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Introduction Ovarian hyperstimulation syndrome (OHSS) is the most significant short-term complication of pharmacological ovarian stimulation. Symptoms range from mild abdominal discomfort to rare complications such as renal failure, thromboembolism and respiratory distress syndrome.Currently, clinical practice typically involves monitoring the patient until the condition becomes severe, at which point they are admitted to hospital, where drainage of ascitic fluid (paracentesis) may take place. Preliminary studies have indicated that earlier outpatient paracentesis may reduce the progression of OHSS and prevent hospitalisation in women.Methods and analysis This UK, multicentre, pragmatic, two-arm, parallel-group, adaptive (group sequential with one interim analysis), open-label, superiority, confirmatory, group sequential, individually randomised controlled trial, with internal pilot will assess the clinical and cost-effectiveness and safety of outpatient paracentesis versus conservative management (usual care) for moderate or severe OHSS. 224 women from 20 National Health Service and private fertility units will be randomised (1:1) and followed up for up to 13.5 months. The primary outcome is the rate of OHSS related hospital admission of at least 24 hours within 28 days postrandomisation. The primary analysis will be an intention to treat with difference in hospitalisation rates as measure of treatment effect. Secondary outcomes include time to resolution of symptoms, patient satisfaction, adverse events and cost-effectiveness. A qualitative substudy will facilitate the feasibility of recruitment. Participant recruitment commenced in June 2022.Ethics and dissemination London—Southeast Research Ethics Committee approved the protocol (reference: 22/LO/0015). Findings will be submitted to peer-reviewed journals and abstracts to relevant national and international conferences, as well as being disseminated to trial participants and patient groups.Trial registration number ISRCTN71978064.

The deadliest anaplastic thyroid cancer (ATC) often transforms from indolent differentiated thyroid cancer (DTC); however, the complex intratumor transformation process is poorly understood. We investigated an anaplastic transformation model by dissecting both cell lineage and cell fate transitions using single-cell transcriptomic and genetic alteration data from patients with different subtypes of thyroid cancer. The resulting spectrum of ATC transformation included stress-responsive DTC cells, inflammatory ATC cells (iATCs), and mitotic-defective ATC cells and extended all the way to mesenchymal ATC cells (mATCs). Furthermore, our analysis identified 2 important milestones: (a) a diploid stage, in which iATC cells were diploids with inflammatory phenotypes and (b) an aneuploid stage, in which mATCs gained aneuploid genomes and mesenchymal phenotypes, producing excessive amounts of collagen and collagen-interacting receptors. In parallel, cancer-associated fibroblasts showed strong interactions among mesenchymal cell types, macrophages shifted from M1 to M2 states, and T cells reprogrammed from cytotoxic to exhausted states, highlighting new therapeutic opportunities for the treatment of ATC.

Objectives The study aims to determine the relative importance of key attributes of a novel intrauterine device. The device monitors uterine oxygen, pH and temperature in real time with the aim of improving our understanding and treatment of reproductive disorders.Design A discrete choice experiment was used to elicit preferences in this novel investigative tool. The attributes and levels used in the choice scenarios were length of time using the device (7, 14 or 28 days), information obtained to guide treatment (limited, majority or all cases), risk of complications (1% or 10%) and discreteness (completely discrete, moderately discrete or indiscrete).Setting Secondary care hospital in Hampshire, UK.Participants 361 women of reproductive age.Primary and secondary outcome measures Conditional logit and latent class logit regression models to determine the preference for each attribute.Results Conditional logit coefficients allow comparison between attributes; women placed most importance on obtaining information to guide treatment in all cases (2.771), followed by having a completely discrete device (1.104), reducing risk of complications by 1% (0.184) and decreased length of time by 1 day (0.0150). All coefficients p

Abstract ALS (Amyotrophic Lateral Sclerosis) is a neurodegenerative disease characterized by the redistribution of the RNA binding protein TDP-43 in affected neurons: from predominantly nuclear to aggregated in the cytosol. However, the determinants of TDP-43 localization and the cellular insults that promote redistribution are incompletely understood. Here, we show that the putative Nuclear Export Signal (NES) is not required for nuclear egress of TDP-43. Moreover, when the TDP-43 domain which contains the putative NES is fused to a reporter protein, YFP, the presence of the NES is not sufficient to mediate nuclear exclusion of the fusion protein. We find that the previously studied “∆NES” mutant, in which conserved hydrophobic residues are mutated to alanines, disrupts both solubility and splicing function. We further show that nuclear export of TDP-43 is independent of the exportin XPO1. Finally, we provide evidence that nuclear egress of TDP-43 is size dependent; nuclear export of dTomato TDP-43 is significantly impaired compared to Flag TDP-43. Together, these results suggest nuclear export of TDP-43 is predominantly driven by passive diffusion.

Abstract. Emerging evidence suggests that dysbiosis of the gut microbiota is associated with the pathogenesis of Parkinson’s disease (PD), a prevalent neurodegenerative disorder. The microbiota–gut–brain axis plays a crucial role in the development and progression of PD, and numerous studies have demonstrated the potential therapeutic benefits of modulations in the intestinal microbiota. This review provides insights into the characterization of the gut microbiota in patients with PD and highlights associations with clinical symptoms and underlying mechanisms. The discussion underscores the increased influence of the gut microbiota in the pathogenesis of PD. While the relationship is not fully elucidated, existing research demonstrates a strong correlation between changes in the composition of gut microbiota and disease development, and further investigation is warranted to explain the specific underlying mechanisms.

Abstract Global warming has profound effects on precipitation patterns, leading to more frequent and extreme precipitation events over the world. These changes pose significant challenges to the sustainable development of socio-economic and ecological environments. This study evaluated the performance of the new generation of the mesoscale Weather Research and Forecasting (WRF) model in simulating long-term extreme precipitation events over the Minjiang River Basin (MRB) of China from 1981 to 2020. We calculated 12 extreme precipitation indices from the WRF simulations and compared them with observations. The spatio-temporal variations of extreme precipitation were further analyzed in terms of intensity, frequency, and duration. The results indicated that the WRF model can appropriately reproduce the spatial distribution of extreme precipitation indices with acceptable biases. The performance is significantly better for intensity and frequency indices compared to duration indices. Except for PRCPTOT and R10mm, WRF accurately captures the interannual variations of extreme precipitation. Meanwhile, the results of the pre-whitening Mann-Kendall (PWMK) test suggested that WRF can identify significant increasing trends in extreme precipitation, particularly for R95p, R99p, and R50mm. This study provides valuable insights for extreme precipitation forecasting and warning in other mountainous regions.

Abstract Acute pancreatitis (AP) is a severe gastrointestinal condition with an increasing incidence of hyperlipidemic etiology. The investigation employed a two-sample, bidirectional Mendelian randomization method to investigate potential causal relationship between lipidome profiles, inflammatory mediators, and AP. Exploration of genetic variants across the genome in a study population of 10,630 AP cases and 844,679 non-AP individuals revealed multiple lipidome entities significantly associated with AP risk. The study identified 23 lipid species with unidirectional causal effects on AP after accounting for heterogeneity, pleiotropy, and potential reverse causation. Additionally, five inflammatory factors (CD5, IL-13, MMP-1, STAMBP, TNFRSF9) showed significant potential causal relationship with AP. Further analysis elucidated the intricate interplay between specific lipid species and inflammatory mediators in influencing AP incidence. Notably, Sterol ester (27:1/20:4) and several phosphatidylcholine species, including PC (17:0_20:4), PC (18:0_20:4), PC (18:0_20:5), and PC (O-18:2_20:4), were negatively associated with AP risk. This protective effect was partially mediated through decreased levels of inflammatory markers, particularly STAMBP and MMP-1. The study found that these phosphatidylcholines and sterol esters significantly reduced the levels of these pro-inflammatory factors, thereby potentially mitigating AP risk. Conversely, Phosphatidylinositol (16:0_18:1) demonstrated a positive association with AP risk. This detrimental effect was partially mediated by increased levels of MMP-1 and STAMBP, suggesting a pro-inflammatory mechanism. The study provides evidence that this specific phosphatidylinositol species may exacerbate AP risk by promoting inflammatory pathways. These findings elucidate the complex interplay between lipid metabolites, inflammation, and AP pathogenesis, potentially informing novel therapeutic strategies. The study highlights the utility of Mendelian randomization in uncovering potential causal relationship in AP. It underscores the requirement for further study into the molecular mechanisms underlying lipid-mediated inflammation in AP, particularly the roles of phosphatidylcholines and sterol esters in modulating inflammatory responses. Further studies are warranted to confirm our observations in laboratory models and assess their translational value in developing AP preventive and therapeutic strategies.

Abstract Extraskeletal osteosarcoma (ESOS) is a very rare malignant tumor. This study aimed to provide more evidence about the natural history and clinical features of ESOS, and clarify the impact of chemotherapy (CT) and radiotherapy (RT) on patient survival and postoperative recurrence for the sake of gaining a better understanding about the disease. Patient/tumor characteristics, recurrence, treatment, and follow-up durations were collected by searching studies in PubMed, Web of Science, Ovid, Elsevier, SpringerLink, Chinese National Knowledge Infrastructure (CNKI), and WAN FANG Data before June 30, 2023. Data were analyzed by SPSS-26. Altogether 1287 patients diagnosed with ESOS were retrieved from the literature. Of them, follow-up data were available in 981 patients, in whom 78 patients (7.6%) had metastases and 730 patients (74.5%) had localized disease at the time of diagnosis. Of the 730 patients with localized disease, 682 (93.4%) received surgical resection. The 5-year OS in all 981 patients, 78 metastatic patients, and 682 patients with localized disease was 33.40%, 4.9% and 41.1%, respectively. Of the 682 surgical patients, 367 patients underwent surgical resection alone, 170 received surgical resection + CT, 82 patients received surgical resection + RT, and 58 patients received both adjuvants. In addition, 348 (51%) of the 682 patients developed recurrence, including local recurrence (n = 102), metastasis (n = 130), and both (n = 116). Univariate analysis of 5-year PFS and 5-year OS showed that age, tumor size, CT, metastasis, and local recurrence were significant prognostic factors in the 682 patients with localized disease. There was no significant difference in 5-year OS between osteosarcoma-type and soft tissue-type regimens (P = 0.273). Multivariate analysis of 431 patients showed that postoperative recurrence and metastasis were significant prognostic factors for survival, and CT was not a significant prognostic factor, though CT decreased the incidence of local recurrence in ≤ 45-year age group (P = 0.047). RT reduced the incidence of local recurrence in patients ≤ 45years (P = 0.035) and patients with tumors > 5 cm (P = 0.044). So, we recommend that CT should be used for patients aged ≤ 45years, and RT can be used for patients ≤ 45years or those with tumors > 5 cm for the sake of decreasing the incidence of local recurrence, which we believe would indirectly benefit the survival of ESOS patients.

Abstract A switching active disturbance rejection control (SADRC) strategy was proposed to solve the composite disturbance challenge arising from gap, LuGre friction, hydraulic spring force, and external load disturbance in the double closed-loop digital hydraulic cylinder position control system. Firstly, leveraging the established mathematical model of the double closed-loop digital hydraulic cylinder, the high-order state equation was derived. Subsequently, the high-order double closed-loop digital hydraulic cylinder control system was transformed into a second-order integral series control system using ADRC strategy. Given the pronounced nonlinear characteristics of double closed-loop digital hydraulic cylinders, combined with the characteristics of switching control, a SADRC strategy was proposed, and the stability of the closed-loop system was proved based on Lyapunov theory and switching rules. Finally, the effectiveness of the proposed control method was verified through simulation and experiment. Results indicate that the system's response speed employing the SADRC strategy outperforms the PID control strategy by 32.56%, with a 2.0% reduction in error. The average error in the response speed of the digital hydraulic cylinder and the MATLAB simulation value of the tracking error are 9.0% and 1.50% respectively. Notably, the simulation and experimental results exhibit a consistent overall trend, affirming the feasibility and effectiveness of the control strategy.

Abstract Background This study investigates the career mobility and employment status of Chinese pharmacy graduates, aiming to address workforce challenges and career planning within the pharmacy profession. Given the rapid expansion of the healthcare sector in China, understanding factors influencing job changes and career decisions is crucial for ensuring workforce stability and professional development. The study covers pharmacy graduates enrolled at Kunming Medical University from 1996 to 2012. Methods A cross-sectional online survey collected data from 231 respondents in April 2022, focusing on demographic characteristics, career choices, job changes, and the factors influencing these decisions. Multivariate logistic regression and Chi-square (χ²) tests were used to analyze the data, with a particular focus on the pharmacy practice, pharmaceutical sciences, and clinical pharmacy. Results Of the 231 respondents, 52.4% (n = 121) had never changed jobs, and 32.5% (n = 75) had changed jobs once or twice. The majority preferred working in governmental institutions (n = 146, 63.2%), with fewer graduates choosing domestic (n = 48, 20.8%) or overseas pharmacy enterprises (n = 20, 8.7%). Income and personal growth were significant factors influencing job changes (p

Abstract Elevated progesterone (EP) or inadequate progesterone levels during ART cycle monitoring may lead to cycle cancellations or further progesterone supplementation, but practice varies. It remains controversial whether modifying clinical practice in the presence or absence of EP improves clinical outcomes. This systematic review aims to investigate if progesterone levels at different phases of fresh and frozen ART cycles influence pregnancy outcomes, in particular, that pertaining to day 3 versus day 5 embryo transfers. A systematic search of EMBASE, MEDLINE, CINAHL, PubMed, SCOPUS and Web of Science identified studies from the year 2000. We included studies with women undergoing fresh and frozen IVF/ICSI cycles; with extractable per woman data on pregnancy outcomes where serum progesterone measurement was performed. We excluded interventional studies that influence clinical decisions or studies with donor cycles. The Newcastle Ottawa Scale (NOS) was used to determine the risk of bias. The primary outcome was LBR, and the secondary outcomes were OPR, CPR and MR. PICOS study protocol was used to include non-randomized studies of interventions (NRSI). Analysis was done using RevMan5 and the studies were pooled using the DerSimonian and Laird for random effects meta-analysis. The study was registered with PROSPERO (registration ID CRD42022382423). 64 studies (N = 57,988 women) were included. In fresh cycles, there is no evidence that at baseline EP impacts LBR (P > 1.5 ng/ml, OR 0.76 [95% CI 0.39–1.49], 2 studies, N = 309) and CPR (P > 1.5 ng/ml, OR 0.81 [0.38–1.71], 2 studies, N = 309). EP at ovulation trigger is associated with a lower LBR (P > 1.0 ng/ml, OR 0.40 [0.23–0.69], 2 studies, N = 2805) and CPR (P > 1.0 ng/ml, OR 0.49 [0.42–0.58], 3 studies, N = 3323; P > 1.1 ng/ml, OR 0.66 [0.53–0.83], 2 studies, N = 2444; P > 1.2 ng/ml, OR 0.61 [0.39–0.96], 6 studies, N = 844; P > 1.5 ng/ml, OR 0.37 [0.17–0.81], 6 studies, N = 13,870; P > 2.0 ng/ml, OR 0.43 [0.31–0.59], 3 studies, N = 1949) with D3 embryo but not D5 [LBR (P > 1.5 ng/ml, OR 1.02 [0.74–1.39], 3 studies, N = 5174) and CPR (P > 1.5 ng/ml, OR 0.88 [0.67–1.14], 6 studies, N = 5705)]. We could not meaningfully meta-analyse studies on the day of egg collection in fresh cycles, embryo transfer in fresh cycles, at ovulation trigger or before ovulation in natural FET cycles and FET cycles due to significant study heterogeneity. We acknowledged the limitations on including studies post year 2000 and the exclusion of studies with multiple observations, which may result in inherent publication bias and some confounding factors uncontrolled for. In conclusion, in controlled ovarian stimulation, EP at baseline did not impact on LBR; EP at ovulation trigger is associated with a lower LBR for D3 but not for D5 embryo transfer. In FET cycles, as the studies were heterogeneous, we were unable to combine the data in a meaningful way. This review is sponsored by Complete Fertility and the Ministry of Health, Malaysia.

Abstract Congenital radioulnar synostosis (CRUS) presents a complex forearm deformity, requiring precise osteotomy planning for anatomical restoration. This study proposes an automatic osteotomy preoperative planning method for forearms with CRUS. Proximal forearm bones are first aligned with the template forearm and then a dual dimensional optimization (DDO) strategy is used to optimize the spatial transformation parameters of the distal fragment. The subsequent optimization aims to maximize the overlap of cross-sections between proximal and distal fragments. Rotational simulations are ultimately conducted to predict postoperative forearm rotational functionality. The DDO strategy effectively restores ideal forearm morphology, with maximum deviations of 1.66 and 2.13 mm for the ulna and radius, respectively. On the coronal, sagittal and transverse planes, the deformity angles of the radius were reduced to 1.35°, 1.39°, 4.83°, respectively, while those of the ulna were reduced to 1.20°, 1.03°, and 8.56°, respectively. Rotation function analysis reveals a noticeable improvement in achievable rotation range compared to plans by senior surgeons. Automated mobilization osteotomy planning, using the DDO strategy, shows potential for individualized CRUS corrective surgery, offering comprehensive and precise preoperative guidance.

Abstract Intracardiac echocardiography (ICE) has been used to guide radio-frequency catheter ablation (RFCA) for better catheter navigation and less radiation exposure in treating atrial fibrillation (AF). This retrospective cohort study enrolled 227 AF patients undergoing ICE- or traditional fluoroscopy (TF)-guided RFCA for AF in a tertiary hospital. ICE was used more often in patients with atrial tachycardia [odds ratio (OR) 3.692, p = 0.062], a higher score of Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol concomitantly (OR 1.541, p = 0.050), or heart failure (OR 2.098, p = 0.156). Based on the comparisons of 47 propensity score-matched pairs from 156 patients only undergoing pulmonary vein isolation (PVI), patients using ICE exhibited a significantly higher success rate in the first transseptal puncture (100% vs. 87.2%, p = 0.041) and less radiation exposure [utilization of radiographic contrast agent (2.7 ml vs. 6.0 ml, p

Abstract Fatigue cracking of rib-to-deck conventional single-sided welded joints is a prevalent issue in orthotropic steel decks (OSDs), significantly impacting their structural integrity and durability. Rib-to-deck innovative double-sided welded joints have the potential to enhance the fatigue resistance of OSD. However, Welding Residual Stresses (WRS) significantly influence the fatigue life of these joints, mandating its consideration in fatigue assessments. This study introduces a novel approach for assessing the fatigue reliability of rib-to-deck double-sided welded joints in OSDs, accounting for the effects of traffic vehicle loading and WRS. Initially, a comprehensive fatigue damage equation for welded joints of OSDs was formulated, integrating WRS and dynamic vehicle loads, utilizing fracture mechanics theory. Subsequently, a measurement-based random traffic model was utilized to derive the vehicle-induced stress spectra at the welded joints. The effects of deck thickness, fatigue crack depth and fatigue crack aspect ratio on the stress intensity factor (SIF) of the crack at the weld toe were analyzed. These three variables were considered as feature vectors for the construction of a polynomial model of the shape functions, which was utilized to calculate the SIF. Finally, the fatigue reliability of the rib-to-deck double-sided welded joints in OSDs subject to traffic vehicle loading considering the WRS was estimated using Monte Carlo simulation. The influence of traffic volume growth on fatigue reliability was discussed. This research underscores the critical role of WRS in the fatigue performance of welded joints in OSDs and offers an innovative framework for assessing the fatigue reliability of steel bridge welds.

Abstract A randomized double-blind phase 3 trial (CHOICE-01, NCT03856411) demonstrated that combining toripalimab with chemotherapy substantially improves progression-free survival (PFS) in advanced non-small cell lung cancer (NSCLC) patients without pretreatment. This study presents the prespecified final analysis of overall survival (OS) and biomarkers utilizing circulating tumor DNA (ctDNA) and tissue-based sequencing. Additionally, the analysis revealed a higher median overall survival (OS, 23.8 months) in the toripalimab group than that in the control group (17.0 months). (HR = 0.69, 95%CI: 0.57–0.93, nominal P = 0.01). This survival benefit was particularly notable in the non-squamous subgroup. As the first phase 3 study to perform both baseline tissue whole-exome sequencing (WES) and peripheral blood ctDNA testing, we investigated efficacy predictive biomarkers based on both tissue and ctDNA, Genomic sequencing of ctDNA showed high concordance with tumor tissue independently confirmed that individuals exhibiting a high tumor mutational burden, as well as mutations in the FA-PI3K-Akt and IL-7 signaling pathways benefited more from the toripalimab treatment. Furthermore, a ctDNA response observed on cycle 3 day 1, was associated with improved clinical outcomes for patients treated with the combination therapy. In conclusion, Toripalimab plus chemotherapy yields significant improvements in OS as a first-line treatment. The study highlights the utility of ctDNA as a proxy for tumor tissue, providing novel prospects for predicting efficacy of immuno-chemotherapy through continuous ctDNA monitoring.

Abstract Chemotherapy-induced neuropathic pain (CINP) is a prevalent side effect of chemotherapy. Total glucosides of paeony (TGP) have been shown to be effective in pain management. This study aimed to investigate the efficacy and mechanism of TGP in alleviating CINP. Sprague–Dawley rats were treated with oxaliplatin to establish CINP models, and BV2 microglia were exposed to lipopolysaccharides (LPS) to induce pyroptosis. The impact of TGP on CINP was assessed by measuring mechanical withdrawal threshold (MWT), cold pain threshold (CPT), and thermal pain threshold (TPT), as well as inflammatory factor levels. Pyroptosis was evaluated using flow cytometry, lactate dehydrogenase (LDH) release, and pyroptosis marker levels. Quantitative real-time PCR and molecular docking were employed to identify TGP targets, while phospho-kinase arrays, western blotting, and co-immunoprecipitation were used to elucidate the mechanism. Results indicated that TGP increased MWT, CPT, and TPT and inhibited inflammatory factor release in CINP rats. Furthermore, TGP suppressed LPS-induced pyroptosis and downregulated KAT2A expression in BV2 cells; this suppression was reversed by KAT2A overexpression. Mechanistically, KAT2A overexpression activated the p38 pathway and promoted p38 succinylation at K295. KAT2A knockdown inhibited pyroptosis in LPS-induced BV2 cells, an effect that was reversed by the p38 activator metformin. Additionally, the improvements in MWT, CPT, TPT, and inflammatory factor levels observed in CINP rats treated with TGP were negated by KAT2A overexpression. In conclusion, TGP alleviated CINP by suppressing microglial pyroptosis through inhibition of the KAT2A-mediated p38 pathway activation and succinylation. This study provides insights into a potential new therapeutic approach for CINP.

Abstract Sacubitril/valsartan, a first-in-class angiotensin receptor neprilysin inhibitor, is widely used to treat heart failure. Despite its efficacy, sacubitril/valsartan inevitably causes adverse events such as hypotension, renal dysfunction, hyperkalemia, and angioedema. Sacubitril/valsartan-associated ototoxicity is often underreported in clinical studies and real-world settings. This study aimed to systematically characterize ototoxicity profiles using post-marketing data. Disproportionality analysis was performed using the Food and Drug Administration Adverse Event Reporting System (FAERS) database from 2015 to 2023. The reporting odds ratio (ROR) and information components (IC) were used to detect potential ototoxicity associated with sacubitril/valsartan. Significant signals were defined as ROR025 > 1 and IC025 > 0 in at least three reports. From 272,790 reports on sacubitril/valsartan and 10,798 (4.0%) reports on ototoxicity, sacubitril/valsartan and ototoxicity showed significant association (IC025 = 1.57; ROR025 = 2.99). Dizziness, hypoacusis, balance disorder, and deafness were detected as positive signals; hypoacusis was the strongest (IC025 = 3.21; ROR025 = 9.29). Median time to onset was 45 (10–99) days, and 62.4% of ototoxicity events occurred within 90 days of sacubitril/valsartan administration. Hospitalization accounted for 32.5% of ototoxic outcomes, while life-threatening events, death, and disabling accounted for only 3.9%, 3.4%, and 2.0%, respectively. Sacubitril/valsartan treatment increased ototoxicity risks. Therefore, promptly identifying and treating sacubitril/valsartan-related ototoxicity is critical.

Abstract Background Severe acute pancreatitis (SAP) is a life-threatening condition that can require invasive mechanical ventilation (IMV) to ensure adequate oxygenation and ventilation. However, IMV can cause delirium, a temporary and fluctuating state of consciousness disorder, which negatively impacts patient outcomes. Perphenazine, an antipsychotic drug that blocks dopamine receptors, can alleviate symptoms such as irritability and restlessness that caused by delirium. This retrospective study aimed to identify risk factors associated with delirium in SAP patients after extubation and withdrawal from IMV, and to determine whether prophylactic use of perphenazine could reduce the incidence of delirium. Methods A total of 40 patients with SAP aged 18–75 years who underwent IMV and were successfully extubated offline after treatment were included. Perphenazine was used consistently 2 mg q12 h for 2 days before extubation. The assessment of delirium began after the removal of the endotracheal tube, using Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) every 12 h. Patients were divided into delirium (n = 9) and non-delirium (n = 31) groups or perphenazine (n = 22) and non-perphenazine (n = 18) groups. The clinical data of patients upon admission and after extubation between groups were analyzed using SPSS 26 software. Binary logistic regression was used to evaluate the risk factors for delirium. Results Patients with a mean age of 42 years and a male to female ratio of 1.58:1 were enrolled. The incidence of delirium was 22.50%. Univariate analysis (P = 0.025) and binary logistic regression (P = 0.035, 95%CI 0.002–0.762) showed that prophylactic use of perphenazine reduced the incidence of delirium. Fentanyl use was a risk factor for delirium in the univariate analysis (P = 0.039). Patients in the delirium group were hospitalized longer than those in the non-delirium group (P

Abstract Circular RNAs (circRNAs) have garnered attention for their potential involvement in the regulation of cellular aging processes. Exploring the role and mechanism of circRNAs in cellular senescence may help to identify new anti-aging therapeutic targets. In the present study, we investigated the role and regulatory mechanism of hsa_circ_0127071 in renal aging. We employed high-throughput sequencing to assess circRNA expression differences in kidney tissues from young and old groups. qRT-PCR confirmed that the expression of hsa_circ_0127071 in kidney tissue of the old group was significantly higher than that of the young group. Cellular senescence was evaluated using SA-β-Gal staining and Masson’s trichrome staining. Using RNA Immunoprecipitation (RIP), RNA Pull-Down Assay (RNA pull down), and Western Blot (WB) to study the interaction between hsa_circ_0127071 and aging related pathway proteins. In this study, we found that the expression of hsa_circ_0127071 in kidney tissue of the old group was significantly higher than that of the young group. Silencing of EIF4A3, a protein involved in the JAK2/STAT5 signaling pathway, was found to delay the aging process. On the basis of silencing EIF4A3 expression, the JAK2/STAT5 signaling pathway was activated by Erythropoietin (EPO) processing, and the senescence of Human glomerular mesangial cells (HGMCs) increased. After treatment with Losartan (LOS), the activity of JAK2/STAT5 pathway was decreased and the aging process of HGMCs was delayed. Our findings demonstrate that hsa_circ_0127071 promotes renal aging through the EIF4A3/JAK2/STAT5 signaling axis, highlighting a novel potential therapeutic target for the management of renal aging and associated disorders.

Abstract Selective Harmonic Elimination Pulse Width Modulation (SHEPWM) has excellent harmonic characteristics, but its nonlinear transcendental system of equations is difficult to be solved, and the practical application encounters a bottleneck. In this paper, a modulation optimization method for seven-level SHEPWM inverter based on the Evolutionary Particle Swarm Optimization (EPSO) algorithm is proposed to address this problem, so that the algorithm quickly converges to the global optimum solution. The EPSO algorithm incorporates a population optimization strategy in two phases to improve the population diversity in real time. In the initialization phase, the initialized population is optimized using Opposition-Based Learning (OBL) to improve the quality of the initial population. In the iterative stage, we combine the adaptive Particle Swarm Optimization (PSO) algorithm, Tunicate Swarm Algorithm (TSA), Adaptive Gaussian Variation, Quasi-Opposition-Based Learning (QOBL) and other optimization methods to solve the problem of insufficient population diversity in the process of searching for the optimal solution, to break through the local optimum, and to improve the convergence speed and accuracy of the algorithm. Experiments of the algorithm in 19 benchmark functions and seven-level SHEPWM inverter optimization modulation show that the optimization ability of the EPSO algorithm is ahead of TSA, INFO, MA (Mayfly Algorithm), EO (Equilibrium Optimizer) and other optimization algorithms. The solution speed is about three times that of PSO, which achieves fast and highly accurate convergence, with a small error in the output of inverter, and better harmonic distortion rate than the standard requirement.

Abstract Background The global outbreak of the coronavirus disease 2019 (COVID-19) has been enormously damaging, in which prolonged shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously 2019-nCoV) infection is a challenge in the prevention and treatment of COVID-19. However, there is still incomplete research on the risk factors that affect delayed shedding of SARS-CoV-2. Methods In a retrospective analysis of 56,878 hospitalized patients in the Fangcang Shelter Hospital (National Convention and Exhibition Center) in Shanghai, China, we compared patients with the duration of SARS-CoV-2 viral shedding > 12 days with those days

Abstract Previous studies have pointed to a potential link between Obstructive Sleep Apnea (OSA) and gastrointestinal diseases, suggesting that this relationship might be influenced by the presence of Metabolic Syndrome. However, the exact role of these factors in determining gastrointestinal diseases has not been thoroughly explored. In our study, we utilized data from the Genome-wide Association Studies (GWAS) database, focusing on OSA, metabolic syndrome characteristics such as Body Mass Index (BMI), waist circumference, triglycerides, cholesterol, hypertension, type 2 diabetes, and common gastrointestinal diseases including chronic gastritis, gastric ulcers, irritable bowel syndrome, colorectal cancer, inflammatory bowel disease, cholecystitis, nonalcoholic fatty liver, and dyspepsia. By applying Single-variable and Multi-variable Mendelian randomization methods, we aimed to assess the correlation between OSA and gastrointestinal diseases and investigate whether this correlation is influenced by metabolic syndrome. Our findings revealed a strong association between OSA and an increased risk of chronic gastritis, gastric ulcers, inflammatory bowel disease, and nonalcoholic fatty liver disease. No significant connections were found with irritable bowel syndrome, colorectal cancer, cholecystitis, or dyspepsia. Additionally, OSA was linked to metabolic syndrome traits like BMI, waist circumference, triglycerides, hypertension, and type 2 diabetes. Further analysis showed that BMI, triglycerides, and hypertension were causally related to inflammatory bowel disease; BMI, waist circumference, hypertension, and type 2 diabetes to nonalcoholic fatty liver disease; and triglycerides, hypertension, and type 2 diabetes to chronic gastritis. The multivariable analysis indicated that hypertension mediates the relationship between OSA and chronic gastritis; BMI, triglycerides, and hypertension mediate the link between OSA and inflammatory bowel disease; and waist circumference mediates the connection between OSA and nonalcoholic fatty liver disease. To wrap up, this finding helps us understand how these issues might be related and stresses the role of metabolic syndrome in preventing them, which could lessen their effect on health.

Abstract In this study, peripheral whole blood samples from 22 hospitalized patients and 10 healthy individuals were analyzed using a combination of Data Independent Acquisition (DIA) and Enzyme-Linked Immunosorbent Assay (ELISA) techniques to identify differentially expressed proteins (DEPs) in sepsis patients’ plasma. The aim was to provide accurate and detailed biomarkers, such as SPP1, for determining the pathological stages of sepsis. SPP1, known as osteopontin1 is a pleiotropic protein with a wide distribution and multifunctional effects. Its protein expression is associated with inflammatory changes, including variations in expression levels in infectious diseases, allergic diseases, and situations involving tissue damage. The registration number was ChiCTR1900021261.The full date of first registration year is 2018. In the affiliated hospital of southwest medical university, 22 sepsis patients were hospitalized from January 2019 to September 2020 and 10 normal healthy individuals were selected for DIA-based quantitative proteomics analysis. In addition to gene ontology analysis and Kyoto Encyclopedia of genes and genomes analysis, enrichment analysis of data was performed and target protein network was screened through joint protein–protein interaction and visualization techniques. The selected protein targets were then validated by Elisa kit. The software was used to analyze the differences comparing the control group to the sepsis group and the sepsis group, as well as between sepsis survivals and non-survivals, and a ROC curve was drawn to evaluate the diagnostic value and prognostic effect of the method of the corresponding target proteins. A total of 174 DEPs were screened by bioinformatics analysis. An analysis of go pathway enrichment revealed the following: These proteins were mainly involved in biological processes among them are the inflammation response, the metabolism of extracellular matrix, the secretion of cell secretions, the activation of cells, and the immune response. According to the Kegg pathway analysis, they were mainly involved in complement cascade polymerization, extracellular protease and glycosylase activation, protein synthesis process, biotin metabolism, leukocyte transmembrane migration, bacterial infection and phagosome formation. SPP1 was identified as a possible plasma biomarker and was therefore further validated using Elisa. As a result of experiments, it has been demonstrated that level in sepsis patients is significantly compared to the normal control group and the level is also higher in non-survivals of sepsis. The ROC curve can be used to see that it can diagnose sepsis more accurately and improve prognostic ability prediction. Cell experiments confirm that SPP1 is highly expressed in sepsis. There is a significant difference in the levels of SPP1 protein between the normal group and the sepsis group; it not only has good diagnostic significance for sepsis, but also provides corresponding reference value for patient prognosis; Therefore, it is more likely to become a biological marker of sepsis over time.

Abstract This study aimed to characterize the role of female sex in the pathogenesis of diabetic retinopathy. In the retinae of female Ins2Akita-diabetic mice (F-IA), ovariectomized female Ins2Akita-diabetic mice (F-IA/OVX), male Ins2Akita-diabetic mice (M-IA), and female STZ-diabetic mice (F-STZ), the formation of reactive metabolites and post-translational modifications, damage to the neurovascular unit, and expression of cellular stress response genes were analyzed. Compared to the male diabetic retina, the concentrations of the glycation adduct fructosyl-lysine, the Maillard product 3-deoxyglucosone, and the reactive metabolite methylglyoxal were significantly reduced in females. In females, there was also less evidence of diabetic damage to the neurovascular unit, as shown by decreased pericyte loss and reduced microglial activation. In the male diabetic retina, the expression of several members of the crystallin gene family (Cryab, Cryaa, Crybb2, Crybb1, and Cryba4) was increased. Clinical data from type 1 diabetic females showed that premenopausal women had a significantly lower prevalence of diabetic retinopathy compared to postmenopausal women stratified for disease duration and glycemic control. These data emphasize the importance of estradiol in protecting the diabetic retina and highlight the pathogenic relevance of sex in diabetic retinopathy.

Abstract Proteasome inhibition emerges as a promising strategy for cancer prevention. PNO1, pivotal for colorectal cancer (CRC) progression, is involved in proteasome assembly in Saccharomyces cerevisiae. Hence, we aimed to explore the role of PNO1 in proteasome assembly and its up- and down-streams in CRC. Here, we demonstrated that PNO1 knockdown suppressed CRC cells growth, proteasome activities and assembly, as well as CDKN1B/p27Kip1 (p27) degradation. Moreover, p27 knockdown partially attenuated the inhibition of HCT116 cells growth by PNO1 knockdown. The up-stream studies of PNO1 identified miR-326 as a candidate miRNA directly targeting to CDS-region of PNO1 and its overexpression significantly down-regulated PNO1 protein expression, resulting in suppression of cell growth, decrease of proteasome activities and assembly, as well as increasing the stability of p27 in CRC cells. These findings indicated that miR-326 overexpression can suppress CRC cell growth, acting as an endogenous proteasome inhibitor by targeting PNO1.

Abstract Background Chimeric antigen receptor (CAR)-NK cell therapy has shown remarkable clinical efficacy and safety in the treatment of hematological malignancies. However, this efficacy was limited in solid tumors owing to hostile tumor microenvironment (TME). Radiotherapy is commonly used for solid tumors and proved to improve the TME. Therefore, the combination with radiotherapy would be a potential strategy to improve therapeutic efficacy of CAR-NK cells for solid tumors. Methods Glypican-3 (GPC3) was used as a target antigen of CAR-NK cell for hepatocellular carcinoma (HCC). To promote migration towards HCC, CXCR2-armed CAR-NK92 cells targeting GPC3 were first developed, and their cytotoxic and migration activities towards HCC cells were evaluated. Next, the effects of irradiation on the anti-tumor activity of CAR-NK92 cells were assessed in vitro and in HCC-bearing NCG mice. Lastly, to demonstrate the potential mechanism mediating the sensitized effect of irradiation on CAR-NK cells, the differential gene expression profiles induced by irradiation were analyzed and the expression of some important ligands for the NK-cell activating receptors were further determined by qRT-PCR and flow cytometry. Results In this study, we developed CXCR2-armed GPC3-targeting CAR-NK92 cells that exhibited specific and potent killing activity against HCC cells and the enhanced migration towards HCC cells. Pretreating HCC cells with irradiation enhanced in vitro anti-HCC effect and migration activity of CXCR2-armed CAR-NK92 cells. We further found that only high-dose (8 Gy) but not low-dose (2 Gy) irradiation in one fraction could significantly enhanced in vivo anti-HCC activity of CXCR2-armed CAR-NK92 cells. Irradiation with 8 Gy significantly up-regulated the expression of NK cell-activating ligands on HCC cells. Conclusions Our results indicate the evidence that irradiation could efficiently enhance the anti-tumor effect of CAR-NK cells in solid tumor model. The combination with radiotherapy would be an attractive strategy to improve therapeutic efficacy of CAR-NK cells for solid tumors.

Abstract The relationship between albumin-corrected anion gap (ACAG) and severe disorder of consciousness (SDOC), in-hospital mortality, and long-term mortality in patients with ischemic stroke (IS) remains unclear. This study investigates the association of ACAG with SDOC and other outcomes in IS using data from the MIMIC-IV database. A total of 2,379 IS patients were included, with a demographic breakdown showing 51% were male and an SDOC incidence of 16.4%. Analysis through Cox proportional hazards models indicated that ACAG is significantly associated with the risks of both SDOC and mortality. Additionally, restricted cubic spline(RCS) analysis suggested a nearly linear relationship between increasing ACAG levels and the incidence of SDOC. Kaplan-Meier curves demonstrated significant differences in the incidence rates of SDOC, in-hospital mortality, and long-term mortality across varying ACAG levels. The findings suggest that ACAG serves as an independent predictor for SDOC, in-hospital mortality, and long-term mortality in IS patients. Nonetheless, further prospective studies are needed to confirm these causal relationships.

Abstract Intestinal stem cells (ISCs) are responsible for intestinal homeostasis and are important for the regeneration of damaged intestine. We established an ionizing radiation (IR)-induced intestinal injury model and observed that Gelsolin KO mice had increased radiosensitivity. The deletion of Gelsolin aggravated intestinal damage and reduced the number of ISCs after lethal IR. The intestinal organoid experiments showed that Gelsolin deletion inhibited ISCs function after IR. Notably, RNA sequencing and RT-PCR results showed IL-17 signaling pathway was down-regulated and Th17 cells differentiation was inhibited in Gelsolin KO mice. Moreover, recombinant IL-17 A ameliorated IR-induced intestinal injury and promoted ISCs regeneration. To figure out the role of Gelsolin in Th17 cells differentiation, flow cytometry was used and we found that Gelsolin targets Th17 cells functionality via the p-STAT3/RORγt axis. By establishing the co-culture system, we proved that Th17 cells promoted self-renewal and budding abilities in Gelsolin-deficient organoids. Finally, we found that Gelsolin was protective against DSS-induced colitis and that this protective effect was not specific or limited to the IR induced intestinal injury model. Based on these results, we proved Gelsolin maintained the regeneration of ISCs by sustaining Th17 cells functions via the p-STAT3/RORγt axis. Graphical abstract

Abstract Background The pathogenic causes of primary gout include urate overproduction and/or renal or extra-renal urate underexcretion. The aim of this study was to evaluate the association of gout subtypes with the response to low-purine diet (LPD). Methods This is a single-center prospective clinical study. Gout patients visiting from 2019 to 2022, from Shandong Gout Clinic Center at the Affiliated Hospital of Qingdao University, China, assigned to three groups according to clinical subtypes, were enrolled and all treated with 2-week low-purine diet. General characteristics, serum uric acid (sUA) and other clinical biochemical variables before and after the diet were evaluated. Results A total of 626 gout patients (age 41.20 ± 13.41 years, male 98.0%) were included. Of these, 69 (11.0%) were overproduction type, 428 (68.37%) were underexcretion type, and 129 (20.61%) were combined type. Overall, there was a substantial decrease in sUA after a 2-week LPD (p combined type (− 65.22 ± 44.13 μmol/L) > underexcretion type (− 57.32 ± 61.19 μmol/L). After adjusting for age, BMI and baseline sUA and eGFR, there were still significant differences in the decline of serum uric acid among different types. Higher baseline sUA (95%CI − 0.285, − 0.191; p

Abstract The catalytic conversion of ortho-hydrogen (o-H2) to para-hydrogen (p-H2) serves as a crucial step in the storage of liquid hydrogen. A variety of iron-cobalt bimetallic catalysts (FCO) were synthesized using a precipitation method, incorporating diverse levels of Co doping into Fe-based catalysts. The effects of Co doping on the crystal structure, porosity, and magnetism of FCO catalysts were studied by XRD, N2 physical adsorption, FTIR, XPS, and VSM analyses. The efficiency of ortho-para hydrogen conversion over FCO at 77 K was evaluated. It was found that the catalyst’s lag coefficient was significantly improved by Co doping, leading to an increase of magnetic moment. The catalyst of FCO-5 with a Fe/(Fe + Co) molar ratio of 0.5 exhibited the highest activity in ortho-para hydrogen conversion. The corresponding conversion rate, outlet p-H2 content, and the reaction rate constant were 99.2%, 49.7% and 291.7 mol·L−1·s−1, respectively, under a gas hourly space velocity of 5400 h−1.

Abstract Prediction of water-conducting fractured zone (WCFZ) of mine overburden is the premise for reducing or eliminating water inrush hazards in undersea mining. To obtain a more robust and precise prediction of WCFZ in undersea mining, a WCFZ prediction dataset with 122 cases of fractured zones was constructed. Five machine learning algorithms (linear regression, XGBRegressor, RandomForestRegressor, LineareSVR, and KNeighborsRegressor) were employed to develop five corresponding predictive models, taking multiple factors into account.The optimal parameters for each model are obtained through ten-fold cross-validation (10CV). The model's predictive performance was validated and assessed using two metrics, namely the coefficient of determination (R2) and mean squared error (MSE). A comparison was made with the regression performance of commonly used empirical formulas. The results indicate that the constructed model outperforms reliance solely on theoretical criteria, showing a high R2 value of up to 0.925 and a low MSE value of 3.61. The proposed model was validated in a recently established mining area on Sanshan Island, China. It shows low absolute and relative errors of 0.71 m and 2.01%, respectively, between the predicted value from the model and observation result from the field, demonstrating a high level of consistency with on-site conditions. This paves a path to leveraging machine learning algorithms for predicting the height of WCFZ.

Abstract Catkins, as a significant source of plant-caused pollution, disrupts daily human activities and industrial processes. Despite their impact, catkins have not been included in official environmental quality monitoring indicators, leading to a deficiency in scientifically rigorous collection and monitoring methodologies, as well as a lack of ecological prevention and management strategies. In this study, we introduced a fine-scale monitoring approach for catkins. Qualitative and quantitative relationships between catkin concentrations, plant community characteristics and microclimate factors were elucidated by analyzing on-site catkin concentration data from 33 representative plant communities in Beijing. Furthermore, we summarized the ecological strategies for the prevention and management of these catkins. The results indicated that (1) TS (three-dimensional green volume of trees in the catkin source layer), SB (three-dimensional green volume of shrubs in the catkin barrier layer), GB (three-dimensional green volume of ground cover plants in the catkin barrier layer), T (three-dimensional green volume of trees in the whole plant community), W (three-dimensional green volume of the whole plant community), species diversity, and relative air humidity were key plant community characteristics and microclimate factors influencing catkin concentration. Among these factors, TS, T, W, and relative air humidity showed a significant positive correlation with catkin concentration, while SB, GB, and species diversity exhibited a significant negative correlation with catkin concentration. (2) All seven key factors exhibited nonlinear relationships with catkin concentration. (3) TS served as the primary deciding factor for catkin concentration within the plant community. When TS > 744.0755 m3, the secondary decision factor for catkin concentration was GB. Otherwise, the determinants were SB and species diversity. The results showed that enhancing tree species diversity, enhancing the three-dimensional green volume of shrubs and ground cover plants, and increasing air humidity were practical means to facilitate the sedimentation of catkins. The measures used to obstruct catkins vary depending on the TS. When catkin source plants are abundant within a plant community, it is advisable to prioritize increasing ground cover plants. Conversely, when fewer sources of such plants exist, emphasis can be placed on augmenting mid-layer shrubs and diversifying plant species. These findings provide a scientific foundation for the planting design and stock optimization of communities containing catkin source plants.

Abstract Hypertension is a significant contributor to premature mortality, and the regular monitoring of blood pressure (BP) enables the early detection of hypertension and cardiovascular disease. There is an urgent need for the development of highly accurate cuffless BP devices. We examined BP measurements based on a target spectral camera’s recordings and evaluated their accuracy. Images of 215 adults’ palms and faces were recorded, and BP was measured. The camera captured RGB wavelength data at 640 × 480 pixels and 150 frames per second (fps). These recordings were analyzed to extract pulse transit time (PTT) values between the face and palm, a key parameter for estimating BP. Continuous BP measurements were taken using a CNAPmonitor500 for validation. Three frequency wavelengths were measured from video images. A machine learning model was constructed to determine hypertension, defined as a systolic BP of 130 mmHg or higher or a diastolic BP of 80 mmHg or higher, using the visualized data. The discrimination between hypertension and normal BP was 95.0% accurate within 30 s and 90.3% within 5 s, based on the captured images. The results of heartbeat-by-heartbeat analyses can be used to determine hypertension based on only one second of camera footage or one heartbeat. The data extracted from a video recorded by a target spectral camera enabled accurate hypertension diagnoses, suggesting the potential for simplified BP monitoring.

Abstract Background Clinical trials have shown that immunotherapy based on Vγ9Vδ2 T cells (Vδ2 T cells) is safe and well-tolerated for various cancers including cervical cancer (CC), but its overall treatment efficacy remains limited. Therefore, exploring the mechanisms underlying the suboptimal efficacy of Vδ2 T cell-based cancer immunotherapy is crucial for enabling its successful clinical translation. Methods Tumor samples from CC patients and CC cell line-derived xenograft (CDX) mice were analyzed using flow cytometry to examine the exhausted phenotype of tumor-infiltrating Vδ2 T cells. The interrelationship between BTN3A1 expression and Vδ2 T cells in CC, along with their correlation with patient prognosis, was analyzed using data from The Cancer Genome Atlas (TCGA) database. CC cell lines with BTN3A1 knockout (KO) and overexpression (OE) were constructed through lentivirus transduction, which were then co-cultured with expanded Vδ2 T cells, followed by detecting the function of Vδ2 T cells using flow cytometry. The pathways and transcription factors (TFs) related to BTN3A1-induced Vδ2 T cells exhaustion and the factors affecting BTN3A1 expression were identified by RNA-seq analysis, which was confirmed by flow cytometry, Western Blot, and gene manipulation. Results Tumor-infiltrating Vδ2 T cells exhibited an exhausted phenotype in both CC patients and CDX mice. BTN3A1 expressed in CC is highly enhancing exhaustion markers, while reducing the secretion of effector molecules in Vδ2 T cells. Blocking TCR or knocking down nuclear receptor subfamily 4 group A (NR4A) 2/3 can reverse BTN3A1-induced exhaustion in Vδ2 T cells. On the other hand, IFN-γ secreted by Vδ2 T cells promoted the expression of BTN3A1 and PD-L1. Conclusions Through binding γδ TCRs, BTN3A1 expressed on tumor cells, which is induced by IFN-γ, can promote Vδ2 T cells to upregulate the expression of TFs NR4A2/3, thereby affecting their activation and expression of exhaustion-related molecules in the tumor microenvironment (TME). Therefore, targeting BTN3A1 might overcome the immunosuppressive effect of the TME on Vδ2 T cells in CC.

Aging is a complex biological process characterized by increased inflammation and susceptibility to various age-related diseases, including cognitive decline, osteoporosis, and type 2 diabetes. Exercise has been shown to modulate mitochondrial function, immune responses, and inflammatory pathways, thereby attenuating aging through the regulation of exerkines secreted by diverse tissues and organs. These bioactive molecules, which include hepatokines, myokines, adipokines, osteokines, and neurokines, act both locally and systemically to exert protective effects against the detrimental aspects of aging. This review provides a comprehensive summary of different forms of exercise for older adults and the multifaceted role of exercise in anti-aging, focusing on the biological functions and sources of these exerkines. We further explore how exerkines combat aging-related diseases, such as type 2 diabetes and osteoporosis. By stimulating the secretion of these exerkines, exercise supports healthy longevity by promoting tissue homeostasis and metabolic balance. Additionally, the integration of exercise-induced exerkines into therapeutic strategies represents a promising approach to mitigating age-related pathologies at the molecular level. As our understanding deepens, it may pave the way for personalized interventions leveraging physical activity to enhance healthspan and improve quality of life.

Objectives This study aimed to explore the spatial and temporal distribution of hepatitis C and its influencing factors in Chongqing, providing a scientific basis for the relevant departments to formulate targeted preventive measures for the high prevalence of hepatitis C in the region and population.Design We collected data on hepatitis C cases in Chongqing (located in the southwest of China) from 2014 to 2020, and analysed the spatiotemporal heterogeneity of hepatitis C incidence in different populations and identified factors that might influence the incidence of hepatitis C by constructing a Bayesian spatiotemporal model.Settings The study subjects included clinically diagnosed cases and confirmed cases of hepatitis C with current address in Chongqing and onset date between 1 January 2014 and 31 December 2020.Participants The study used aggregated data, including 33 900 clinically diagnosed cases and confirmed cases of hepatitis C.Results From 2014 to 2020, the high-risk areas of hepatitis C were primarily concentrated in the main and new urban areas of Chongqing. In contrast, the low-risk areas were mainly found in southeast and northeast Chongqing. There was also an increasing trend in the risk of incidence in the low-risk areas. Analysis of different populations revealed that men aged 45–59 years had a higher risk of developing hepatitis C in the main urban area compared with other age groups. Additionally, the risk for this population group showed an increasing trend in the southeast and northeast of Chongqing as well as the main urban area. Among women, the rising trend of hepatitis C risk was stronger for those aged 30–44 years in southeast Chongqing and for those aged 45–59 years in northeast Chongqing compared with other age groups. The analysis of influencing factors found that gross domestic product per capita, population density and the proportion of tertiary industry were associated with an increased risk of hepatitis C.Conclusions High-risk areas for hepatitis C virus were mainly located in the main and new urban areas of Chongqing, where the male prime-age population was the focus of prevention and treatment. In the future, the relevant authorities should concentrate on high-risk areas and at the same time strengthen screening and serological surveys for hepatitis C in low-risk areas and various populations, and raise public awareness of prevention, so as to reduce the incidence of hepatitis C.

Objective To explore the complex mechanisms of keloid, new approaches have been developed by different strategies. However, conventional treatment did not significantly reduce the recurrence rate. This study aimed to identify new biomarkers and mechanisms for keloid progression through bioinformatics analyses.Methods In our study, microarray datasets for keloid were downloaded from the GEO database. Differentially expressed genes (DEGs) were identified by R software. Multiple bioinformatics tools were used to identify hub genes, and reverse predict upstream miRNAs and lncRNA molecules of target hub genes. Finally, the total RNA-sequencing technique and miRNA microarray were combined to validate the identified genes.Results Thirty-one DEGs were screened out and the upregulated hub gene SPP1 was finally identified, which was consistent with our RNA-sequencing analysis results and validation dataset. In addition, a ceRNA network of mRNA (SPP1)-miRNA (miR-181a-5p)-lncRNA (NEAT1, MALAT1, LINC00667, NORAD, XIST and MIR4458HG) was identified by the bioinformatics databases. The results of our miRNA microarray showed that miR-181a-5p was upregulated in keloid, also we found that the lncRNA NEAT1 could affect keloid progression by retrieving the relevant literature.Conclusions We speculate that SPP1 is a potential candidate biomarker and therapeutic target for patients with keloid, and NEAT1/miR-181a-5p/SPP1 might be the RNA regulatory pathway that regulates keloid formation.

Abstract Inferior vena cava filter (IVCF) implantation is a common method of thrombus capture. By implanting a filter in the inferior vena cava (IVC), microemboli can be effectively blocked from entering the pulmonary circulation, thereby avoiding acute pulmonary embolism (PE). Inspired by the helical flow effect in the human arterial system, we propose a helical retrievable IVCF, which, due to the presence of a helical structure inducing a helical flow pattern of blood in the region near the IVCF, can effectively avoid the deposition of microemboli in the vicinity of the IVCF while promoting the cleavage of the captured thrombus clot. It also reduces the risk of IVCF dislodging and slipping in the vessel because its shape expands in the radial direction, allowing its distal end to fit closely to the IVC wall, and because its contact structure with the inner IVC wall is curved, increasing the contact area and reducing the risk of the vessel wall being punctured by the IVCF support structure. We used ANSYS 2023 software to conduct unidirectional fluid–structure coupling simulation of four different forms of IVCF, combined with microthrombus capture experiments in vitro, to explore the impact of these four forms of IVCF on blood flow patterns and to evaluate the risk of IVCF perforation and IVCF dislocation. It can be seen from the numerical simulation results that the helical structure does have the function of inducing blood flow to undergo helical flow dynamics, and the increase in wall shear stress (WSS) brought about by this function can improve the situation of thrombosis accumulation to a certain extent. Meanwhile, the placement of IVCF will change the flow state of blood flow and lead to the deformation of blood vessels. In in vitro experiments, we found that the density of the helical support rod is a key factor affecting the thrombus trapping efficiency, and in addition, the contact area between the IVCF and the vessel wall has a major influence on the risk of IVCF displacement.

Objective(s): The combination of TNF-α inhibitors and vitamin D in colitis remains to be elucidated. In the present study, we revealed the benefit of infliximab (IFX) and vitamin D in a mouse model of Ulcerative colitis (UC). Materials and Methods: A dextran sulfate sodium-induced colitis model was used. The therapeutic effect of the combination was evaluated by symptom and histopathology analysis. The synergistic mechanism was explored by detecting the regulatory effect of the combined therapy on Regulatory T cell (Treg) differentiation.Results: IFX and 1,25-dihydroxyvitamin D3 (VitD3) synergistically prevented the development of colitis by improving clinical signs, pathological and hematological manifestation, and inhibiting intestinal inflammation (decreasing TNF-α, IL-1β, and IL-6). Coadministration of IFX (2.5 mg/kg) with VitD3 or IFX (5.0 mg/kg) with VitD3 was more effective than administration of IFX (2.5 mg/kg, 5.0 mg/kg). There was no difference in therapeutic effect between IFX (5.0 mg/kg) and VitD3+ IFX (2.5 mg/kg) groups or between the VitD3+IFX (5.0 mg/kg) and VitD3+ Azathioprine (AZA) groups. VitD3 or combination therapy showed more powerful regulation of splenetic Treg differentiation and IL-10 production than IFX alone. Moreover, VitD3 alone or in combination induced higher levels of Foxp3 and IL-10 than IFX in colon tissue. In ulcerative colitis patients, serum VitD3 levels positively correlated with Treg levels.Conclusion: VitD3 and IFX synergistically inhibit colitis based on their powerful regulation of Treg differentiation. VitD3 combined with IFX is an alternative therapy for patients who are intolerant to standard doses of IFX or combination of IFX and AZA.

Abstract Background There is increasing evidence that gut fungi dysbiosis plays a crucial role in the development and progression of colorectal cancer (CRC). It has been reported that gut fungi exacerbate the severity of CRC by regulating tumor immunity. Our previous studies have shown that the opportunistic pathogenic fungal pathogen, Candida tropicalis (C. tropicalis) promotes CRC progression by enhancing the immunosuppressive function of MDSCs and activating the NLRP3 inflammasome of MDSCs. However, the relationship between IL-1β produced by NLRP3 inflammasome activation and the immunosuppressive function of MDSCs enhanced by C. tropicalis in CRC remains unclear. Methods The TCGA database was used to analyze the relationship between IL-1β and genes related to immunosuppressive function of MDSCs in human CRC. The expression of IL-1β in human CRC tissues was detected by immunofluorescence staining. The proteomic analysis was performed on the culture supernatant of C. tropicalis-stimulated MDSCs. The experiments of supplementing and blocking IL-1β as well as inhibiting the NLRP3 inflammasome activation were conducted. A mouse colon cancer xenograft model was established by using MC38 colon cancer cell line. Results Analysis of CRC clinical samples showed that the high expression of IL-1β was closely related to the immunosuppressive function of tumor-infiltrated MDSCs. The results of in vitro experiments revealed that IL-1β was the most secreted cytokine of MDSCs stimulated by C. tropicalis. In vitro supplementation of IL-1β further enhanced the immunosuppressive function of C. tropicalis-stimulated MDSCs and NLRP3-IL-1β axis mediated the immunosuppressive function of MDSCs enhanced by C. tropicalis. Finally, blockade of IL-1β secreted by MDSCs augmented antitumor immunity and mitigated C. tropicalis-associated colon cancer. Conclusions C. tropicalis promotes excessive secretion of IL-1β from MDSCs via the NLRP3 inflammasome. IL-1β further enhances the immunosuppressive function of MDSCs to inhibit antitumor immunity, thus promoting the progression of CRC. Therefore, targeting IL-1β secreted by MDSCs may be a potential immunotherapeutic strategy for the treatment of CRC.

Objective To obtain the monitoring measurement range of quality indicators of red blood cells, plasma and derivatives and leukocyte-reduced apheresis platelets provided by blood stations in Hebei province, explore the distribution of monitoring values and the change of monitoring level, so as to further strengthen the homogenization construction of quality control laboratories in blood stations in Hebei. Methods In 2023, the sampling data of 12 blood stations in Hebei from 2015 to 2022 were collected, scatter plots were made and the range markers were set, and the "mean±SD" line was taken as the upper limit and lower limit of the measurement range. In 2024, the monitoring values in 2023 were added, and the changes of two measurement ranges were compared to analyze the stability and overall level. Results Comparison of the measurement range from 2015 to 2022 and the measurement range from 2015 to 2023 showed that the standard deviation of the content of deleukocyte suspension of red blood cells-hemoglobin, washed erythrocyte-hemoglobin, washed erythrocyte-supernatant protein, cryoprecipitate coagulation factor-FⅧ, fresh frozen plasma-FⅧ, leukocyte-reduced apheresis platelets-leukocyte residue and leukocyte-reduced apheresis platelet-red blood cell concentration decreased from 8.132 to 7.993, 6.252 to 6.104, 0.273 to 0.267, 57.506 to 56.276, 0.920 to 0.892, 0.653 to 0.644 and 2.653 to 2.603, respectively.The narrowing of the standard deviation range of the above items led to more concentrated monitoring values and reduced dispersion. Comparison of the measurement range from 2015 to 2022 and the measurement range from 2015 to 2023 showed that the mean value of leukocyte residue of the deleukocyte suspension of red blood cells, hemoglobin content of the wash erythrocyte, protein content of supernatant of the wash erythrocyte, hemolysis rate of the wash erythrocyte, FⅧ content of the cryoprecipitate coagulation factor, plasma protein content of the fresh frozen plasma, FⅧ content of the fresh frozen plasma, platelet content of the leukocyte-reduced apheresis platelets changed from 0.362 to 0.476, 44.915 to 44.861, 0.280 to 0.283, 0.137 to 0.142, 133.989 to 133.271, 60.262 to 60.208, 1.301 to 1.277 and 3.036 to 3.033, respectively, and was closer to the national standard line, which reflects an increase in the number of unqualified monitoring values or values close to the national standard line in 2023. The long-term qualified rate of coagulation items was low, and no improvement has been observed. The stability of biochemical items has been enhanced but overall deviation has occurred, with the average value close to the national standard line. The possibility of subsequent testing failure has increased. The counting items showed no obvious common characteristics. Conclusion The use of "mean±SD" in the analysis can visually display the distribution of monitoring values of different items in Hebei, forming an indicator measurement range covering the past nine years. It shows the characteristics of each item, and provides reference for subsequent quality control laboratory data analysis of each blood stations to takes active measures to improve the monitoring level.