABSTRACT: Silymarin, a botanical medicine derived from milk thistle seeds and is known to improve chicken growth and gut health when added to the feed. However, its role in the prevention and treatment of chicken coccidiosis remains unclear. This study investigated the efficacy of various doses of silymarin in preventing and treating Eimeria tenella infection in chicks. A total of 180 one-day-old specific pathogen-free chicks were randomized into six groups of 30 chicks each, no treatment (NC group); E. tenella infection (CC group); diclazuril medication during d 14 to 21 and E. tenella infection (DC group); and three groups infected with E. tenella and administered low, medium, or high doses of silymarin during d 12 to 21. All groups except NC were infected with E. tenella on d 14, with indicators observed on d 21. The growth performance was higher in the silymarin treated groups than that in the CC group, and the oocyst count per gram of manure, blood stool, and cecal lesion scores decreased. The medium-dose silymarin group exhibited the best treatment effect. Additionally, the silymarin groups displayed improved histological, morphology, and intestinal barrier integrity. The amounts of proinflammatory factors and harmful bacteria in the cecum were also reduced. Additionally, the activity of serum and cecal antioxidant enzymes, as well as the abundance of beneficial gut microbiota, increased in the cecum. In conclusion, this study demonstrated that silymarin can prevent and treat E. tenella infections. These data provide a scientific and conceptual basis for the development of a botanical dietary supplement from silymarin for the treatment and control of coccidiosis in chicks.

In this paper, we explore a distributed collaborative caching and computing model to support the distribution of adaptive bit rate video streaming. The aim is to reduce the average initial buffer delay and improve the quality of user experience. Considering the difference between global and local video popularities and the time-varying characteristics of video popularity, a two-stage caching scheme is proposed to push popular videos closer to users and minimize the average initial buffer delay. Based on both long-term content popularity and short-term content popularity, the proposed caching solution is decouple into the proactive cache stage and the cache update stage. In the proactive cache stage, we develop a proactive cache placement algorithm that can be executed in an off-peak period. In the cache update stage, we propose a reactive cache update algorithm to update the existing cache policy to minimize the buffer delay. Simulation results verify that the proposed caching algorithms can reduce the initial buffer delay efficiently.

Abstract Background Studies has suggested that receiving social support improves the professional identity of health professional students. According to the two-way social support theory, social support includes receiving social support and giving social support. However, the effect of the two-way social support on health professional students’ professional identity has not been clarified yet. Methods To explore the mechanism of how two-way social support affects health professional students’ professional identity, an observational, cross-sectional study was conducted among a convenience and cluster sample of 1449 health professional students from two medical schools in western China. Measures included a short version of the two-way social support scale, a health professional students’ professional identity questionnaire, an achievement motivation scale, and a meaning in life scale. (Data were analyzed by use of SPSS26.0 software, Amos 28.0 software, and PROCESSv4.0 plug-in.). Results Receiving social support, giving social support, achievement motivation, meaning in life, and professional identity were positively correlated with each other. Receiving and giving social support not only directly predicted health professional students’ professional identity, but also indirectly predicted health professional students’ professional identity through the mediating roles of achievement motivation and meaning in life, and the chain mediating roles of achievement motivation and meaning in life, respectively. The effectiveness of predicting health professional students’ professional identity varied among different types of two-way social support, which could be depicted as two-way social support > mainly giving social support > mainly receiving social support > low two-way social support. Conclusion In the medical education, the awareness and ability of health professional students to receive and give social support should be strengthened. More attention should be drawn on the chain mediating effect of achievement motivation and meaning in life between two-way social support and professional identity. The current results shed new light on exploring effective ways of improving health professional students’ professional identity, which suggested that more attention should be paid to the positive effects of mainly giving social support and two-way social support rather than only on the effects of receiving social support.

Abstract Background Although papillary thyroid carcinoma (PTC) has a favorable prognosis, it could affect patient life quality and become a serious threat because of invasion and metastasis. Many investigations have suggested that circular RNAs (circRNAs) are involved in different cancer regulations. Nevertheless, circRNAs role in invasive PTC remains unclear. Methods In the present investigation, next-generation sequencing was applied to explore abnormal circRNA expression. The expression of circRNA phosphoglycerate dehydrogenase (circPHGDH) in PTC cell lines and tissues were examined. Then, we investigated regulatory mechanism and circPHGDH downstream targets using bioinformatics analysis and luciferase reporting analysis. Then transwell migration, Cell Counting Kit-8 (CCK8) and 5-ethynyl-2’-deoxyuridine (EdU) assays were used for cells migration and proliferation analysis. In vivo metastasis and tumorigenesis assays were also employed to evaluate the circPHGDH role in PTC. Results The data showcased that circPHGDH expression increased in both PTC cell lines and tissues, which suggested that circPHGDH functions in PTC progression. circPHGDH downregulation suppressed PTC invasion and proliferation in both in vivo and in vitro experiments. Bioinformatics and luciferase reporter results confirmed that both microRNA (miR)-122-5p and pyruvate kinase M2 subtype (PKM2) were downstream targets of circPHGDH. PKM2 overexpression or miR-122-5p suppression reversed PTC cell invasion and proliferation post silencing circPHGDH by restoring aerobic glycolysis. Conclusion Taken together, our research found that circPHGDH downregulation reduced PTC progression via miR-122-5p/PKM2 axis regulation mediated by aerobic glycolysis.

Abstract Purpose To assess the clinical safety, accuracy, and efficacy of percutaneous kyphoplasty (PKP) surgery using an enhanced method of unilateral puncture on the convex side for the treatment of painful osteoporotic vertebral compression fractures (P-OVCF) with scoliosis. Methods Clinical and radiographic data of P-OVCF patients with scoliosis who underwent PKP via unilateral puncture on the convex side from January 2018 to December 2021 were retrospectively analyzed. This technique’s detailed surgical steps and tips were described. The local kyphosis angle (LKA), scoliosis Cobb angle (SCA), and local scoliosis Cobb angle (LSCA) were measured using X-ray and compared at pre-operation, post-operation, and the last follow-up. The width of pedicle (POW), inner inclination angle (IIA), lateral distance (LD), and puncture course length (PCL) were measured on the axial computed tomography image and compared between two sides. Postoperative computed tomography was employed to evaluate the condition of cement distribution and puncture. Clinical outcomes were evaluated using the Oswestry Disability Index (ODI) and Visual Analog Scale (VAS) for back pain (BP). Results Thirty-six patients, 23 women and 13 men, with an average age of 76.31 ± 6.28 years were monitored for 17.69 ± 4.70 months. The median surgical duration of single vertebrae was 35 min. The volume of bone cement for single vertebrae was 3.81 ± 0.87 ml and the proportion of sufficient cement distribution of the patients was 97.22. LKA was considerably improved from pre-operation to post-operation and sustained at the last follow-up. SCA and LSCA were not significantly modified between these three-time points. IIA, PCL, and LD were lower on the convex side than on the concave side. POW was considerably wider on the convex side. The ODI and VAS-BP scores were significantly improved after surgery and sustained during the follow-up. Conclusions Combining with the proper assessment of the pre-injured life status of patients, PKP surgery using unilateral puncture on the convex side for the treatment of P-OVCF with scoliosis can achieve safe, excellent clinical, and radiographic outcomes.

Abstract This prospective, non-randomized, comparative study aimed to compare the visual outcomes and patient satisfaction after implantations of three presbyopia-correcting intraocular lenses (IOLs) after myopic refractive surgery. It was conducted from January 2020 to December 2021 in Shanghai Heping Eye Hospital. Patients were divided into three groups based on the type of IOL implanted. The visual acuity, refractive stability, high-order aberrations, objective visual quality, spectacle independence, and visual function index 14 questionnaire scores of the three groups were compared. This study included 78 eyes of 39 patients: 26 eyes with 839MP, 26 eyes with MF30, and 26 eyes with ZXR00. Uncorrected distance visual acuity improved significantly for all three groups. For a pupil diameter of 4.0 mm, the spherical aberrations of the three groups were 0.33 ± 0.16 μ, 0.50 ± 0.08 μ, and 0.39 ± 0.10 μ, respectively. The spectacle independence for distance vision was over 90% in each group; for near vision, it was only 25% for the ZXR00 group. All three types of presbyopia-correcting IOLs improved visual quality in post-LASIK or PRK patients. However, the high incidence of photic phenomena after presbyopia-correcting IOL implantation in patients who have undergone myopic LASIK should not be neglected.

Abstract Background Supracrestal gingival tissue dimensions (SGTDs) has been considered to be an essential element of periodontal phenotype (PP) components. This study aimed to explore the relationship between SGTDs and other PP components by digital superposition method that integrated cone beam computed tomography (CBCT) with intraoral scanning. Methods This cross-sectional study was conducted at the Stomatology Hospital of Fujian Medical University. Participants were recruited based on the inclusion and exclusion criteria. The data obtained from the digital scanner (TRIOS 3, 3Shape, Denmark) and CBCT images were imported into the TRIOS software (Implant Studio, 3Shape, Denmark) for computing relevant parameters. The significant level was set at 0.05. Results A total of 83 participants with 498 maxillary anterior teeth were finally included. The mean values of supracrestal gingival height (SGH) and the distance from the cementoenamel junction (CEJ) to the crest of the alveolar ridge (CEJ-ABC) on the buccal site were significantly higher than palatal SGH (SGH-p) and palatal CEJ-ABC (CEJ-ABC-p). Men exhibited taller CEJ-ABC and SGH-p than women. Additionally, tooth type was significantly associated with the SGH, SGH-p and CEJ-ABC-p. Taller SGH was associated with wider crown, smaller papilla height (PH), flatter gingival margin, thicker bone thickness (BT) and gingival thickness (GT) at CEJ, the alveolar bone crest (ABC), and 2 mm apical to the ABC. Smaller SGH-p displayed thicker BT and GT at CEJ, the ABC, and 2 and 4 mm apical to the ABC. Higher CEJ-ABC showed lower interproximal bone height, smaller PH, flatter gingival margin, thinner GT and BT at CEJ, and 2 mm apical to the ABC. Smaller CEJ-ABC-p displayed thicker BT at CEJ and 2 and 4 mm apical to the ABC. On the buccal, thicker GT was correlated with thicker BT at 2 and 4 mm below the ABC. Conclusion SGTDs exhibited a correlation with other PP components, especially crown shape, gingival margin and interdental PH. The relationship between SGTDs and gingival and bone phenotypes depended on the apico-coronal level evaluated. Trial registration This study was approved by the Biomedical Research Ethics Committee of Stomatology Hospital of Fujian Medical University (approval no. 2023-24).

Abstract In China, traditional medications for osteoporosis have significant side effects, low compliance, and high costs, making it urgent to explore new treatment options. Probiotics have demonstrated superiority in the treatment of various chronic diseases, and the reduction of bone mass in postmenopausal osteoporosis (PMOP) is closely related to the degradation and metabolism of intestinal probiotics. It is crucial to explore the role and molecular mechanisms of probiotics in alleviating PMOP through their metabolites, as well as their therapeutic effects. We aim to identify key probiotics and their metabolites that affect bone loss in PMOP through 16srDNA sequencing combined with non-targeted metabolomics sequencing, and explore the impact and possible mechanisms of key probiotics and their metabolites on the progression of PMOP in the context of osteoporosis caused by estrogen deficiency. The sequencing results showed a significant decrease in Lactobacillus acidophilus and butyrate in PMOP patients. In vivo experiments confirmed that the intervention of L. acidophilus and butyrate significantly inhibited osteoclast formation and bone resorption activity, improved intestinal barrier permeability, suppressed B cells, and the production of RANKL on B cells, effectively reduced systemic bone loss induced by oophorectomy, with butyric acid levels regulated by L. acidophilus. Consistently, in vitro experiments have confirmed that butyrate can directly inhibit the formation of osteoclasts and bone resorption activity. The above research results indicate that there are various pathways through which L. acidophilus inhibits osteoclast formation and bone resorption activity through butyrate. Intervention with L. acidophilus may be a safe and promising treatment strategy for osteoclast related bone diseases, such as PMOP.

Abstract Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Currently, there are no approved treatments that address the underlying genetic cause of this disease, representing a significant unmet need. Mutations in Plakophilin-2 (PKP2), encoding a desmosomal protein, account for approximately 40% of ARVC cases and result in reduced gene expression. Methods Our goal is to examine the feasibility and the efficacy of adeno-associated virus 9 (AAV9)-mediated restoration of PKP2 expression in a cardiac specific knock-out mouse model of Pkp2. Results We show that a single dose of AAV9:PKP2 gene delivery prevents disease development before the onset of cardiomyopathy and attenuates disease progression after overt cardiomyopathy. Restoration of PKP2 expression leads to a significant extension of lifespan by restoring cellular structures of desmosomes and gap junctions, preventing or halting decline in left ventricular ejection fraction, preventing or reversing dilation of the right ventricle, ameliorating ventricular arrhythmia event frequency and severity, and preventing adverse fibrotic remodeling. RNA sequencing analyses show that restoration of PKP2 expression leads to highly coordinated and durable correction of PKP2-associated transcriptional networks beyond desmosomes, revealing a broad spectrum of biological perturbances behind ARVC disease etiology. Conclusions We identify fundamental mechanisms of PKP2-associated ARVC beyond disruption of desmosome function. The observed PKP2 dose-function relationship indicates that cardiac-selective AAV9:PKP2 gene therapy may be a promising therapeutic approach to treat ARVC patients with PKP2 mutations.

In this paper, a novel ultrasonic treatment technique was proposed in nodular cast iron melt with the aim of improving the microstructure and mechanical properties of nodular cast iron. The effects of ultrasound on the microstructures and properties were investigated by comparing experiments with and without ultrasound. The results showed that compared with the NO UT specimen, the mean equivalent diameter of graphite nodules was reduced by 46% in the UT 105 s specimen, while the mean roundness and nodule count per unit area were increased by 33.9% and 43.6%, respectively. In addition, the ultrasonic treatment of melt could increase the pearlite content, refine the matrix microstructure and reduce the pearlite interlamellar spacing from 392.7 nm to 231.3 nm. Compared with the NO UT specimen, the mechanical properties of the UT specimen were improved significantly, and could up to UTS of 739 MPa, YS of 579 MPa and El of 9.4% in the UT 105 s specimen. In this work, the mechanism of ultrasonic action on nodular cast iron also was discussed in detail.

In this study, we describe an Enterobacter ludwigii clinical isolate that is resistant to both carbapenems and colistin in South Korea. Antimicrobial susceptibility testing revealed that E. ludwigii CRE2104-31 was non-susceptible to all tested antibiotics except fosfomycin. Whole genome sequencing identified a 323-kbp IncHI2 plasmid, pCRE2104-31a, that was co-harbouring mobile colistin resistance (mcr)-9.1 and blaIMP-1. In comparison with other full plasmids, pCRE2104-31a exhibited the closest similarity to a plasmid from the Klebsiella pneumoniae strain CNR48 from France, with 19.9% query coverage and 99% identity. Notably, we observed five tandem repeats of blaIMP-1 and aac(6′)-Il genes, accompanied by multiple attCs within a class I integron on the Tn402-like transposon. The unit of blaIMP-1-attC-aac(6′)-Il-attC might have accumulated due to multiple convergent events. In addition to mcr-9.1 and blaIMP-1, various other antibiotic resistance-associated genes were identified in the plasmid, as follows: blaTEM-1B, aph(3′)-I, aph(3′)-Ia, aac(6′)-Il, aac(6′)-IIc, aac(6′)-IIa, aph(6)-Id, aph(3′')-Ib, aadA2b, aac(6′)-Ib3, sul, dfrA19, qnrB2, aac(6′)-Ib-cr, ere(A), and qacE. A conjugation assay showed that the mcr-9.1/blaIMP-1-co-bearing plasmid was self-transmissible to E. coli J53. However, colistin and carbapenem resistance could not be transferred to E. coli due to high incompatibility. The convergence of mcr and carbapenemase genes is thought to be host-dependent among Enterobacteriaceae. The emergence of extensively drug-resistant E. ludwigii co-harbouring MCR-9.1 and a multicopy of blaIMP-1 would pose a significant threat within the compatible Enterobacteriaceae.

Abstract Purpose To compare the rotational stability of a monofocal and a diffractive multifocal toric intraocular lens(IOLs) with identical design and material. Methods This prospective study enrolled patients who underwent plate-haptic toric IOL (AT TORBI 709 M and AT LISA 909 M) implantation. Propensity score matching (PSM) was performed to balance baseline factors. Follow-up examinations were conducted at 1 h, 1 day, 3 days, 1 week, 2 weeks, 1 month, and 3 months postoperatively. A linear mixed model of repeated measures was used to investigate the changes in IOL rotation over time. A 2-week timeframe was utilized to assess differences in IOL rotation between the two groups. Result After PSM, a total of 126 eyes were selected from each group for further analysis. Postoperatively, the time course of IOL rotation change in the two groups remained consistent, with the greatest rotation occurring between 1 h and 1 day postoperatively. At the 2-week postoperative mark, the monofocal toric IOL exhibited a higher degree of rotation compared to the multifocal toric IOL (5.40 ± 7.77° vs. 3.53 ± 3.54°, P = 0.015). In lens thickness(LT) ≥ 4.5 mm and white-to-white distance(WTW) ≥ 11.6 mm subgroups, the monofocal toric IOL rotated greater than the multifocal toric IOL (P = 0.026 and P = 0.011, respectively). Conclusion The diffractive multifocal toric IOL exhibits superior rotational stability compared to the monofocal toric IOL, especially in subgroups LT ≥ 4.5 mm and WTW ≥ 11.6 mm. Moreover, the time course of IOL rotation change is consistent for both, with the maximum rotation occurring between 1 h and 1 day postoperatively.

Abstract Heart failure with preserved ejection fraction (HFpEF) poses therapeutic challenges due to the limited treatment options. Building upon our previous research that demonstrates the efficacy of histone deacetylase 6 (HDAC6) inhibition in a genetic cardiomyopathy model, we investigate HDAC6’s role in HFpEF due to their shared mechanisms of inflammation and metabolism. Here, we show that inhibiting HDAC6 with TYA-018 effectively reverses established heart failure and its associated symptoms in male HFpEF mouse models. Additionally, in male mice lacking Hdac6 gene, HFpEF progression is delayed and they are resistant to TYA-018’s effects. The efficacy of TYA-018 is comparable to a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and the combination shows enhanced effects. Mechanistically, TYA-018 restores gene expression related to hypertrophy, fibrosis, and mitochondrial energy production in HFpEF heart tissues. Furthermore, TYA-018 also inhibits activation of human cardiac fibroblasts and enhances mitochondrial respiratory capacity in cardiomyocytes. In this work, our findings show that HDAC6 impacts on heart pathophysiology and is a promising target for HFpEF treatment.