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Abstract Background Rib fractures are one of the most common traumatic injuries and may result in significant morbidity and mortality. Despite growing evidence, technological advances and increasing acceptance, surgical stabilization of rib fractures (SSRF) remains not uniformly considered in trauma centers. Indications, contraindications, appropriate timing, surgical approaches and utilized implants are part of an ongoing debate. The present position paper, which is endorsed by the World Society of Emergency Surgery (WSES), and supported by the Chest Wall Injury Society, aims to provide a review of the literature investigating the use of SSRF in rib fracture management to develop graded position statements, providing an updated guide and reference for SSRF. Methods This position paper was developed according to the WSES methodology. A steering committee performed the literature review and drafted the position paper. An international panel of experts then critically revised the manuscript and discussed it in detail, to develop a consensus on the position statements. Results A total of 287 studies (systematic reviews, randomized clinical trial, prospective and retrospective comparative studies, case series, original articles) have been selected from an initial pool of 9928 studies. Thirty-nine graded position statements were put forward to address eight crucial aspects of SSRF: surgical indications, contraindications, optimal timing of surgery, preoperative imaging evaluation, rib fracture sites for surgical fixation, management of concurrent thoracic injuries, surgical approach, stabilization methods and material selection. Conclusion This consensus document addresses the key focus questions on surgical treatment of rib fractures. The expert recommendations clarify current evidences on SSRF indications, timing, operative planning, approaches and techniques, with the aim to guide clinicians in optimizing the management of rib fractures, to improve patient outcomes and direct future research.

Abstract Background Post-stroke cognitive impairment (PSCI) not only increases patient mortality and disability, but also adversely affects motor function and the ability to perform routine daily activities. Current therapeutic approaches for, PSCI lack specificity, primarily relying on and medication and traditional cognitive therapy supplemented by a limited array of tools. Both transcranial direct current stimulation (tDCS) and virtual reality (VR) training have demonstrated efficacy in improving cognitive performance among PSCI patients. Previous findings across various conditions suggest that implementing a therapeutic protocol combining tDCS and VR (tDCS - VR) may yield superior in isolation. Despite this, to our knowledge, no clinical investigation combining tDCS and VR for PSCI rehabilitation has been conducted. Thus, the purpose of this study is to explore the effects of tDCS - VR on PSCI rehabilitation. Methods This 4-week, single-center randomized clinical trial protocol will recruit 200 patients who were randomly assigned to one of four groups: Group A (tDCS + VR), Group B (tDCS + sham VR), Group C (sham tDCS + VR), Group D (sham tDCS + sham VR). All four groups will receive conventional cognitive rehabilitation training. The primary outcome measurement utilizes the Mini-Mental State Examination (MMSE). Secondary outcome measures include the Montreal Cognitive Assessment, Frontal Assessment Battery, Clock Drawing Test, Digital Span Test, Logic Memory Test, and Modified Barthel Index. Additionally, S-YYZ-01 apparatus for diagnosis and treating language disorders assesses subjects’ speech function. Pre- and post-four-week intervention assessments are conducted for all outcome measures. Functional near-infrared spectroscopy (fNIRS) is employed to observe changes in oxygenated hemoglobin (HbO), deoxy-hemoglobin (HbR), and total hemoglobin (HbT) in the cerebral cortex. Discussion Our hypothesis posits that the tDCS - VR therapy, in opposed to individual tDCS or VR interventions, could enhance cognitive function, speech ability and daily living skills in PSCI patients while concurrently augmenting frontal cortical activity. This randomized study aims to provide a robust theoretical foundation supported by scientific evidence for the practical implementation of the tDCS - VR combination as a secure and efficient PSCI rehabilitation approach. Trial registration Chictr.org.cn Identifier: ChiCTR2300070580. Registered on 17th April 2023.

Abstract Background Calibrated electromyography (EMG)-driven musculoskeletal models can provide insight into internal quantities (e.g., muscle forces) that are difficult or impossible to measure experimentally. However, the need for EMG data from all involved muscles presents a significant barrier to the widespread application of EMG-driven modeling methods. Synergy extrapolation (SynX) is a computational method that can estimate a single missing EMG signal with reasonable accuracy during the EMG-driven model calibration process, yet its performance in estimating a larger number of missing EMG signals remains unknown. Methods This study assessed the accuracy with which SynX can use eight measured EMG signals to estimate muscle activations and forces associated with eight missing EMG signals in the same leg during walking while simultaneously performing EMG-driven model calibration. Experimental gait data collected from two individuals post-stroke, including 16 channels of EMG data per leg, were used to calibrate an EMG-driven musculoskeletal model, providing “gold standard” muscle activations and forces for evaluation purposes. SynX was then used to predict the muscle activations and forces associated with the eight missing EMG signals while simultaneously calibrating EMG-driven model parameter values. Due to its widespread use, static optimization (SO) applied to a scaled generic musculoskeletal model was also utilized to estimate the same muscle activations and forces. Estimation accuracy for SynX and SO was evaluated using root mean square errors (RMSE) to quantify amplitude errors and correlation coefficient r values to quantify shape similarity, each calculated with respect to “gold standard” muscle activations and forces. Results On average, compared to SO, SynX with simultaneous model calibration produced significantly more accurate amplitude and shape estimates for unmeasured muscle activations (RMSE 0.08 vs. 0.15, r value 0.55 vs. 0.12) and forces (RMSE 101.3 N vs. 174.4 N, r value 0.53 vs. 0.07). SynX yielded calibrated Hill-type muscle–tendon model parameter values for all muscles and activation dynamics model parameter values for measured muscles that were similar to “gold standard” calibrated model parameter values. Conclusions These findings suggest that SynX could make it possible to calibrate EMG-driven musculoskeletal models for all important lower-extremity muscles with as few as eight carefully chosen EMG signals and eventually contribute to the design of personalized rehabilitation and surgical interventions for mobility impairments.

Abstract Ice core oxygen isotope (δ18O) records from low-latitude regions preserve high-resolution climate records in the past, yet the interpretation of these ice core δ18O records is still facing difficulty due to the uncertainty of ice core dating. Here we present a new established δ18O time series from Qiangtang (QT) No. 1 ice core retrieved from the central Tibetan Plateau. Due to the vague seasonal signals in the QT ice core, we investigated the spectral properties of δ18O record with depth and discussed the implications of significant spectral power peaks in the QT ice core. We employed a variational mode decomposition (VMD) analysis for the upper part of the QT ice core to decompose the δ18O depth series in order to separate the El Niño Southern Oscillation (ENSO) mode, a signal strongly preserved in the QT ice core δ18O record. With this approach, we established a time series of 335 years (1677–2011 CE) for the upper 50 m of the QT ice core. Subsequently, we examined the frequency of the new established δ18O time series and detected strong signals of the bidecadal and multidecadal modes of Pacific Decadal Oscillation (PDO). The PDO consists of two modes with periods of approximately 25–35 years and 50–70 years, and we found that the 50–70 years periodicity has persisted since 1700 CE, succeeded by dominance of the 25–75 years periodicity after 1900 CE. Additionally, we analyzed the δ18O series of the QT ice core during the past century and determined that the increasing frequency of El Niño events is an important factor contributing to the increase in recent ice core δ18O.

Abstract The electrocatalytic reduction of nitrate toward ammonia under mild conditions addresses many challenges of the Haber-Bosch reaction, providing a sustainable method for ammonia synthesis, yet it is limited by sluggish reduction kinetics and multiple competing reactions. Here, the titanium hydride electrocatalyst is synthesized by electrochemical hydrogenation reconstruction of titanium fiber paper, which achieves a large ammonia yield rate of 83.64 mg h−1 cm−2 and a high Faradaic efficiency of 99.11% with an ampere-level current density of 1.05 A cm−2 at −0.7 V versus the reversible hydrogen electrode. Electrochemical evaluation and kinetic studies indicate that the lattice hydrogen transfer from titanium hydride promotes the electrocatalytic performance of nitrate reduction reaction and the reversible equilibrium reaction between lattice hydrogen and activate hydrogen not only improves the electrocatalytic activity of nitrate reduction reaction but also demonstrates notable catalytic stability. These finding offers a universal design principle for metal hydrides as catalysts for effectively electrochemical ammonia production, highlighting their potential for sustainable ammonia synthesis.

Abstract Glioblastomas (GBM) are most common types of primary brain tumors and miRNAs play an important role in pathogenesis of glioblastomas. Here, we reported a new miRNA, miR-3154, which regulates glioblastoma proliferation and metastasis. miR-3154 was elevated in glioblastoma tissue and cell lines, and its elevation was associated with grade of glioblastomas. Knockdown of miR-3154 in cell lines weakened ability of proliferation and colony formation, and caused cell cycle arrested and higher percentage of apoptosis. Knockdown of miR-3154 also impaired ability of migration and invasion in glioblastoma cells. In mechanism, miR-3154 bound directly to Tumor Protein P53 Inducible Nuclear Protein 1 (TP53INP1), down-regulating TP53INP1 expression at both mRNA and protein level. Silence of TP53INP1 reversed the effect of miR-3154 knockdown on proliferation and metastasis of glioblastoma cells. These findings show that miR-3154 promotes glioblastoma proliferation and metastasis via targeting TP53INP1.

Abstract Hemipteran insects transmit viruses when infesting plants, during which vectors activate salicylic acid (SA)-regulated antiviral defenses. How vector-borne plant viruses circumvent these antiviral defenses is largely unexplored. During co-infections of begomoviruses and betasatellites in plants, betasatellite-encoded βC1 proteins interfere with SA signaling and reduce the activation of antiviral resistance. βC1 inhibits SA-induced degradation of NbNPR3 (Nicotiana benthamiana nonexpressor of pathogenesis-related genes 3), a negative regulator of SA signaling. βC1 does not bind directly to NbNPR3, but regulates NbNPR3 degradation via heat shock protein 90s (NbHSP90s). NbHSP90s bind to both NbNPR3 and βC1 and suppress SA signaling. This viral success strategy appears to be conserved as it is also documented for viral proteins encoded by two aphid-borne viruses. Our findings reveal an exquisite mechanism that facilitates the persistence of vector-borne plant viruses and provide important insights into the intricacies of the virus life cycle.

Abstract Proton-exchange-membrane fuel cells demand highly efficient catalysts for the oxygen reduction reaction, and core-shell structures are known for maximizing precious metal utilization. Here, we reported a controllable “carbon defect anchoring” strategy to prepare Pt1Ni1@Pt/C core-shell nanoparticles with an average size of ~2.6 nm on an in-situ transformed defective carbon support. The strong Pt–C interaction effectively inhibits nanoparticle migration or aggregation, even after undergoing stability tests over 70,000 potential cycles, resulting in only 1.6% degradation. The stable Pt1Ni1@Pt/C catalysts have high oxygen reduction reaction mass activity and specific activity that reach 1.424 ± 0.019 A/mgPt and 1.554 ± 0.027 mA/cmPt 2 at 0.9 V, respectively, attributed to the optimal compressive strain. The experimental results are generally consistent with the theoretical predictions made by our comprehensive microkinetic model which incorporates essential kinetics and thermodynamics of oxygen reduction reaction. The consistent results obtained in our study provide compelling evidence for the high accuracy and reliability of our model. This work highlights the synergy between theory-guided catalyst design and appropriate synthetic methodologies to translate the theory into practice, offering valuable insights for future catalyst development.

For decades micoorganisms have been engineered for the utilization of lignocellulose-based second-generation (2G) feedstocks, but with the concerns of increased levels of atmospheric CO2 causing global warming there is an emergent need to transition from the utilization of 2G feedstocks to third-generation (3G) feedstocks such as CO2 and its derivatives. Here, we established a yeast platform that is capable of simultaneously converting 2G and 3G feedstocks into bulk and value-added chemicals. We demonstrated that by adopting 3G substrates such as CO2 and formate, the conversion of 2G feedstocks could be substantially improved. Specifically, formate could provide reducing power and energy for xylose conversion into valuable chemicals. Simultaneously, it can form a concentrated CO2 pool inside the cell, providing thermodynamically and kinetically favoured amounts of precursors for CO2 fixation pathways, e.g., the Calvin–Benson–Bassham (CBB) cycle. Furthermore, we demonstrated that formate could directly be utilized as a carbon source by yeast to synthesize endogenous amino acids. The engineered strain achieved a one-carbon (C1) assimilation efficiency of 9.2%, which was the highest efficiency observed in the co-utilization of 2G and 3G feedstocks. We applied this strategy for productions of both bulk and value-added chemicals, including ethanol, free fatty acids (FFAs), and longifolene, resulting in yield enhancements of 18.4%, 49.0%, and ∼100%, respectively. The strategy demonstrated here for co-utilization of 2G and 3G feedstocks sheds lights on both basic and applied research for the up-coming establishment of 3G biorefineries.

Cataract patients look forwards to fewer postoperative complications and higher vision quality after surgery. However, the current intraocular lens (IOL) implanted after cataract surgery neither can adjust focal length in response to ciliary muscle contraction as natural lens nor have the ability to prevent postoperative complications. Herein, a thermosensitve Poloxamer based hybrid hydrogel with antibacterial anti-inflammatory and photothermal functional elements doping was designed and used as injectable, in situ curable, and adjustable IOL (FHTAB IOL). The FHTAB IOL was composed of thermosensitve triblock-polymer F127DA and a small amount of HAMA, combined with BP NS, TA, and Ag NPs. FHTAB IOL can be injected into the empty lens capsule after cataract surgery via an injectable thermos-gel under NIR illumination and then be rapidly cured to form a full-size IOL under short-time blue light irradiation. The designed injectable FHTAB IOL possesses high transparency and transmittance, with a refractive index similar to the natural lens and adjustable properties. It was stabilized as a refractive medium without any leakage in the eye. In addition, the TA and Ag NPs loaded in the FHTAB IOL displayed significant antibacterial and anti-inflammatory effects in vitro and vivo. This study presents a potentially effective new strategy for the development of multifunctional adjustable IOLs.

Abstract Tryptophan (Trp) metabolism involves three primary pathways: the kynurenine (Kyn) pathway (KP), the 5-hydroxytryptamine (serotonin, 5-HT) pathway, and the indole pathway. Under normal physiological conditions, Trp metabolism plays crucial roles in regulating inflammation, immunity, and neuronal function. Key rate-limiting enzymes such as indoleamine-2,3-dioxygenase (IDO), Trp-2,3-dioxygenase (TDO), and kynurenine monooxygenase (KMO) drive these metabolic processes. Imbalances in Trp metabolism are linked to various cancers and often correlate with poor prognosis and adverse clinical characteristics. Dysregulated Trp metabolism fosters tumor growth and immune evasion primarily by creating an immunosuppressive tumor microenvironment (TME). Activation of the KP results in the production of immunosuppressive metabolites like Kyn, which modulate immune responses and promote oncogenesis mainly through interaction with the aryl hydrocarbon receptor (AHR). Targeting Trp metabolism therapeutically has shown significant potential, especially with the development of small-molecule inhibitors for IDO1, TDO, and other key enzymes. These inhibitors disrupt the immunosuppressive signals within the TME, potentially restoring effective anti-tumor immune responses. Recently, IDO1 inhibitors have been tested in clinical trials, showing the potential to enhance the effects of existing cancer therapies. However, mixed results in later-stage trials underscore the need for a deeper understanding of Trp metabolism and its complex role in cancer. Recent advancements have also explored combining Trp metabolism inhibitors with other treatments, such as immune checkpoint inhibitors, chemotherapy, and radiotherapy, to enhance therapeutic efficacy and overcome resistance mechanisms. This review summarizes the current understanding of Trp metabolism and signaling in cancer, detailing the oncogenic mechanisms and clinical significance of dysregulated Trp metabolism. Additionally, it provides insights into the challenges in developing Trp-targeted therapies and future research directions aimed at optimizing these therapeutic strategies and improving patient outcomes.

Abstract Alzheimer’s disease (AD) is a metabolic disorder. Discovering the metabolic products involved in the development of AD may help not only in the early detection and prevention of AD but also in understanding its pathogenesis and treatment. This study investigated the causal association between the latest large-scale plasma metabolites (1091 metabolites and 309 metabolite ratios) and AD. Through the application of Mendelian randomization analysis methods such as inverse-variance weighted (IVW), MR-Egger, and weighted median models, 66 metabolites and metabolite ratios were identified as potentially having a causal association with AD, with 13 showing significant causal associations. During the replication validation phase, six metabolites and metabolite ratios were confirmed for their roles in AD: N-lactoyl tyrosine, argininate, and the adenosine 5’-monophosphate to flavin adenine dinucleotide ratio were found to exhibit protective effects against AD. In contrast, ergothioneine, piperine, and 1,7-dimethyluric acid were identified as contributing to an increased risk of AD. Among them, argininate showed a significant effect against AD. Replication and sensitivity analyses confirmed the robustness of these findings. Metabolic pathway analysis linked “Vitamin B6 metabolism” to AD risk. No genetic correlations were found, but colocalization analysis indicated potential AD risk elevation through top SNPs in APOE and PSEN2 genes. This provides novel insights into AD’s etiology from a metabolomic viewpoint, suggesting both protective and risk metabolites.

Abstract Van der Waals integration of freestanding perovskite-oxide membranes with two-dimensional semiconductors has emerged as a promising strategy for developing high-performance electronics, such as field-effect transistors. In these innovative field-effect transistors, the oxide membranes have primarily functioned as dielectric layers, yet their great potential for structural tunability remains largely untapped. Free of epitaxial constraints by the substrate, these freestanding membranes exhibit remarkable structural tunability, providing a unique material system to achieve huge strain gradients and pronounced flexoelectric effects. Here, by harnessing the excellent structural tunability of PbTiO3 membranes and modulating the underlying substrate’s elasticity, we demonstrate the tip-pressure-induced polarization switching with an ultralow pressure (down to 0.06 GPa). Moreover, as an application demonstration, we develop a prototype non-volatile ferroelectric field-effect transistor integrated on silicon that can be operated mechanically and electrically. Our findings underscore the great potential of oxide membranes for utilization in advanced non-volatile electronics and highly sensitive pressure sensors.

Abstract Hydrogen-bonded assembly of multiple components into well-defined icosahedral capsules akin to virus capsids has been elusive. In parallel, constructing robust zeolitic-like cluster-based supramolecular frameworks (CSFs) without any coordination covalent bonding linkages remains challenging. Herein, we report a cluster-based pseudoicosahedral H-bonded capsule Cu60, which is buckled by the self-organization of judiciously designed constituent copper clusters and anions. The spontaneous formation of the icosahedron in the solid state takes advantage of 48 charge-assisted CH···F hydrogen bonds between cationic clusters and anions (PF6 -), and is highly sensitive to the surface protective ligands on the clusters with minor structural modification inhibiting its formation. Most excitingly, an extended three-periodic robust zeolitic-like CSF, is constructed by edge-sharing the resultant icosahedrons. The perpendicular channels of the CSF feature unusual 3D orthogonal double-helical patterns. The CSF material not only keeps its single-crystal character in the desolvated phase, but also exhibits excellent chemical and thermal stabilities as well as long-lived phosphorescence emission.

Abstract Backgroud Anti-melanoma differentiation-associated protein 5 antibody-positive dermatomyositis (anti-MDA5-positvie DM) is a subtype of dermatomyositis with a poor prognosis, characterized by rapidly progressive interstitial lung disease (RP-ILD). The study aims to investigate the significance of serum cytokines profiles and peripheral lymphocytes in predicting prognoses of anti-MDA5-positvie DM with RP-ILD. Furthermore, it seeks to analyze longitudinal data of lymphocytes during hospitalization to identify distinct trajectories and cluster patients accordingly. Methods A total of 168 patients with anti-MDA5-positive DM were enrolled in this retrospective study from two cohorts. Univariate and multivariate Cox regression analyses were conducted to determine the predictors of 6-month all-cause mortality and RP-ILD. Group-based trajectory modeling (GBTM) was employed to model the trajectories of longitudinal peripheral lymphocytes. Results In the multivariate Cox regression analysis, IL-6 ≥ 13.41pg/mL, lymphocytes

Abstract Background Genetic factors, including the Hedgehog Interacting Protein (HHIP) gene, play a crucial role in Chronic Obstructive Pulmonary Disease (COPD) susceptibility. This study examines the association between HHIP gene polymorphisms and COPD susceptibility, phenotypes, and serum IL-17 and IL-18 levels in a Han Chinese population. Methods A case-control study was conducted with 300 COPD patients and 300 healthy controls in Chinese Han population. Participants underwent genotyping for HHIP gene polymorphisms, pulmonary function tests, and quantitative CT scans. DNA samples were sequenced using a custom chip targeting the HHIP gene. Serum IL-17 and IL-18 levels were measured by enzyme-linked immunosorbent assay. Associations between SNPs, COPD susceptibility, and phenotypes were analyzed using logistic and multiple linear regression models, adjusting for confounders. Results Our study identified the rs11100865 polymorphism in the HHIP gene as significantly associated with COPD susceptibility (OR 2.479, 95% CI 1.527–4.024, P = 2.39E-04) after screening 114 SNPs through rigorous quality control. Stratified analyses further indicated this association was particularly in individuals aged 60 or older. Serum levels of IL-17 and IL-18 were significantly elevated in COPD patients compared to controls, with rs11100865 showing a notable association with IL-18 levels (B = 49.654, SE = 19.627, P = 0.012). However, no significant associations were observed between rs11100865 and serum IL-17 levels, COPD-related imaging parameters, or clinical phenotypes. Conclusion This study identified a significant association between HHIP gene polymorphisms and COPD susceptibility in a Han Chinese population, with connections to inflammation, but found no significant associations between this SNP and COPD-related imaging or clinical phenotypes. Trial registration www.chictr.org.cn ID: ChiCTR2300071579 2023-05-18.

Abstract Background The self-reported KIDSCREEN questionnaires are ideal for capturing children’s and adolescents’ health-related quality of life (HRQoL) and have gained worldwide popularity. Responding to demands for the concise nature of KIDSCREEN among Chinese Mainland researchers and practitioners, this study aimed to evaluate the psychometric properties of the Mandarin Chinese self-reported KIDSCREEN-27 (KS-27) and KIDSCREEN-10 index (KS-10), which are short versions of the self-reported KIDSCREEN-52 (KS-52). Methods This study reanalyzed the validation dataset of the Mandarin Chinese self-reported KS-52. The dataset originated from a cross-sectional survey conducted in Weifang City, the Chinese Mainland, from October to November 2016. Adolescents aged 11–17 years (N = 4385) were surveyed, and sub-samples (N = 841) were retested. Statistical analyses were conducted on the feasibility, item and dimension properties, reliability, and validity of the Mandarin Chinese self-reported KS-27 and KS-10. Results Indirect evidence from the Small Group Pilot Survey indicated that the Mandarin Chinese self-reported KS-27 and KS-10 can be completed on average in less than 12.33 mins. Their response rate exceeded 90% regardless of the unit- and item (dimension)-level. The psychometric properties of items and dimensions were likewise found to be satisfactory. Internal consistency was robust with inter-item and item-total correlations (0.173–0.873, 0.422–0.786), Cronbach’s alpha (0.786–0.881), Guttman’s lambda-2 and - 6 (0.807–0.889, 0.829–0.896), and McDonald’s omega (0.725–0.886). Test–retest reliability at both item- and dimension-level was excellent, with intraclass correlation coefficients (ICCs) of (0.590–0.696, 0.785–0.842); standard error of measurements (SEMs) of (0.352–0.635, 0.949–1.949). Confirmatory factor analysis (CFA) confirmed their five- and one-dimensional structures, albeit with slight modifications. Moreover, the multi-group confirmatory factor analysis (MG-CFA) substantiated their configural and metric invariance across gender and grade groups. Convergent validity was robust, with stronger correlations observed with comparable dimensions of the Mandarin Chinese self-reported PedsQL™ 4.0, while discriminant validity was evident with low correlations observed with less comparable dimensions. The known-group validity was mainly supported by medium to large effect sizes concerning differences in socioeconomic status (η2 = 0.07–0.17, Cohen’s d = 0.55–1.03) and mental health status (η2 = 0.09–0.40, Cohen’s d = 0.73–1.83). The Mandarin Chinese self-reported KS-52 served as the criterion; the ICCs between the Mandarin Chinese self-reported KS-27 and KS-10 and their comparable dimensions were stronger, indicating robust criterion validity. Conclusions The Mandarin Chinese self-reported KS-27 and KS-10 demonstrated excellent psychometric properties, indicating their good potential for measuring HRQoL for children and adolescents in the Chinese Mainland.

Theoretical research on betavoltaic batteries require calculating characteristic parameters of the radiation-voltage conversion device，in order to predict the output characteristics under irradiation. Through the calculated output characteristics，important theoretical references for the design of betavoltaic batteries are provided. Our algorithm calculates the characteristic parameters of the radiation-voltage conversion device based on the tested dark current-voltage curve and evaluates the quality of the characteristic parameters by statistical methods. To prove the effectiveness of the algorithm，the current-voltage curves under irradiation were predicted，and compared with those obtained by exposing to a real radioactive source. Calculation results achieved good results in both curve fitting and output characteristic prediction of the radiation-voltage conversion device. The results show our algorithm can predict the output of betavoltaic battery through the dark current-voltage curve without irradiation and provide guidance for the design of batavoltaic batteries.

ObjectiveTo explore the impact of sluggish cognitive tempo (SCT) on the efficacy of atomoxetine in the treatment of attention-deficit/hyperactivity disorder (ADHD). MethodsA prospective study was conducted. Pediatric patients aged 6-12 years with a diagnosis of ADHD were selected from the Department of Psychiatry, Xijing Hospital, Air Force Military Medical University from May 2020 to May 2023. All the patients were treated with atomoxetine for 8 weeks. ADHD symptoms and SCT symptoms were assessed by Swanson, Nolan, and Pelham-Ⅳ rating scale (SNAP-Ⅳ) and SCT rating scale at baseline (before treatment), 4 weeks and 8 weeks after treatment. Pearson correlation analysis was used to analyze the correlation between SCT and SNAP-Ⅳ scores. ResultsA total of 61 pediatric patients were enrolled, including 10 cases of inattentive type and 51 cases of mixed type. Baseline SCT score was positively correlated with baseline SNAP-Ⅳ score (r＝0.490, P＜0.001) and reduction rate of SNAP-Ⅳ score at week 8 (r＝0.670, P＜0.001). The total SCT score at week 8 was positively correlated with total SNAP-Ⅳ score at baseline (r＝0.320, P＝0.012). The baseline SCT score of patients with mixed type was positively correlated with reduction rate of SNAP-Ⅳ score at week 8 (r＝0.578, P＜0.001). ConclusionsThe severity of SCT symptoms is positively correlated with the SNAP-Ⅳ reduction rate 8 weeks after atomoxetine treatment, which could be a predictor of the efficacy of atomoxetine.

This paper employs statistical methods to analyze the relationship between vegetation and climatology variables.Additionally， it quantitatively assesses vegetation feedback over East Asia using the equilibrium feedback assessment （EFA） method.The study reveals a significant correlation between vegetation and climate variables， including temperature and precipitation.In middle and high latitudes， positive feedback is observed between vegetation and temperature， while negative feedback is identified between vegetation and precipitation.In middle and low latitudes， positive feedback is observed between vegetation and precipitation， while negative feedback is identified between vegetation and temperature.In high latitudes， the positive vegetation anomaly tends to reduce the albedo by shading effect， leading to increased energy absorption and warming air during winter and spring.The analysis highlights that in low latitudes， the correlation between leading vegetation and precipitation is highly sensitive.It is mainly because the high year-round temperature in this area leads to the vegetation being dominated by precipitation signals.The study also finds a positive correlation between leading vegetation and precipitation in low latitudes.The increased vegetation stimulates moisture convergence and enhances evapotranspiration， resulting in more precipitation.The vegetation feedback parameter for temperature is positive in regions around the Da Hinggan Mountains and Baikal Lake， predominantly covered by evergreen needle-leaf forests.The feedback parameter in this area is approximately 1 to 2 ℃·(0. 1FPAR ) -1.The positive feedback parameter is identified in the southern part of China， ranging from 0.2 to 1 ℃·(0. 1FPAR ) -1.Regarding precipitation， the feedback parameter exhibits significant noise， making it challenging to distinguish signals except for the positive signal around the North China Plain.In the North China Plain， the feedback parameter for precipitation is approximately 1.5 cm·mon-1 ·(0. 1FPAR ) -1.

Abstract Objectives The study aimed to investigate the interaction of intraoperative stress hyperglycemia with monocyte functions and their impact on major adverse events (MAEs) in acute aortic dissection (AAD) patients who underwent open repair surgery. Methods A total of 321 adults who underwent open surgery for AAD at two tertiary medical centers in China were enrolled in the study. The primary endpoint was defined as the incidence and characteristics of perioperative stress hyperglycemia. The secondary endpoints included the incidence of postoperative MAEs, postoperative monocyte counts and inflammatory cytokine expression. Multi-logistic, linear regression and receiver operating characteristic (ROC) curve analyses were used to establish relationships between intraoperative time-weighted average glucose (TWAG), day-one postoperative monocyte counts, serum inflammatory cytokines and postoperative outcomes. In addition, in vitro experiments were conducted to evaluate changes in the inflammatory features of monocytes under high glucose conditions. Results Intraoperative hyperglycemia, as indicated by a TWAG level over 142 mg/dL, was associated with elevated postoperative monocyte counts and inflammatory cytokines, which correlated with extended intensive care unit (ICU) stays and worsened outcomes. In vitro, high glucose treatment induced mitochondrial impairment in monocytes, increased the release of inflammatory cytokines and the proportion of classical monocytes from AAD patients. Conclusions Intraoperative stress hyperglycemia, in combination with day-one postoperative monocyte counts, were clinically significant for predicting adverse outcomes in AAD patients undergoing open repair surgery. Elevated glucose concentrations shaped the inflammatory features of monocytes in AAD by impairing mitochondrial functions. Graphical abstract High glucose-driven mitochondrial functional impairment mediates a more pronounced monocytic inflammatory state in Stanford type-A AAD.

Abstract Background It is common knowledge that people’s intestinal microbiota is significantly influenced by the external environment. Although the Antarctic continent has been discovered for nearly 200 years, it is still unclear how this environment affects the human intestinal microbiota, especially that of the Chinese Han population. Methods Twelve explorers underwent a one-year Antarctic deployment from December 2017 to December 2018. The gut microbiota and clinical indexes at five time points, including two months (T1), five months (T2), eight months (T3), 11 months (T4) of residence in Antarctica and 7 months after returning to China (T5), were investigated. Results The intestinal microbiota of the participants was changed after one-year Antarctic deployment even after they left Antarctica. For the microbiota tested after returning to China (T5), the amount of Citrobacter, Akkermansia and conditional pathogens such as Escherichia-Shigella increased significantly (P

Abstract Background Degenerative lumbar disease significantly impairs the quality of life in elderly individuals, with short-segment lumbar degenerative disease being particularly prevalent. When conservative treatment proves ineffective, surgical intervention becomes the optimal choice for managing lumbar disease. The implementation of Enhanced Recovery After Surgery (ERAS) in spinal surgery has been progressively refined, leading to greater patient benefits. However, age and the associated decline in physiological function remain critical factors influencing surgical decision-making. Currently, there is a paucity of research focused on elderly patients undergoing lumbar fusion surgery to substantiate that advanced age does not diminish the benefits derived from ERAS in this demographic. Methods This is a retrospective cohort study of prospectively collected data. Patients who underwent short-segment (1 or 2 segments) transforaminal lumbar interbody fusion (TLIF) under the care of the same surgical team at our institution were recruited, and divided into no-ERAS-elder, ERAS-elder, and ERAS-younger groups. Subsequently, time to physiological function recovery and other outcomes were compared. Results The outcomes of the ERAS-elder group (n = 113) and the no-ERAS-elder group (n = 120) were compared. The overall physiological function recovery was significantly faster (6.71 ± 2.6 days vs. 8.6 ± 2.67 days, p = 0.01) in the ERAS-elder group. Next, the outcomes of the ERAS-elder group (n = 113) were compared with those of the ERAS-younger group (n = 100), and no significant difference in total physiological function recovery was found between the two groups (6.71 ± 2.6 days vs. 6.14 ± 1.63 days, p = 0.252). Conclusions This study shows that the implementation of the ERAS program can effectively shorten the recovery time of physiological function in elderly patients after short-segment lumbar surgery, reduce the incidence of some complications, alleviate pain, and significantly shorten the length of hospital stay. ERAS enables elderly patients to achieve outcomes comparable to those of younger patients.

Abstract The objective of this study was to ascertain the relationship between the weight-adjusted waist index (WWI) and the risk of stroke in an elderly hypertensive population, a relationship that has not been previously elucidated. The Cox regression model was employed to assess the correlation between baseline WWI measurements and the incidence of stroke. To further elucidate the shape of the association between baseline WWI and stroke, restricted cubic splines were employed. Furthermore, subgroup analyses and interaction tests were carried out to investigate potential heterogeneities. Our study cohort comprised 4962 hypertensive individuals aged 60 years or older with no prior history of stroke. Over a median follow-up of 3.2 years, we found 547 new-onset stroke cases. After adjusting for confounding variables, the Cox regression analysis revealed a positive association between baseline WWI and the risk of stroke, with hazard ratios (HRs) escalating progressively as WWI values increased. When compared to the lowest quartile of WWI, the highest quartile demonstrated an HR of 1.87 (95% CI, 1.44–2.42) for stroke. Subgroup analyses confirmed the consistency of this relationship across different demographic and clinical strata. The study findings indicate that an elevated WWI is significantly related with a higher risk of new-onset stroke among elderly patients with hypertension. These results underscore the importance of WWI as a potential risk stratification tool. To confirm these results and explore the causal mechanisms behind the observed correlation, more study is necessary.

Abstract Triptolide (TP), a major active component of the herb Tripterygium wilfordii Hook F, has been shown excellent pharmacological effects on rheumatoid arthritis. However, TP is prone to causing severe organ toxicity, which limits its clinical application. In recent years, microneedle technology has provided a new option for the treatment of arthritis due to its advantages of efficient local transdermal drug delivery. In this study, we constructed a microneedle platform to deliver TP locally to the joints, thereby enhancing TP penetration and reducing systemic toxicity. Additionally, we investigated whether acupoint drug delivery can produce a synergistic effect of needles and drugs. First, TP was loaded into microneedles using polyvinylpyrrolidone and hyaluronic acid as matrix materials. Next, we established a rat adjuvant-induced arthritis (AIA) model to evaluate the therapeutic effect of TP-loaded microneedles. The experiments showed that TP-loaded microneedles alleviated the AIA rats’ inflammatory response, joint swelling, and bone erosion. However, there was no significant difference in the therapeutic effect observed in the acupoint and non-acupoint administration groups. In conclusion, TP-loaded microneedles have the advantages of safety, convenience, and high efficacy over conventional administration routes, laying a foundation for the transdermal drug delivery system-based treatment of rheumatoid arthritis.

Abstract The growing popularity of ChatGPT and other large language models (LLMs) has led to many studies investigating their susceptibility to mistakes and biases. However, most studies have focused on models trained exclusively on English texts. This is one of the first studies that investigates cross-language political biases and inconsistencies in LLMs, specifically GPT models. Using two languages, English and simplified Chinese, we asked GPT the same questions about political issues in the United States (U.S.) and China. We found that the bilingual models’ political knowledge and attitude were significantly more inconsistent regarding political issues in China than those in the U.S. The Chinese model was the least negative toward China’s problems, whereas the English model was the most critical of China. This disparity cannot be explained by GPT model robustness. Instead, it suggests that political factors such as censorship and geopolitical tensions may have influenced LLM performance. Moreover, both the Chinese and English models tended to be less critical of the issues of their “own country,” represented by the language used, than of the issues of “the other country.” This suggests that multilingual GPT models could develop an “in-group bias” based on their training language. We discuss the implications of our findings for information transmission in an increasingly divided world.

Abstract The COVID-19 pandemic has led to a surge in medical waste generation, posing hazards to both the environment and global health. The impacts of the COVID-19 pandemic’s medical waste hazard may persist long after the pandemic itself subsides. Improper disposal of medical waste can contaminate environment, posing risks to ecosystems and public health. Discarded medical rubber gloves, for example, can become a source of infection, improper disposal of these gloves can escalate the spread of infectious diseases and increase the risk of transmission of the virus to the general public. This study proposes an innovative and sustainable method to reinforce cement mortar by adding recycled glove rubber as an additive to cement mortar to increase its resistance to impact loads. This study conducted uniaxial compression tests, separating hopkinson pressure bar (SHPB) experiments and SEM observations to evaluate the quasi-static compressive strength and dynamic stress of recycled rubber fiber mortar (RRFM) with varying recycled rubber fiber (RRF) contents (0, 1%, 2%, 3%). Strain curves, dynamic increase factor (DIF), energy absorption rules, failure modes, and microstructure of RRFM mixtures. The experimental results demonstrate that with the addition of RRF, the dynamic stress-strain curve flattens and the peak strain gradually increases. The RRFM sample shows stronger toughness. In comparison to regular cement mortar (NM), RRFM has a higher DIF and specific absorbed energy, a faster increase in dynamic compressive strength, and the ability to absorb more energy per unit volume. Under the same impact load, RRFM has fewer and smaller cracks than NM. Scanning electron microscopy (SEM) testing also observed that RRF formed a strong connection pattern with the cement mortar matrix.

Abstract Gastric cancer (GC) is a highly heterogeneous and aggressive malignant tumor that seriously affects the life safety of people all over the world. Its early manifestations are subtle. The present study aimed to investigate the clinical significance of serum lipid profiles, insulin resistance markers including the triglyceride-glucose (TyG) index and the atherosclerotic index (AI), in GC patients. A retrospective analysis encompassed 215 GC patients and 827 healthy individuals. The study results show that the total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein levels, and the TyG index of GC patients were significantly lower than those of the control group before and after propensity score matching analysis. In the GC group, the levels of CEA, CA199, CA125, and CA724 tumor markers were higher than those in the healthy control group. Patients in advanced stages exhibited lower serum levels of serum lipids and TyG index compared to those in early stages. ROC analysis revealed that the TyG index, CA125, and CA199 combination yielded the highest positive prediction rate for GC at 98.6%. TyG index is significantly associated with the risk of adverse reactions after chemotherapy (OR = 1.104, 95% CI 1.028–1.186, P

Abstract Duck plague virus (DPV) causes the highly pathogenic duck plague, and the envelope glycoprotein I (gI), as one of the key virulence genes, has not yet had its critical virulence sites identified through screening. This study used reverse genetics technology to target the gI, specifically within the DPV genome. Four DPV mutants with gI N-glycosylation site mutations were designed and constructed, and these mutant strains were successfully rescued. Our results confirmed that three asparagine residues of gI (N69, N78, and N265) are N-glycosylation sites, and western blot analysis substantiated that glycosylation at each predicted N-glycosylation site was compromised. The deglycosylation of gI leads to the protein misfolding and subsequent retention in the endoplasmic reticulum (ER). The subsequent deglycosylated gI is carried into the Golgi apparatus (GM130) in the interaction of gE. Compared to the parental virus, the mutated virus shows a 66.3% reduction in intercellular transmission capability. In ducks, the deglycosylation of gI significantly reduces DPV replication in vivo, thereby weakening the virulence of DPV. This study represents the first successful creation of a weak DPV virus strain by specific mutation at the N-glycosylation site. The findings provide a foundational understanding of DPV pathogenesis and form the basis for developing live attenuated vaccines against the disease.

Abstract Background The family Lauraceae is subdivided into six main lineages: Caryodaphnopsideae, Cassytheae, Cryptocaryeae, Hypodaphnideae, Laureae, and Neocinnamomeae. However, phylogenetic relationships among these lineages have been debatable due to incongruence between trees constructed using nuclear ribosomal DNA (nrDNA) sequences and chloroplast (cp) genomes. As with cp DNA, the mitochondrial (mt) DNA of most flowering plants is maternally inherited, so the phylogenetic relationships recovered with mt genomes are expected to be consistent with that from cp genomes, rather than nrDNA sequences. Results The mitogenome of Machilus yunnanensis, with a length of 735,392 bp, has a very different genome size and gene linear order from previously published magnoliid mitogenomes. Phylogenomic reconstructions based on 41 mt genes from 92 Lauraceae mitogenomes resulted in highly supported relationships: sisterhood of the Laureae and a group containing Neocinnamomeae and Caryodaphnopsideae, with Cassytheae being the next sister group, followed by Cryptocaryeae. However, we found significant incongruence among the mitochondrial, chloroplast, and nuclear phylogenies, especially for the species within the Caryodaphnopsideae and Neocinnamomeae lineages. Time-calibrated phylogenetic analyses showed that the split between Caryodaphnopsideae and Neocinnamomeae dated to the later Eocene, around 38.5 Ma, Laureae originated in the Late Cretaceous, around 84.9 Ma, Cassytheae originated in the mid-Cretaceous around 102 Ma, and Cryptocaryeae originated in the Early Cretaceous around 116 Ma. From the Late Cretaceous to the Paleocene, net diversification rates significantly increased across extant clades of major lineages, and both speciation rates and net diversification rates continued steady growth towards the present. Conclusions The topology obtained here for the first time shows that mt genes can be used to support relationships among lineages of Lauraceae. Our results highlight that both Caryodaphnopsideae and Neocinnamomeae lineages are younger than previously thought, likely first diversifying in the Eocene, and species in the other extant lineages of Lauraceae dates in a long-time span from the Early Cretaceous to the Eocene, and the climate of a period of about 90 million years was relatively warm, while the extant species of Lauraceae then continuously diversified with global cooling from the Eocene to the present day.

Abstract Background Cerebral venous thrombosis (CVT) is a rare but serious condition that can lead to significant morbidity and mortality. Virchow’s triad elucidates the role of blood hypercoagulability, blood flow dynamics, and endothelial damage in the pathogenesis of CVT. Cerebral venous congestion (CVC) increases the risk of cerebral venous sinus thrombosis and can lead to recurrent episodes and residual symptoms. However, the precise mechanism by which blood congestion leads to thrombosis remains unclear. Our objective was to investigate the cellular and molecular alterations linked to CVC through analysis of the pathological morphology of venous sinus endothelial cells and transcriptomic profiling. Results This study demonstrated a remarkable correlation between CVC and the phenotypic transformation of endothelial cells from an anticoagulant to a procoagulant state. The findings revealed that cerebral venous stasis results in tortuous dilatation of the venous sinuses, with slow blood flow and elevated pressure in the sinuses and damaged endothelial cells of the retroglenoid and internal jugular vein ligation (JVL) rat model. Mechanistically, analysis of transcriptomic results of cerebral venous sinus endothelial cells showed significant activation of platelet activation, complement and coagulation cascades pathway in the JVL rats. Furthermore, the expression of von Willebrand factor (vWF) and coagulation factor VIII (F8) in the complement and coagulation cascades and Fgg and F2 in the platelet activation was increased in the cerebral venous sinuses of JVL rats than in sham rats, suggesting that endothelial cell injury in the venous sinus induced by CVC has a prothrombotic effect. In addition, endothelial cell damage accelerates coagulation and promotes platelet activation. Significantly, the concentrations of vWF, F2 and F8 in venous sinus blood of patients with internal jugular vein stenosis were higher than in their peripheral blood. Conclusion Collectively, our data suggest that CVC can induce endothelial cell damage, which then exhibits a procoagulant phenotype and ultimately increases the risk of CVT. This research contributes to our understanding of the pathophysiology of CVC associated with procoagulant factors and reexamines the components of Virchow’s triad in the context of CVC.

Abstract Background Cyberbullying and health risk behaviors are pervasive issues for secondary vocational students that not only detrimentally impact their academic achievement but also pose a significant threat to overall health. The purpose of this study was to understand the current situation of cyberbullying and health risk behaviors among secondary vocational students in China and to explore the relationships among cyberbullying, self-control, self-control over internet usage, and health risk behaviors through a mediation model. Methods This was a cross-sectional study. From March to April 2023, a self-administered questionnaire was completed by a cluster sample of 1184 students from grades 1 to 3 at three secondary vocational schools in Jilin Province. The researchers utilized a sociodemographic questionnaire, the Cyberbullying and Cybervictimization Scale (CAV), the Adolescent Health Related Risky Behavior Inventory (AHRBI), the Self-Control Scale (SCS), and the Internet Usage Self-Control Scale (IUSCS-CS) to assess the prevalence and impact of cyberbullying and health risk behaviors. Descriptive statistics, spearman correlation analyses. Finally, the Process plug-in V2.16.3 was used to analyze a mediation model for the data. Results Among secondary vocational students, 839 individuals (70.86%) experienced cyberbullying and 1036 individuals (87.50%) had one or more health risk behaviors. A chi-square test showed that the differences in cyberbullying incidence were statistically significant (P

Nonalcoholic steatohepatitis (NASH) may soon become the leading cause of end-stage liver disease worldwide with limited treatment options. Liver fibrosis, which is driven by chronic inflammation and hepatic stellate cell (HSC) activation, critically determines morbidity and mortality in patients with NASH. Pyruvate kinase M2 (PKM2) is involved in immune activation and inflammatory liver diseases; however, its role and therapeutic potential in NASH-related fibrosis remain largely unexplored. Bioinformatics screening and analysis of human and murine NASH livers indicated that PKM2 was upregulated in nonparenchymal cells (NPCs), especially macrophages, in the livers of patients with fibrotic NASH. Macrophage-specific PKM2 knockout (PKM2FL/FLLysM-Cre) significantly ameliorated hepatic inflammation and fibrosis severity in three distinct NASH models induced by a methionine- and choline-deficient (MCD) diet, a high-fat high-cholesterol (HFHC) diet, and a western diet plus weekly carbon tetrachloride injection (WD/CCl4). Single-cell transcriptomic analysis indicated that deletion of PKM2 in macrophages reduced profibrotic Ly6Chigh macrophage infiltration. Mechanistically, PKM2-dependent glycolysis promoted NLR family pyrin domain containing 3 (NLRP3) activation in proinflammatory macrophages, which induced HSC activation and fibrogenesis. A pharmacological PKM2 agonist efficiently attenuated the profibrotic crosstalk between macrophages and HSCs in vitro and in vivo. Translationally, ablation of PKM2 in NPCs by cholesterol-conjugated heteroduplex oligonucleotides, a novel oligonucleotide drug that preferentially accumulates in the liver, dose-dependently reversed NASH-related fibrosis without causing observable hepatotoxicity. The present study highlights the pivotal role of macrophage PKM2 in advancing NASH fibrogenesis. Thus, therapeutic modulation of PKM2 in a macrophage-specific or liver-specific manner may serve as a novel strategy to combat NASH-related fibrosis.

University admission consultation is a professional service that assists students with the university application process. Typically, accessing this service entails exploring university websites, directly contacting faculty members and officers via phone calls or emails, and engaging educational intermediaries. University admission consultation is crucial for both students and institutions. However, conventional consultation methods face challenges such as time and spatial constraints, leading to a growing interest in utilizing chatbots for university admission consultation. In this study, we propose a novel approach that leverages generative pretrained transformer (ChatGPT 3.5) models and implements the retrieval-augmented generation technique using the LlamaIndex framework. To evaluate the effectiveness of this approach, we applied it to undergraduate admission data from three universities: a science and technology university in the United States, a comprehensive university in Kenya, and a comprehensive university in Hong Kong. We also gathered feedback from 53 high school students who tested the chatbot. The results demonstrated a significant improvement in average accuracy, from 41.4% with the ChatGPT 3.5 model to 89.5% with the proposed chatbot, with peak accuracy reaching 94.7%. User reviews also indicated a generally positive perception of the admission chatbot. This methodology has the potential to revolutionize university admissions by utilizing chatbots based on large language models with retrieval-augmented generation.

Enrico Torre,1 Sergio Di Matteo,2 Chiara Martinotti,2 Giacomo Matteo Bruno,3 Umberto Goglia,4 Gianni Testino,5 Alberto Rebora,1 Luigi Carlo Bottaro,6 Giorgio Lorenzo Colombo3 1Diabetology and Metabolic Diseases Unit - ASL3, Genoa, Italy; 2Center of Research, SAVE Studi - Health Economics and Outcomes Research, Milan, Italy; 3Department of Drug Sciences, University of Pavia, Pavia, Italy; 4Territorial Diabetology Unit, ASLCN1, Cuneo, Italy; 5Units of Addiction and Hepatology, ASL3, Genoa, Italy; 6General Direction, ASL3, Genoa, ItalyCorrespondence: Giorgio Lorenzo Colombo, Email giorgio.colombo@unipv.itBackground: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multisystem condition destined to become pandemic in the coming decades. This study aimed at evaluating the economic impact of MASLD in the Italian population from the Italian National Healthcare Service (NHS) perspective.Methods: The economic impact of the MASLD was assessed by developing a calculation model in Microsoft Excel® from the Italian NHS perspective, considering healthcare resources and direct costs. The target population was based on the prevalence data. Through a literature search, complications of MASLD were identified, including MASH, with relative risk of evolution into CC, DCC, HCC, T2DM, cardiovascular diseases, in particular AMI and stroke, CKD, and CRC. The differential impact between complication development in the population with MASLD and the same sample size population without-MASLD was evaluated. Differential risk data, mortality rates, and event unit costs were drawn from the published international literature. Frequency and cost data were applied to the total target population, the total annual costs and mortality data, referring to the two arms, were then calculated, and the differential value was obtained.Results: Based on an estimated 11,546,370 MASLD target population, an annual illness impact of € 12,251,631,822 was calculated, corresponding to a difference of € 7,731,674,054 compared with the same sample size without MASLD. Moreover, the MASLD population is expected to experience 13,438 additional deaths annually.Conclusion: The growing epidemiological impact of MASLD and its complications represent a huge economic burden for healthcare services worldwide. An integrated approach, including changes in lifestyle behaviors, will be the first step. Specific drugs for MASLD are not yet available; however, studies are underway, and combined pharmaceutical therapies may be an inevitable choice to achieve adequate control of MASLD and its complications.Keywords: metabolic associated fatty liver disease MASLD, complications, MASLD burden in Italy, healthcare costs, treatment and perspectives

Abstract In recent years, immunotherapy has developed rapidly as a new field of tumour therapy. However, the efficacy of tumour immunotherapy is not satisfactory due to the immune evasion mechanism of tumour cells, induction of immunosuppressive tumour microenvironment (TME), and reduction of antigen delivery, etc. CRISPR/Cas9 gene editing technology can accurately modify immune and tumour cells in tumours, and improve the efficacy of immunotherapy by targeting immune checkpoint molecules and immune regulatory genes, which has led to the great development and application. In current clinical trials, there are still many obstacles to the application of CRISPR/Cas9 in tumour immunotherapy, such as ensuring the accuracy and safety of gene editing, overcoming overreactive immune responses, and solving the challenges of in vivo drug delivery. Here we provide a systematic review on the application of CRISPR/Cas9 in tumour therapy to address the above existing problems. We focus on CRISPR/Cas9 screening and identification of immunomodulatory genes, targeting of immune checkpoint molecules, manipulation of immunomodulators, enhancement of tumour-specific antigen presentation and modulation of immune cell function. Second, we also highlight preclinical studies of CRISPR/Cas9 in animal models and various delivery systems, and evaluate the efficacy and safety of CRISPR/Cas9 technology in tumour immunotherapy. Finally, potential synergistic approaches for combining CRISPR/Cas9 knockdown with other immunotherapies are presented. This study underscores the transformative potential of CRISPR/Cas9 to reshape the landscape of tumour immunotherapy and provide insights into novel therapeutic strategies for cancer patients.

Abstract Diabetic encephalopathy (DE) is a severe complication of diabetes, but its pathogenesis remains unclear. This study aimed to investigate the roles and underlying mechanisms of high glucose (HG)- and advanced glycosylation end product (AGE)-induced oxidative stress (OS) in the cognitive decline in DE. The DE mouse model was established using a high-fat diet and streptozotocin, and its cognitive functions were evaluated using the Morris Water Maze, novel object recognition, and Y-maze test. The results revealed increased reactive oxygen species (ROS) generation, mitophagy inhibition, and decreased prohibitin 2 (PHB2) expression in the hippocampal neurons of DE mice and HG- or AGE-treated HT-22 cells. However, overexpression of PHB2 reduced ROS generation, reversed mitophagy inhibition, and improved mitochondrial function in the HG- or AGE-treated HT-22 cells and ameliorated cognitive decline, improved mitochondrial structural damage, and reversed mitophagy inhibition of hippocampal neurons in DE mice. Further analysis revealed that the Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was involved in the HG- or AGE-mediated downregulation of PHB2 in HT-22 cells. These results demonstrate that HG- or AGE-induced OS inhibits the mitophagy of hippocampal neurons via the Keap1–Nrf2–PHB2 pathway, thereby contributing to the cognitive decline in DE.

Abstract Background Hepatitis B virus (HBV) clearance depends on an effective adaptive immune response, especially HBV-specific T cell-mediated cellular immunity; however, it is difficult to produce enough HBV-specific T cells effectively. Results In this work, we investigated the proportions of stimulated cells, serum, and culture media as the three primary factors to determine the most effective procedure and applied it to HLA-A2 (+) people. In parallel, we also examined the correlation between clinical parameters and HBV-specific immunity. Concerning amplification efficiency, 4 × 105 cells stimulation was superior to 2 × 106 cells stimulation, AIM-V medium outperformed 1640 medium, and fetal bovine serum (FBS) exceeded human AB serum under comparable conditions. As expected, this procedure is also suitable for developing HBV-specific CD8 + T cells in HLA-A2(+) individuals. Expanded HBV-specific T cell responses decreased with treatment time and were negatively correlated with HBV DNA and HBsAg. Furthermore, the number of HBV-specific IFN-γ + SFCs was strongly correlated with the ALT level and negatively correlated with the absolute lymphocyte count and the ALB concentration. Conclusions We confirm that stimulating 4 × 105 PBMCs in AIM-V medium supplemented with 10% FBS is the best approach and that HBeAg, HBsAg, and ALB are independent predictors of HBV-specific T-cell responses.

Abstract Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors (TKIs), possess immunomodulatory properties and have shown promising outcomes when combined with anti-PD-1 antibodies. The OASIS phase II trial (NCT04503967) is designed to determine the clinical activity and safety of nivolumab (anti-PD-1) and anlotinib hydrochloride (a multi-targets TKI) as second-line or above therapy in patients with advanced gastric adenocarcinoma (GAC) and esophageal squamous cell carcinoma (ESCC). From December 2020 to September 2022, 45 patients with GAC and 3 with ESCC were enrolled in this study. The pre-specified endpoints were reached, with the primary endpoint of overall response rate achieving 29.2%. For secondary objectives, disease control rate was 64.6%; median progression-free survival was 4.0 months; and median overall survival was 11.1 months with a manageable toxicity profile. The exploratory analyses unveiled that the balance of gut bacteria and the presence of a pre-existing immune signature characterized by a high percentage of CD68+PD-L1+ PD-1+ macrophages and low pretreatment variant allele frequencies (VAF), as well as low expression of certain cytokines were significantly associated with improved clinical outcomes in patients with GAC.

Abstract Immune checkpoint blockade (ICB) is a promising cancer therapy; however, resistance frequently develops. To explore ICB resistance mechanisms, we develop Immunotherapy Resistance cell-cell Interaction Scanner (IRIS), a machine learning model aimed at identifying cell-type-specific tumor microenvironment ligand-receptor interactions relevant to ICB resistance. Applying IRIS to deconvolved transcriptomics data of the five largest melanoma ICB cohorts, we identify specific downregulated interactions, termed resistance downregulated interactions (RDI), as tumors develop resistance. These RDIs often involve chemokine signaling and offer a stronger predictive signal for ICB response compared to upregulated interactions or the state-of-the-art published transcriptomics biomarkers. Validation across multiple independent melanoma patient cohorts and modalities confirms that RDI activity is associated with CD8 + T cell infiltration and highly manifested in hot/brisk tumors. This study presents a strongly predictive ICB response biomarker, highlighting the key role of downregulating chemotaxis-associated ligand-receptor interactions in inhibiting lymphocyte infiltration in resistant tumors.

Intense precipitation infiltration and intricate excavation processes are crucial factors that impact the stability and security of towering and steep rock slopes within mining sites. The primary aim of this research was to investigate the progression of cumulative failure within a cracked rock formation, considering the combined effects of precipitation and excavation activities. The study was conducted in the Huangniuqian eastern mining area of the Dexing Copper Mine in Jiangxi Province, China. An engineering geological investigation was conducted, a physical model experiment was performed, numerical calculations and theoretical analysis were conducted using the matrix discrete element method (MatDEM), and the deformation characteristics and the effect of the slope angle of a fractured rock mass under different scenarios were examined. The failure and instability mechanisms of the fractured rock mass under three slope angle models were analyzed. The experimental results indicate that as the slope angle increases, the combined effect of rainfall infiltration and excavation unloading is reduced. A novel approach to simulating unsaturated seepage in a rock mass, based on the van Genuchten model (VGM), has been developed. Compared to the vertical displacement observed in a similar physical experiment, the average relative errors associated with the slope angles of 45°, 50°, and 55° were 2.094%, 1.916%, and 2.328%, respectively. Accordingly, the combined effect of rainfall and excavation was determined using the proposed method. Moreover, the accuracy of the numerical simulation was validated. The findings contribute to the seepage field in a meaningful way, offering insight that can inform and enhance existing methods and theories for research on the underlying mechanism of ultra-high and steep rock slope instability, which can inform the development of more effective risk management strategies.

Abstract Background The enhancement of nurses’ disaster literacy is crucial for effective disaster emergency management, especially for clinical nurses with no prior experience in disaster rescue. This study aims to explore the perspectives of nurses who have been involved in disaster rescue operations on strategies to advance nurses’ disaster literacy. Methods A qualitative descriptive study, which follows unified qualitative study reporting guidelines. Thirty disaster rescue nurses were recruited to participate in this study, who came from 30 third-class hospitals in China. From October to December 2021, information was acquired by conducting semi-structured telephone interviews with participants. Qualitative content analysis was used to examine the data. Results Six categories and eleven subcategories were created. Strengthening disaster education and training was the main focus, and its subcategories included continuing education, nursing curriculum development, and disaster rescue experience guide. The second focus, which included scene simulation, actual combat/military simulation, and virtual reality simulation, was strengthening disaster simulation and drill. The third focus was on providing psychosocial support, which included improving self-psychological adjustment, developing resilience, and engaging in active coping. The fourth category was to strengthen nurse/hospital managers roles and leadership, which included enhancing professional identity and policies/leadership support. The fifth category was disaster preparedness, and the sixth was enhancing knowledge transformation. Conclusions Government agencies or healthcare organizations should actively promote the formation of nurses’ disaster literacy from multiple viewpoints. Disaster education and training, simulation exercises, and psychosocial support should be prioritized.

Abstract Inflammation plays a crucial role in cancer development. The neutrophil-to-lymphocyte ratio (NLR), a measure of inflammation, is obtained from a complete blood count. However, little is known about the association between NLR and cancer in the general adult population in the United States. This study aimed to evaluate whether NLR is associated with cancer in American adults. This retrospective cross-sectional study included 28,016 adult participants from the National Health and Nutrition Examination Survey (NHANES) dataset spanning 2005 to 2018. Data on demographics (age, sex, race, marital status, Poverty-Income Ratio, education level), lifestyle factors (smoking, alcohol consumption, body mass index), medical conditions (hypertension, diabetes, cardiovascular disease), and laboratory parameters (hemoglobin, platelet count, alanine aminotransferase, creatinine, albumin, and lactate dehydrogenase), were collected. Logistic regression analysis was used to investigate the research objectives. Of the total 28,016 participants, 2639 had cancer. The mean age was 49.6 ± 17.6 years, and 50% were male. A positive association between NLR and cancer risk was observed after multivariate adjustment (OR = 1.20, 95% confidence interval (CI) = 1.05–1.36, p = 0.006). Similar patterns were observed in subgroup analyses (all p-values for interaction > 0.05). A higher NLR was directly correlated with an increased risk of developing cancer in adults.

Abstract Low serum albumin levels increase coronary morbidity, mortality, and postoperative cardiovascular risk. Therefore, this study investigated the relationship between these levels and the length of hospital stay in patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome. A total of 350 patients were divided into quartiles according to serum albumin levels. Univariate and multivariate analyses were performed to identify factors associated with the length of hospital stay. A non-linear regression analysis of serum albumin and length of hospital stay was also performed. The results of the multifactorial analysis revealed low serum albumin levels as an independent predictor of longer hospital stay, even in the fully adjusted model. In the segmented linear regression model, serum albumin level showed a U-shaped relationship with the length of hospital stay. In conclusion, low serum albumin level was an independent predictor of longer hospital stay in patients undergoing PCI for acute coronary syndrome, with shorter stays observed for increasing serum albumin levels. Low serum albumin can be used to identify patients who require longer hospitalization and may need additional nutritional support or interventions to improve their prognosis.

Abstract In the control of unipolar sinusoidal excited switched reluctance motors (SRMs), deadbeat predictive current controllers (DPCCs) have gained attention for their enhanced dynamic performance. However, periodic disturbances caused by mismatches between the predictive model’s nominal and actual system parameters degrade the control performance of SRMs. To address this issue, a robust DPCC with multi-parameter compensation is proposed to improve dq0-axes current control performance. By analyzing the impact of parameter mismatches, a Kalman filter (KF) is developed to compensate for inductance coefficient mismatches, mitigating periodic disturbances. Additionally, a disturbance estimator with measurement noise suppression is integrated into the DPCC for both state and disturbance estimation to handle residual uncertainties, including winding resistance mismatches, magnetic saturation, and unmodeled dynamics. Compared simulation and experimental results validate the effectiveness of the proposed robust DPCC.

Abstract Previous studies suggest that a high body mass index (BMI) may be a risk factor for keratoconus (KC), but the causal relationship remains unclear. This study used Mendelian randomization (MR) to investigate this connection and explore the mediating role of circulating serum metabolites and inflammatory factors in this association. Two-sample MR analysis was conducted to assess the relationship between BMI and KC. The study employed a two-step MR approach to evaluate the mediating roles of 91 inflammatory markers and 249 serum metabolites in the BMI-KC relationship. Inverse variance weighting (IVW) was the primary method, and multiple sensitivity analyses were performed to ensure robustness. IVW analysis revealed a positive causal relationship between BMI and KC (OR IVW = 1.811, 95% CI 1.005–3.262, P = 0.048). Although IL-12β and IL-4 were causally associated with KC, they did not mediate the BMI-KC relationship. Five serum metabolites were identified as potential mediators, with HDL cholesterol and triglyceride ratios showing significance. This study clarified the causal relationship between high BMI and KC, suggesting that high BMI may induce KC through lipid metabolism abnormalities. These findings underscore the importance of managing BMI for KC prevention.