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Abstract Purpose To investigate the impact and safety of canagliflozin combined with metformin on reducing cardiovascular risk in patients with type 2 diabetes mellitus (T2DM). Methods A total of 258 patients with T2DM admitted to our hospital from March 2021 to March 2022 were selected and divided into a control group and an observation group using a random number table. The control group received metformin combined with a placebo, while the observation group received canagliflozin combined with metformin therapy. All patients received drug treatment for 52 weeks. The primary endpoint of the study was major adverse cardiovascular events (MACE), including myocardial infarction, ischemic stroke, and cardiovascular death. Other study parameters included safety after medication, severe adverse reactions, levels of glycated hemoglobin (HbA1c), body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and estimated glomerular filtration rate (eGFR). Results After treatment, HbA1c, FPG, BMI, SBP, and DBP in both groups were lower than before treatment, and those indicators in the observation group were lower than those in the control group (P 0.05). Conclusion In patients with T2DM who received the canagliflozin combined with metformin, the mortality rate of cardiovascular causes was significantly reduced. Compared with metformin monotherapy, there is no significant difference in the incidence of serious adverse reactions, and the safety of medication is better, while the blood sugar, blood pressure, and weight of T2DM patients are more actively improved. For T2DM patients with high risk of cardiovascular disease, the combination of canagliflozin and metformin could have a higher benefit in cardiovascular outcomes.

Abstract There is insufficient evidence to guide dose and frequency optimization with repeated-dose ketamine for depression. This study assessed the value of symptomatic non-improvement after the first few ketamine infusions as a predictor of overall non-response in depression for early decision-making to discontinue treatment. A total of 135 individuals with major depressive disorder or bipolar disorder experiencing a current major depressive episode were administered six repeated doses of intravenous ketamine. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline, 4 h after the first infusion, and 24 h after each infusion. Improvement, partial response, and response were defined as a reduction rate of ≥ 20%, 30%, and 50% in MADRS scores, respectively. This study examined the relationship between improvement (as opposed to non-improvement after each infusion or consecutive non-improvements after the first few infusions) and partial response and response after the sixth infusion. This analysis was summarized using sensitivity, specificity, and other diagnostic test parameters. The sensitivities of improvement at 24 h post-infusion 4 and improvement at 24 h post-infusion 3, vs. three consecutive non-improvements, as predictors for overall partial response and response exceeded 90%. No significant reduction in depressive symptoms was seen in non-improvers following the remaining infusions after the above-identified point. Our study suggests that non-improvement after four infusions, or more conservatively three consecutive non-improvements after three infusions, could serve as a signal of overall non-response to repeated-dose intravenous ketamine for depression and that subsequent treatments would not be warranted.

Abstract Background The prevalence of obesity is escalating. Previous research has concentrated on the link between frailty and obesity; however, the association between prefrailty and obesity has been less studied. Prefrailty screening and intervention may prevent or postpone frailty in older persons. Objective The study was to investigate into the relationship between prefrailty and several obesity indicators in Chinese community-dwelling older individuals. Methods This research employed the Frailty Screening Index to investigate the frailty phenotype of people living in Shanghai. Bioelectrical impedance analysis was used for evaluating body composition. Results There were 510 participants (39.0%) with high visceral adipose areas. Participants with a high visceral adipose area showed a higher risk of prefrailty (adjusted OR, 1.53; 95% CI, 1.19–1.96), according to multivariate models. When body mass index (BMI) and visceral fat area (VFA) were combined, it was discovered that having an overweight BMI with normal VFA was a protective factor for prefrailty (corrected OR, 0.62; 95% CI, 0.43–0.90), but having a normal weight but excess VFA increased the risk of prefrailty (corrected OR, 1.87; 95% CI, 1.15–3.03). Conclusion Visceral fat obesity is an independent risk factor for prefrailty in Chinese older adults. Implementing targeted interventions, such as dietary modifications, increased physical activity, and other lifestyle changes, could play a crucial role in reducing the risk of prefrailty and improving overall health outcomes in this population.

Objective To explore the enrichment conditions and main controlling factors of shale gas in the Lower Wuerhe Formation of the Permian System in the Junggar Basin, the Lower Wuerhe Formation in the Dongdaohaizi Sag was selected as the research object. Methods Based on the data of outcrop, core, well logging, well-calibrated seismic reflections and the technologies of total organic carbon (TOC) content determination, whole-rock X-ray diffraction, gas adsorption (N2, CO2), the distribution characteristics, organic matter development characteristics, reservoir characteristics, and gas bearing characteristics of the Lower Wuerhe Formation shale were studied. Results The results show that: (1) The organic matter of the Lower Wuerhe Formation shale is dominated by Ⅱ2 and Ⅲ types and shows an average TOC content of 1.58%. The average vitrinite reflectance (Ro) of organic matter is 1.46%, which indicates the mature stage. The average thickness of the source rock is 75 m. Summarily, the source rock is good and has a high gas potential. The basin simulation results show an average shale gas content of 1.89 m3/t in the Lower Wuerhe Formation. (2) The pores and microfractures in shale reservoirs are highly developed, and gas is primarily adsorbed in micropores and mesopores. The average porosity and permeability are 6.10% and 0.27×10-3 μm2 respectively, which are favourable for shale gas accumulation. (3) The shale has a high clay mineral content, with an average of 29.6%, providing a significant specific surface area and enhancing the gas adsorption capacity of the shale. Additionally, the average brittle mineral content is 50.9%, indicating good frackability. (4) Moreover, the shale reservoir exhibits a relatively large pressure coefficient of 1.58, indicating the favourable conservation conditions. The analysis of the regional tectonic-sedimentary environment and geochemical parameters indicates that the main factors controlling shale gas accumulation in the Lower Wuerhe Formation of the Dongdaohaizi Sag are geochemical parameters and preservation conditions. The key factors influencing shale gas accumulation include the high thermal evolution maturity of organic matter, large shale thickness, high TOC content, and good preservation conditions. These conditions suggest that the favourable area for shale gas exploration and development in the Dongdaohaizi Sag is located in the northeastern slope area of the sag's abdomen. Conclusion The results of this research reveal the enrichment conditions and main controlling factors of shale gas in the Lower Wuerhe Formation in the Dongdaohaizi Sag, which has reference value for deep oil and gas exploration in the abdominal area of the Junggar Basin.

Abstract The RATIONALE-306 study revealed that patients with advanced or metastatic oesophageal squamous cell carcinoma (OSCC) could benefit from treatment with tislelizumab plus chemotherapy. This study aimed to evaluate the cost-effectiveness of tislelizumab plus chemotherapy for treating OSCC from the perspective of the Chinese healthcare system. Partitioned survival model estimated the cost-effectiveness of tislelizumab plus chemotherapy compared with chemotherapy alone for treating OSCC using RATIONALE-306 data. Costs and utilities were obtained from local databases and published studies. Costs, quality-adjusted life-years (QALYs), life-years, incremental cost-effectiveness ratios (ICER), incremental net health benefits (INHB), and incremental net monetary benefits (INMB) were outcomes. Price simulation were conducted at the willingness-to-pay (WTP) threshold. Sensitivity and subgroup analyses were performed to assess model robustness. Compared with chemotherapy alone, tislelizumab plus chemotherapy yielded an ICER of USD 27,896/QALY, gained an additional 0.414 QALYs and 0.751 life-years, and increased the cost by USD 11,560. Probabilistic sensitivity analysis revealed that tislelizumab plus chemotherapy was cost-effective at the WTP of USD 38,258/QALY with probability of 94.43%. When the price in China was less than USD 3.714 per mg, the price simulation results indicated that tislelizumab plus chemotherapy was cost-effective at a WTP threshold of USD 38,258. Tislelizumab plus chemotherapy yielded an INHB of 0.112 QALYs and an INMB of USD 4,279 compared with chemotherapy alone at a WTP threshold of USD 38,258. Based on the sensitivity analyses, the above results were stable. A general trend was observed for subgroups with better survival benefits related to a higher probability of cost-effectiveness. From the Chinese healthcare perspective, tislelizumab plus chemotherapy is more cost-effective than chemotherapy alone as a first-line therapy for OSCC. These findings can help clinicians make optimal clinical decisions and assist decision-makers in evaluating the cost-effectiveness of tislelizumab in clinical practice.

Abstract Patients with PD-L1-positive esophageal squamous-cell carcinoma (ESCC) were significantly more likely to survive when treated with serplulimab plus cisplatin plus 5-fluorouracil (serplulimab-CF). At this point, it is unknown whether this expensive therapy is cost-effective. From the Chinese healthcare system's perspective, we aimed to evaluate serplulimab-CF versus CF alone for cost-effectiveness. A partitioned survival model was constructed based on the ASTRUM-007 trial. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER) were calculated. A further analysis of subgroups and scenarios was conducted. The willingness to pay (WTP) threshold of $38,258/QALY or $84,866/QALY is defined as three times the per capita gross domestic product value of the general region or affluent region. Compared with CF alone, in the overall (scenario 1), patients with PD-L1 expression level of 1 ≤ CPS

Abstract To achieve high-efficiency combustion of heavy fuel oil (HFO), this study investigated the combustion characteristics of methanol/HFO droplets with methanol content from 10 to 30% using the suspension method under ambient temperature from 923 to 1023 K. The combustion of methanol/HFO droplets was summarized as a two-phase process consisting of six typical stages, emphasizing liquid phase. Especially, the fluctuation evaporation stage, induced by frequent and intense puffing, was identified as prominent character. Both the ignition delay and lifetime of HFO and methanol/HFO droplets decreased with increasing ambient temperatures. For the methanol/HFO droplet, the ignition delay and droplet lifetime increased with the increasing methanol content. Prominently, compared to HFO, HM10 had the most significant reduction in droplet lifetime and TINL under the same operating conditions, which indicated that the addition of 10% methanol accelerated the combustion process and reduced soot generation. Additionally, the thermos-dynamic characteristics of methanol/HFO droplets were investigated. Puffing was primarily attributed to superheating of methanol and pyrolysis of heavy components in HFO, which resulted in active and passive rupture of bubbles. Similarity and maximum deformation were employed to qualitatively distinguish between them. The obtained findings aimed to develop a promising alternative fuel to reduce emissions and preserve energy.

Abstract Huanglian Jiedu Decoction (HJD) is a well-known Traditional Chinese Medicine formula that has been used for liver protection in thousands of years. However, the therapeutic effects and mechanisms of HJD in treating drug-induced liver injury (DILI) remain unknown. In this study, a total of 26 genes related to both HJD and DILI were identified, which are corresponding to a total of 41 potential active compounds in HJD. KEGG analysis revealed that Tryptophan metabolism pathway is particularly important. The overlapped genes from KEGG and GO analysis indicated the significance of CYP1A1, CYP1A2, and CYP1B1. Experimental results confirmed that HJD has a protective effect on DILI through Tryptophan metabolism pathway. In addition, the active ingredients Corymbosin, and Moslosooflavone were found to have relative strong intensity in UPLC-Q-TOF-MS/MS analysis, showing interactions with CYP1A1, CYP1A2, and CYP1B1 through molecule docking. These findings could provide insights into the treatment effects of HJD on DILI.

Abstract Semantic communication and spectrum sharing are pivotal technologies in addressing the perennial challenge of scarce spectrum resources for the sixth-generation (6G) communication networks. Notably, scant attention has been devoted to investigating semantic resource allocation within spectrum sharing semantic communication networks, thereby constraining the full exploitation of spectrum efficiency. To mitigate interference issues between primary users and secondary users while augmenting legitimate signal strength, the introduction of Intelligent Reflective Surfaces (IRS) emerges as a salient solution. In this study, we delve into the intricacies of resource allocation for IRS-enhanced semantic spectrum sharing networks. Our focal point is the maximization of semantic spectral efficiency (S-SE) for the secondary semantic network while upholding the minimum quality of service standards for the primary semantic network. This entails the joint optimization of parameters such as semantic symbol allocation, subchannel allocation, reflective coefficients of IRS elements, and beamforming adjustment of secondary base station. Recognizing computational intricacies and interdependence of variables in the non-convex optimization problem formulated, we present a judicious approach: a hybrid intelligent resource allocation approach leveraging dueling double-deep Q networks coupled with the twin-delayed deep deterministic policy. Simulation results unequivocally affirm the efficacy of our proposed resource allocation approach, showcasing its superior performance relative to baseline schemes. Our approach markedly enhances the S-SE of the secondary network, thereby establishing its prowess in advancing the frontiers of semantic spectrum sharing (S-SE).

Background The correlation between hearing loss (HL) and physical performance in patients receiving maintenance hemodialysis (MHD) remains poorly investigated. This study explored the association between HL and physical performance in patients on MHD. Methods This multicenter cross-sectional study was conducted between July 2020 and April 2021 in seven hemodialysis centers in Shanghai and Suzhou, China. The hearing assessment was performed using pure-tone average (PTA). Physical performance was assessed using the Timed Up and Go Test (TUGT), handgrip strength, and gait speed. Results Finally, 838 adult patients (male, 516 [61.6%]; 61.2 ± 2.6 years) were enrolled. Among them, 423 (50.5%) had mild to profound HL (male, 48.6% and female, 53.4%). Patients with HL had poorer physical performance than patients without HL (p < 0.001). TUGT was positively correlated with PTA (r = 0.265, p < 0.001), while handgrip strength and gait speed were negatively correlated with PTA (r = –0.356, p < 0.001 and r = –0.342, p < 0.001, respectively). Physical performance in patients aged

Abstract Background Freezing stress is one of the major abiotic stresses that causes extensive damage to plants. LEA (Late embryogenesis abundant) proteins play a crucial role in plant growth, development, and abiotic stress. However, there is limited research on the function of LEA genes in low-temperature stress in Brassica napus (rapeseed). Results Total 306 potential LEA genes were identified in B. rapa (79), B. oleracea (79) and B. napus (148) and divided into eight subgroups. LEA genes of the same subgroup had similar gene structures and predicted subcellular locations. Cis-regulatory elements analysis showed that the promoters of BnaLEA genes rich in cis-regulatory elements related to various abiotic stresses. Additionally, RNA-seq and real-time PCR results indicated that the majority of BnaLEA family members were highly expressed in senescent tissues of rapeseed, especially during late stages of seed maturation, and most BnaLEA genes can be induced by salt and osmotic stress. Interestingly, the BnaA.LEA6.a and BnaC.LEA6.a genes were highly expressed across different vegetative and reproductive organs during different development stages, and showed strong responses to salt, osmotic, and cold stress, particularly freezing stress. Further analysis showed that overexpression of BnaA.LEA6.a increased the freezing tolerance in rapeseed, as evidenced by lower relative electrical leakage and higher survival rates compared to the wild-type (WT) under freezing treatment. Conclusion This study is of great significance for understanding the functions of BnaLEA genes in freezing tolerance in rapeseed and offers an ideal candidate gene (BnaA.LEA6.a) for molecular breeding of freezing-tolerant rapeseed cultivars.

Abstract Background and purpose Interstitial lung disease (ILD) represents a significant complication of rheumatoid arthritis (RA) that lacks effective treatment options. This study aimed to investigate the intrinsic mechanism by which resveratrol attenuates rheumatoid arthritis complicated with interstitial lung disease through the AKT/TMEM175 pathway. Methods We established an arthritis model by combining chicken type II collagen and complete Freund’s adjuvant. Resveratrol treatment was administered via tube feeding for 10 days. Pathological changes in both the joints and lungs were evaluated using HE and Masson staining techniques. Protein expression of TGF-β1, AKT, and TMEM175 was examined in lung tissue. MRC-5 cells were stimulated using IL-1β in combination with TGF-β1 as an in vitro model of RA-ILD, and agonists of AKT, metabolic inhibitors, and SiRNA of TMEM175 were used to explore the regulation and mechanism of action of resveratrol RA-ILD. Results Resveratrol mitigates fibrosis in rheumatoid arthritis-associated interstitial lung disease and reduces oxidative stress and inflammation in RA-ILD. Furthermore, resveratrol restored cellular autophagy. When combined with the in vitro model, it was further demonstrated that resveratrol could suppress TGF-β1 expression, and reduce AKT metamorphic activation, consequently inhibiting the opening of AKT/MEM175 ion channels. This, in turn, lowers lysosomal pH and enhances the fusion of autophagosomes with lysosomes, ultimately ameliorating the progression of RA-ILD. Conclusion In this study, we demonstrated that resveratrol restores autophagic flux through the AKT/MEM175 pathway to attenuate inflammation as well as fibrosis in RA-ILD by combining in vivo and in vitro experiments. It further provides a theoretical basis for the selection of therapeutic targets for RA-ILD. Graphical Abstract

Abstract Depression is a serious psychiatric illness that causes great inconvenience to the lives of elderly individuals. However, the diagnosis of depression is somewhat subjective. Nontargeted gas chromatography (GC)/liquid chromatography (LC)–mass spectrometry (MS) was used to study the plasma metabolic profile and identify objective markers for depression and metabolic pathway variation. We recruited 379 Chinese community-dwelling individuals aged ≥ 65. Plasma samples were collected and detected by GC/LC‒MS. Orthogonal partial least squares discriminant analysis and a heatmap were utilized to distinguish the metabolites. Receiver operating characteristic curves were constructed to evaluate the diagnostic value of these differential metabolites. Additionally, metabolic pathway enrichment was performed to reveal metabolic pathway variation. According to our standard, 49 people were included in the depression cohort (DC), and 49 people age- and sex-matched individuals were included in the non-depression cohort (NDC). 64 metabolites identified via GC‒MS and 73 metabolites identified via LC‒MS had significant contributions to the differentiation between the DC and NDC, with VIP values > 1 and p values

ABSTRACTUrban growth has accelerated significantly in recent decades, categorized into two spatial patterns: adjacent and outlying growth. Traditional Cellular Automata (CA)-based models excel at simulating adjacent growth but exhibit limitations in modeling outlying growth, which can be summarized into two issues: 1) the overestimation of neighborhood effects caused by models’ excessive dependence on neighboring cell states; and 2) the ignorance of spatial heterogeneity in the relative importance of land suitability and neighborhood effects on urban growth. To address these problems, a novel CA model with Separate Extraction and Adaptive Fusion of land suitability and neighborhood effects (SEAF-CA) is proposed. In this model, a dual-path convolution structure is employed to extract spatial features from driving factors and cell states; geographical coordinates of each cell then input into a multilayer perceptron to derive spatially varying weights for feature fusion. Finally, the derived conversion probability is integrated with CA to simulate urban growth. Land use data collected from 2000 to 2020 in Wuhan are selected to evaluate the proposed model. Experimental results illustrate that SEAF-CA outperforms three typical CA models, achieving the closest outlying growth proportion to reality and the highest simulation accuracy. In addition, the source code of SEAF-CA is now available at GitHub (https://github.com/ohXu/SEAF-CA).

Abstract Multidimensional health function impairments are common in older patients with chronic kidney disease (CKD). The purpose of this study was to explore whether the risk or severity of geriatric syndrome increased with a decline in renal function. This survey was conducted for CKD patients aged ≥ 60 years and hospitalized at West China Hospital of Sichuan University (Center of Gerontology and Geriatrics, Nephrology, and Endocrinology) and Chengdu Kangfu Kidney Disease Hospital from September 01, 2013 to June 30, 2014. Patients underwent multidimensional individualized assessments by trained doctors. Logistic regression analysis found that the risk of assisted walking (P = 0.001) and urinary incontinence (P = 0.039) increased with a decline in renal function. Regression analysis revealed that the scores of activities of daily living (P = 0.024), nutritional status (P = 0.000), total social support (P = 0.014), and objective support (P = 0.000) decreased with a decline in renal function.

Abstract Chiral recognition of amino acids is very important in both chemical and life sciences. Although chiral recognition with luminescence has many advantages such as being inexpensive, it is usually slow and lacks generality as the recognition module relies on structural complementarity. Here, we show that one single molecular-solid sensor, L-phenylalanine derived benzamide, can manifest the structural difference between the natural, left-handed amino acid and its right-handed counterpart via the difference of room-temperature phosphorescence (RTP) irrespective of the specific chemical structure. To realize rapid and reliable sensing, the doped samples are obtained as nanocrystals from evaporation of the tetrahydrofuran solutions, which allows for efficient triplet-triplet energy transfer to the chiral analytes generated in situ from chiral amino acids. The results show that L-analytes induce strong RTP, whereas the unnatural D-analytes produce barely any afterglow. The method expands the scope of luminescence chiral sensing by lessening the requirement for specific molecular structures.

Abstract In the CheckMate 651 study, nivolumab plus ipilimumab versus EXTREME (cisplatin/carboplatin + cetuximab + fluorouracil) regimen was compared for effectiveness. It is not known whether these immunotherapy agents are cost-effective for recurrent or metastatic squamous cell carcinomas of the head and neck (R/M SCCHN). The purpose of this study was to compare the cost-effectiveness of nivolumab plus ipilimumab with EXTREME in the first-line setting from the standpoint of third-party payers in the United States. The projecting of costs and outcomes over 15 years was done using a three-state partitioned survival model discounted by 3% per year. Long-term extrapolation of CheckMate 651 was used to model progression-free survival and overall survival (OS). The incremental net health benefit (INHB), incremental net monetary benefit (INMB), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) were calculated. The uncertainty and stability of the model were accounted for via one-way and probabilistic sensitivity analyses. As compared with nivolumab plus ipilimumab, EXTREME was associated with an increase of 0.154 life-years and 0.076 QALYs, as well as a cost increase of $572 per patient. The corresponding ICERs were $7545/QALY along with the values of INMB and INHB were $113,267 and 0.076 QALYs, respectively, at a willingness to pay (WTP) threshold of $150,000/QALY. The probability of nivolumab plus ipilimumab being cost-effective was > 99% in patients with combined positive score (CPS) ≥ 1, CPS 1–19, or CPS ≥ 20. Moreover, hazard ratio for OS and body weight were the most sensitive parameters for the model. According to sensitivity analyses, these results were generally robust. In overall populations with R/M SCCHN, the EXTREME regimen is cost-effective compared with nivolumab plus ipilimumab. Given a WTP threshold of $150,000 per QALY, the probability of the EXTREME regiment being cost-effective compared with nivolumab and ipilimumab, was 64%. Importantly, there was heterogeneity in the cost-effectiveness probabilities, based on primary sites and expression levels of PD-L1. Therefore, tailored treatment based on individual patient and clinical characteristics, remains important, and may impact the cost-effectiveness of the regimens under study.

Background: Diabetic foot is a major complication of diabetes. The bone transverse transport method could be applied in clinics for treatment, which could improve the metabolism of the tissues via lasting distraction forces. However, the process’ specific regulating mechanism is still unknown. Methods: Based on the notion that the healing of bones involves the recruitment of calcium ions, in this study, we established the model of tibial cortex transverse transport (TTT) on rats and then used tissue immunologic detection, such as the double fluorescent staining to explore the expression of the calcium channels’ calcium release-activated calcium modulator 1 (Orai1)/stromal interaction molecule 1 (STIM1), which belong to the store-operated calcium entry (SOCE) signaling pathways on the tissues around the bone transport area. By using the laser capture microdissection (LCM) tool, we acquired samples of tissues around the bone and endeavored to identify pivotal protein molecules. Subsequently, we validated the functions of key protein molecules through in vitro and in vivo experiments. Results: After protein profile analysis, we found the differentially expressed key protein osteopontin (OPN). The in vitro experiments verified that, being stimulated by OPN, the migration, proliferation, and angiogenesis of human umbilical vein endothelial cells (HUVEC) were observed to be enhanced. The activation of Orai1/STIM1 might increase the activity of endothelial nitric oxide synthase (eNOS) and its effect on releasing nitric oxide (NO). Subsequently, the migration and proliferation of the HUVECs are improved, which ultimately accelerates wound healing. These signaling pathway was also observed in the OPN-stimulated healing process of the skin wound surface of diabetic mice. Conclusion: This study identifies the molecular biological mechanism of OPN-benefited the migration and proliferation of the HUVECs and provides ideas for searching for new therapeutic targets for drugs that repair diabetes-induced wounds to replace invasive treatment methods. The translational potential of this article: The OPN is highly expressed in the tissues surrounding the TTT bone transfer area, which may possibly stimulate the activation of eNOS to increase NO release through the SOCE pathway mediated by Orai1/STIM1. This mechanism may play a significant role in the angiogenesis of diabetic foot's wounds promoted by TTT, providing new therapeutic strategies for the non-surgical treatment for this disease.

Abstract Background Delays in malaria treatment can not only lead to severe and even life-threatening complications, but also foster transmission, putting more people at risk of infection. This study aimed to investigate the factors influencing treatment delays among malaria patients and their health-seeking behaviour. Methods The medical records of 494 patients diagnosed with malaria from 6 different malaria-endemic provinces in China were analysed. A bivariate and multivariable regression model was used to investigate the association between delays in seeking treatment and various factors. A Sankey diagram was used to visualize the trajectories of malaria patients seeking medical care. Total treatment delays were categorized as patient delays and doctor delays. Results The incidence of total delays in seeking malaria treatment was 81.6%, of which 28.4% were delayed by patients alone and 34.8% by doctors alone. The median time from the onset of symptoms to the initial healthcare consultation was 1 day. The median time from the initial healthcare consultation to the conclusive diagnosis was 2 day. After being subjected to multiple logistic regression analysis, living in central China was less likely to experience patient delays (OR = 0.43, 95% CI 0.24–0.78). The factors significantly associated with the lower likelihood of doctor delays included: age between 30 to 49 (OR = 0.43, 95% CI 0.23–0.81), being single/divorce/separated (OR = 0.48, 95% CI 0.24–0.95), first visiting a county-level health institution (OR = 0.25, 95% CI 0.14–0.45), first visiting a prefectural health institution (OR = 0.06, 95% CI 0.03–0.12) and first visiting a provincial health institution (OR = 0.05, 95%CI 0.02–0.12). Conversely, individuals with mixed infections (OR = 2.04, 95% CI 1.02–4.08) and those experiencing periodic symptoms (OR = 1.71, 95% CI 1.00–2.92) might face increased doctor delays. Furthermore, higher financial burden and complications were found to be associated with patient delays. Doctor delays, in addition to incurring these two consequences, were associated with longer hospital stays. Conclusion There was a substantial delay in access to health care for malaria patients before China was certified malaria free. Region, marital status, periodic symptoms and the level of health institutions were factors contributing to delays in treatment-seeking among malaria patients.

Abstract Background Untargeted metabolomics can be used to expand our understanding of the pathogenesis of sarcopenia. However, the metabolic signatures of sarcopenia patients have not been thoroughly investigated. Herein, we explored metabolites associated with sarcopenia by untargeted gas chromatography (GC)/liquid chromatography (LC)–mass spectrometry (MS) and identified possible diagnostic markers. Methods Forty-eight elderly subjects with sarcopenia were age and sex matched with 48 elderly subjects without sarcopenia. We first used untargeted GC/LC–MS to analyze the plasma of these participants and then combined it with a large number of multivariate statistical analyses to analyze the data. Finally, based on a multidimensional analysis of the metabolites, the most critical metabolites were considered to be biomarkers of sarcopenia. Results According to variable importance in the project (VIP > 1) and the p-value of t-test (p

Abstract Background The purpose of this study was to explore the separate and combined associations of obstructive sleep apnea (OSA) risk and sleep duration with ideal cardiovascular health metrics in hemodialysis (HD) patients. Methods 470 HD participants (average: 59.48 ± 12.89 y, 281 men) were included in this study. Sleep duration was measured as self-reported average sleep time during the previous month. The OSA risk was assessed using the STOP-BANG questionnaire. Participants were divided into three groups based on the number of ideal cardiovascular health (CVH) metrics: 0–2,3–4, and 5–7. Ordinal logistic regression was conducted to model the associations of CVH metrics with sleep duration, OSA risk, and their combined effects by adjusting for specific covariates. Results After adjusting for covariates, short sleep duration (

Soil thermal conductivity (λ) is required to investigate coupled heat and water transport in disciplines such as agriculture, hydrology and engineering. Parameterization schemes or models of λ are also the critical input parameter for various numerical simulation programs like the widely used HYDRUS, one of the most commonly used models for mimicking water, heat, and solute transport. However, λ has not received enough attention in HYDRUS, and it remains unclear how different λ schemes affect the simulated soil water and thermal regimes. Thus, we programmed 24 λ schemes (including two built-in schemes) used in mainstream land surface, hydrological, and soil–vegetation–atmosphere transfer models into HYDRUS-1D (freezing module) to assess the effects of different λ schemes on soil temperature and water content simulations under freezing–thawing. The results showed that the 24 λ schemes performed differently in the simulation of soil temperature within 1 m below ground, with eight λ schemes, i.e., de Vries 1963 scheme/DV1963 (R=0.99), Camillo and Schmugge 1981/CS1981 scheme (R=0.98), Desborough and Pitman 1998/DP1998 scheme (R=0.97), Cass et al. 1984/CS1984 scheme (R=0.96), Shmakin 1998/SA1998 scheme (R=0.95), Dharssi et al. 2009/DI2009 scheme (R=0.95), Becker et al. 1992/BB1992 scheme (R=0.95), Hubrechts 1998/HL1998 scheme (R=0.94), performing superiorly to the built-in λ schemes. This study highlights the importance of choosing appropriate λ schemes in soil water and heat simulations.

Abstract Reliable detection of hydrogen (H2) leakage at low temperatures (e.g.,

IntroductionEltrombopag (EPAG), a thrombopoietin receptor agonist, was approved for the treatment of severe aplastic anemia (SAA) combined with immunosuppressive therapy (IST). However, EPAG contains a typical biphenyl structure, which causes liver function damage.MethodsTwenty patients with SAA who were intolerant or refractory to EPAG were enrolled in a multicenter prospective registry of the Chinese Eastern Collaboration Group of Anemia (ChiCTR2100045895) from October 2020 to June 2023.ResultsEight patients who were ineffective to EPAG, six with kidney impairment, and nine with abnormal liver function (two with concomitant liver and kidney impairment) were converted to avatrombopag (AVA) therapy with the median duration of AVA treatment was 6 (3-24) months. 17 cases (85%) achieved trilineage hematological response (HR): complete remission (CR) in 3 cases (15%), good partial remission (GPR) in 4 cases (20%), partial remission (PR) in 10 cases (50%), and no response (NR) in 3 cases (15%). The median time to response was 1.7 (0.5-6.9) months, with 16 cases (94%) achieving response within six months and 17 cases (100%) within 12 months. 9 cases (50%) achieved transfusion independence. AVA converted treatment was associated with higher neutrophil counts (0.8×109/L vs 2.2×109/L, p=0.0003), platelet counts (11×109/L vs 39×109/L, p=0.0008), hemoglobin count (59g/L vs 98g/L, p=0.0002), red cell count (1.06×1012/L vs 2.97×1012/L, p=0.001), and absolute reticulocyte count (31.99 ×109/L vs 67.05×109/L p=0.0004) were all significantly elevated compared with the pre-treatment level. After the conversion to AVA therapy, liver and kidney function indexes were maintained within the normal range, no AVA related grade 2 or higher adverse events occurred, and no thrombotic events occurred.ConclusionThe conversion to AVA was an optimal choice for patients with SAA who were EPAG intolerant or refractory.Clinical trial registrationhttp://www.chictr.org.cn/showproj.html?proj=125480, identifier ChiCTR2100045895.

IntroductionSport anxiety not only impacts the performance of college athletes but also influences their psychological well-being. The psychological well-being of sports students is crucial for both academic performance and competition, as they need to balance their academic performance with professional athletic training.MethodBased on self-determination theory, this study examines the relationship between various factors in sport anxiety (somatic anxiety, worry, and concentration disruption) and subjective happiness, as well as the mediating role of need satisfaction in this relationship. A total of 835 college athletic students participated in the study, completing the Sport Anxiety Scale-2, Basic Psychological Needs Satisfaction Scale-in General, and Subjective Happiness Scale.ResultsAn analysis of gender differences revealed that female participants scored significantly higher on somatic anxiety (t = −2.21, df = 833, p = 0.028, Cohen’s d = −0.155) and worry (t = −3.17, df = 833, p = 0.002, Cohen’s d = −0.223) compared to males. In the analysis by sport type, participants engaged in team sports scored significantly higher on somatic anxiety (t = 2.70, df = 833, p = 0.007, Cohen’s d = 0.187), Worry (t = 1.97, df = 833, p = 0.049, Cohen’s d = 0.136), and concentration disruption (t = 2.73, df = 833, p = 0.007, Cohen’s d = 0.189) than those in individual sports. Additionally, in the analysis by grade level, freshman college athletes exhibited significantly lower sport anxiety compared to sophomore athletes [F(4, 830) = 4.06, p = 0.003, ηp2=0.019]. The mediation analysis revealed that concentration disruption in sport anxiety is significantly and negatively related to subjective happiness. Additionally, need satisfaction (competence, autonomy, and relatedness) mediates the relationship between worry, as well as concentration disruption in sport anxiety and subjective happiness.DiscussionFuture research should build on the current study by employing longitudinal designs and integrating multiple objective measures to further explore the relationship between sport anxiety and subjective happiness.

Aims: This study explored the molecular and biologic mechanisms underlying the association between circadian rhythm disorders (CRD) and increased risk for hepatocellular carcinoma (HCC). Background: CRD are linked to increased risk for HCC, but the molecular and biologic mechanisms underlying this association are limited.ObjectiveThe study constructed and validated a CRD related gene model as an independent prognostic factor for HCC, providing insight into the molecular mechanisms linking CRD to increased HCC risk and identifying potential indicators for the efficacy of immunotherapy and anticancer drugs. This helps provide important clues for personalized treatment strategies for HCC patients. Methods: Gene sets correlated with circadian rhythm were obtained from the Molecular Signatures Database (MSigDB) to intersect with differentially expressed genes (DEGs) between tumor samples and control samples in The Cancer Genome Atlas (TCGA) and HCCDB18 from Hepatocellular Carcinoma Cell DataBase (HCCDB). The CRD related gene model was developed by univariate Cox and stepwise multivariate analysis. Immune checkpoint blockade (ICB) therapy and anticancer drugs were analyzed using the tumor immune dysfunction and exclusion (TIDE) and pRRophetic, respectively. Seurat determined the cell type of HCC by analyzing single-cell data, and malignant cells were identified using Copykat. To detect the mRNA levels of genes in the CRD related gene model, quantitative real-time polymerase chain reaction (qRT-PCR) was carried out. Results: The activity of circadian rhythm in HCC tissue was significantly lower than that in control tissue. Subsequently, EZH2, IMPDH2, TYMS and SERPINE1 were selected to construct the CRD related gene model, which was an independent factor for HCC prognosis. Notably, low-risk patients had lower levels of immune cell infiltration and lower TIDE scores compared to high-risk patients with HCC, indicating that patients with a low risk may derive more benefit from immunotherapy. IMPDH2, TYMS and SERPINE1 expressed significantly higher in malignant cells than in benign epithelial cells. Conclusions: This study presents a CRD related gene model to reveal the molecular perspective of the dependent mechanism of the association between CRD and cancer, which provides a potential indicator for understanding the preclinical efficacy of ICB and anticancer drugs.

Viral diseases pose a major threat to salmonids aquaculture, and mixed infections against salmonids are common. Early detection and identification of viral pathogens are crucial for effective prevention and control measures. This study used samples of infectious hematopoietic necrosis virus (IHNV), infectious pancreatic necrosis virus (IPNV), infectious salmon anemia virus (ISAV), salmonid alphavirus (SAV), and viral hemorrhagic septicemia virus (VHSV) to evaluate a multiplex RT-PCR assay developed for the simultaneous detection of these viruses. A liquid chip technique combined with multiplex RT-PCR was developed. The RT-PCR amplification products were tested using a liquid chip probe. The sensitivity of the assay system was evaluated using 10-fold serial dilutions of RNA extracted from IHNV, IPNV, ISAV, SAV, and VHSV with concentrations of 0.1, 0.4, 2, 0.9, and 1.6 pg µL−1, respectively. The assay was highly specific for these different viruses owing to the use of two nested degenerate primers and one probe. No cross-reactions occurred among the viruses nor did any non-specific reactions occur with other pathogens. The proposed method can be used for rapid, accurate, sensitive, and simultaneous detection of five salmon and trout viruses, thereby contributing to the rapid and accurate quarantine of aquatic animal samples.

BackgroundUntargeted metabonomics has provided new insight into the pathogenesis of sarcopenia. In this study, we explored plasma metabolic signatures linked to a heightened risk of sarcopenia in a cohort study by LC-MS-based untargeted metabonomics.MethodsIn this nested case–control study from the Adult Physical Fitness and Health Cohort Study (APFHCS), we collected blood plasma samples from 30 new-onset sarcopenia subjects (mean age 73.2 ± 5.6 years) and 30 healthy controls (mean age 74.2 ± 4.6 years) matched by age, sex, BMI, lifestyle, and comorbidities. An untargeted metabolomics methodology was employed to discern the metabolomic profile alterations present in individuals exhibiting newly diagnosed sarcopenia.ResultsIn comparing individuals with new-onset sarcopenia to normal controls, a comprehensive analysis using liquid chromatography-mass spectrometry (LC-MS) identified a total of 62 metabolites, predominantly comprising lipids, lipid-like molecules, organic acids, and derivatives. Receiver operating characteristic (ROC) curve analysis indicated that the three metabolites hypoxanthine (AUC=0.819, 95% CI=0.711–0.927), L-2-amino-3-oxobutanoic acid (AUC=0.733, 95% CI=0.598–0.868) and PC(14:0/20:2(11Z,14Z)) (AUC= 0.717, 95% CI=0.587–0.846) had the highest areas under the curve. Then, these significant metabolites were observed to be notably enriched in four distinct metabolic pathways, namely, “purine metabolism”; “parathyroid hormone synthesis, secretion and action”; “choline metabolism in cancer”; and “tuberculosis”.ConclusionThe current investigation elucidates the metabolic perturbations observed in individuals diagnosed with sarcopenia. The identified metabolites hold promise as potential biomarkers, offering avenues for exploring the underlying pathological mechanisms associated with sarcopenia.

Human induced pluripotent stem cell (hiPSC)-derived mesenchymal stem cells (iMSCs) are ideal candidates for the production of standardised and scalable bioengineered bone grafts. However, stable induction and osteogenic differentiation of iMSCs pose challenges in the industry. We developed a precise differentiation method to produce homogeneous and fully differentiated iMSCs. In this study, we established a standardised system to prepare iMSCs with increased osteogenic potential and improved bioactivity by introducing a CHIR99021 (C91)-treated osteogenic microenvironment (COOME). COOME enhances the osteogenic differentiation and mineralisation of iMSCs via canonical Wnt signalling. Global transcriptome analysis and co-culturing experiments indicated that COOME increased the pro-angiogenesis/neurogenesis activity of iMSCs. The superior osteogenic differentiation and mineralisation abilities of COOME-treated iMSCs were also confirmed in a Bio3D module generated using a polycaprolactone (PCL) and cell-integrated 3D printing (PCI3D) system, which is the closest model to in vivo research. This COOME-treated iMSCs differentiation system offers a new perspective for generating highly osteogenic, bioactive, and anatomically matched grafts for clinical applications. Statement of significance: Although human induced pluripotent stem cell-derived MSCs (iMSCs) are ideal seed cells for synthetic bone implants, the challenges of stable induction and osteogenic differentiation hinder their clinical application. This study established a standardised system for the scalable preparation of iMSCs with improved osteogenic potential by combining our precise iMSC differentiation method with the CHIR99021 (C91)-treated osteocyte osteogenic microenvironment (COOME) through the activation of canonical Wnt signalling. Moreover, COOME upregulated the pro-angiogenic and pro-neurogenic capacities of iMSCs, which are crucial for the integration of implanted bone grafts. The superior osteogenic ability of COOME-treated iMSCs was confirmed in Bio3D modules generated using PCL and cell-integrated 3D printing systems, highlighting their functional potential in vivo. This study contributes to tissue engineering by providing insights into the functional differentiation of iMSCs for bone regeneration.

Abstract Overexpressed pro-survival B-cell lymphoma-2 (BCL-2) family proteins BCL-2 and BCL-XL can render tumor cells malignant. Leukemia drug venetoclax is currently the only approved selective BCL-2 inhibitor. However, its application has led to an emergence of resistant mutations, calling for drugs with an innovative mechanism of action. Herein we present cyclic peptides (CPs) with nanomolar-level binding affinities to BCL-2 or BCL-XL, and further reveal the structural and functional mechanisms of how these CPs target two proteins in a fashion that is remarkably different from traditional small-molecule inhibitors. In addition, these CPs can bind to the venetoclax-resistant clinical BCL-2 mutants with similar affinities as to the wild-type protein. Furthermore, we identify a single-residue discrepancy between BCL-2 D111 and BCL-XL A104 as a molecular “switch” that can differently engage CPs. Our study suggests that CPs may inhibit BCL-2 or BCL-XL by delicately modulating protein-protein interactions, potentially benefiting the development of next-generation therapeutics.

Abstract Toxic amyloid-beta (Aβ) plaque and harmful inflammation are two leading symptoms of Alzheimer’s disease (AD). However, precise AD therapy is unrealizable due to the lack of dual-targeting therapy function, poor BBB penetration, and low imaging sensitivity. Here, we design a near-infrared-II aggregation-induced emission (AIE) nanotheranostic for precise AD therapy. The anti-quenching emission at 1350 nm accurately monitors the in vivo BBB penetration and specifically binding of nanotheranostic with plaques. Triggered by reactive oxygen species (ROS), two encapsulated therapeutic-type AIE molecules are controllably released to activate a self-enhanced therapy program. One specifically inhibits the Aβ fibrils formation, degrades Aβ fibrils, and prevents the reaggregation via multi-competitive interactions that are verified by computational analysis, which further alleviates the inflammation. Another effectively scavenges ROS and inflammation to remodel the cerebral redox balance and enhances the therapy effect, together reversing the neurotoxicity and achieving effective behavioral and cognitive improvements in the female AD mice model.

Abstract Background Patients with depression, especially women, are associated with low bone mineral density (BMD). Traditional antidepressants are associated with negative effects on BMD. Few studies have examined the effect of ketamine on BMD, and it remains unclear whether there are sex differences in the effects of ketamine on BMD in patients with depression. Methods A total of 102 patients with unipolar and bipolar depression were administered six infusions of intravenous ketamine over a 12-day period. Plasma levels of eight bone markers were examined at baseline, 24 h after the sixth infusion and again 2 weeks (Days 13 and 26). Results Linear mixed models showed all bone markers had significant time main effect (all p

Abstract Dental implants are widely used to replace missing teeth, providing patients with unparalleled levels of effectiveness, convenience, and affordability. The biological basis for the clinical success of dental implants is osseointegration. Bone aging is a high-risk factor for the reduced osseointegration and survival rates of dental implants. In aged individuals, mesenchymal stem cells (MSCs) in the bone marrow show imbalanced differentiation with a reduction in osteogenesis and an increase in adipogenesis. This leads to impaired osseointegration and implant failure. This review focuses on the molecular mechanisms underlying the dysfunctional differentiation of aged MSCs, which primarily include autophagy, transcription factors, extracellular vesicle secretion, signaling pathways, epigenetic modifications, microRNAs, and oxidative stress. Furthermore, this review addresses the pathological changes in MSCs that affect osseointegration and discusses potential therapeutic interventions to enhance osseointegration by manipulating the mechanisms underlying MSC aging.

Objective To evaluate the efficacy and safety of trephine resection combined with fractional ablative CO2 laser for pitted acne scars. Methods Sixty eight patients with facial pitted acne scars were enrolled from the Medical Cosmetology Center of Zhengzhou People's Hospital from February 2019 to February 2022. The patients were randomly divided into the observation (30 patients) and the control groups (38 patients). The observation group was treated with trephine resection combined with CO2 laser, and the control group was treated with fractional ablative CO2 laser alone. The efficacy and the ECCA scale (Echelle d 'Evaluation Clinique des Cicatrices d 'acne) were compared between the two groups after 6-month treatment. Results Before the treatment, ECCA scores were comparable between the observation and the control groups [50.00 (43.75, 60.00) vs. 47.50 (37.50, 60.00), P=0.535]. After 6-month treatment, the ECCA scores in both groups were significantly lower than the baseline (both P

Environmental DNA (eDNA) technology has revolutionized biomonitoring, but challenges remain regarding water sample processing. The passive eDNA sampler (PEDS) represents a viable alternative to active, water filtration-based eDNA enrichment methods, but the effectiveness of PEDS for surveying biodiverse and complex natural water bodies is unknown. Here, we collected eDNA using filtration and glass fiber filter-based PEDS (submerged in water for 1 d) from 27 sites along the final reach of the Yangtze River and the coast of the Yellow Sea, followed by eDNA metabarcoding analysis of fish biodiversity and quantitative PCR (qPCR) for a critically endangered aquatic mammal, the Yangtze finless porpoise. We ultimately detected 98 fish species via eDNA metabarcoding. Both eDNA sampling methods captured comparable local species richness and revealed largely similar spatial variation in fish assemblages and community partitions between the river and sea sites. Notably, the Yangtze finless porpoise was detected only in the metabarcoding of eDNA collected by PEDS at five sites. Also, species-specific qPCR revealed that the PEDS captured porpoise eDNA at more sites (7 vs. 2), in greater quantities, and with a higher detection probability (0.803 vs. 0.407) than did filtration. Our results demonstrate the capacity of PEDS for surveying fish biodiversity, and support that continuous eDNA collection by PEDS can be more effective than instantaneous water sampling at capturing low abundance and ephemeral species in natural waters. Thus, the PEDS approach can facilitate more efficient and convenient eDNA-based biodiversity surveillance and rare species detection.

Background Contextual cueing refers to the phenomenon in which individuals utilize frequently encountered environmental contexts, comprised of distractors, as cues to expedite a target search. Due to the conflict between the widespread occurrence of contextual cue transfer and the observed impact of changing the identity of distractors on contextual cue learning, the content of contextual cue representations remains contentious. Considering the independent nature of contextual cue learning and expression, our proposition is twofold: (1) Contextual cue representations are stimulus-specific, and (2) their expression is highly flexible. Methods To validate the model, two experiments were conducted. Experiment 1 aimed to confirm the hypothesis that contextual cue representations are stimulus-specific. We manipulated the identity consistency of distractors within repeated scenes during contextual cue learning. Difficulty in contextual cue learning under the identity-changing condition would suggest the necessity of identity within contextual cue representation, indicating the stimulus-specific nature of these representations. Experiment 2 was designed to affirm the conclusion of Experiment 1 and explore the flexibility in the expression of contextual cue representations. This experiment comprised two phases: learning and testing. During the learning phase, participants were exposed to two sets of repeated scenes in different colors under two learning conditions: load and no-load. Working memory load was introduced to interfere with the expression to prevent it from becoming automatic. In the subsequent testing phase, the colors of the two scene sets were interchanged to impede retrieval based on identity. If both load and no-load conditions demonstrate similar levels of contextual cue effects during the testing phase, it implies the flexibility in the expression of contextual cue representations and confirms the conclusion of Experiment 1. Results In Experiment 1, a notable contextual cue learning effect was observed under the identity-consistent condition (p = 0.001). However, this effect was not evident under the identity-changing condition (p = 0.286). This finding strongly supports the stimulus-specific nature of contextual cue representation. In Experiment 2, the contextual cueing effect appeared but did not show a significant difference between the two conditions (t(23) = 0.02, p = 0.987, BF10 = 0.215), indicating the cognitive system’s ability to flexibly redefine retrieval cues. This adaptability aligns with our hypothesis and confirms the high flexibility in the expression process of contextual cue representations and confirms the conclusion of Experiment 1.

ObjectivesImmune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). However, the application of ICIs can also cause treatment-related adverse events (trAEs) and immune-related adverse events (irAEs). This study was to evaluate both the irAEs and trAEs of different ICI strategies for NSCLC based on randomized clinical trials (RCTs). The study also examined real-world pharmacovigilance data from the Food and Drug Administration Adverse Event Reporting System (FAERS) regarding claimed ICI-associated AEs in clinical practice.MethodsBased on Pubmed, Embase, Medline, and the Cochrane CENTRAL, we retrieved RCTs comparing ICIs with chemotherapy drugs or with different ICI regimens for the treatment of NSCLC up to October 20, 2023. Bayesian network meta-analysis (NMA) was performed using odds ratios (ORs) with 95% credible intervals (95%CrI). Separately, a retrospective pharmacovigilance study was performed based on FAERS database, extracting ICI-associated AEs in NSCLC patients between the first quarter (Q1) of 2004 and Q4 of 2023. The proportional reports reporting odds ratio was calculated to analyze the disproportionality.ResultsThe NMA included 51 RCTs that involved a total of 26,958 patients with NSCLC. Based on the lowest risk of any trAEs, cemiplimab, tislelizumab, and durvalumab were ranked as the best. Among the agents associated with the lowest risk of grades 3-5 trAEs, tislelizumab, avelumab, and nivolumab were most likely to rank highest. As far as any or grades 3-5 irAEs are concerned, atezolizumab plus bevacizumab plus chemotherapy is considered the most safety option. However, it is associated with a high risk of grades 3-5 trAEs. As a result of FAERS pharmacovigilance data analysis, 9,420 AEs cases have been identified in 7,339 NSCLC patients treated with ICIs, and ICIs were related to statistically significant positive signal with 311 preferred terms (PTs), and comprehensively investigated and identified those AEs highly associated with ICIs. In total, 152 significant signals were associated with Nivolumab, with malignant neoplasm progression, death, and hypothyroidism being the most frequent PTs.ConclusionThese findings revealed that ICIs differed in their safety profile. ICI treatment strategies can be improved and preventive methods can be developed for NSCLC patients based on our results.

Background Driving is a complex skill involving various cognitive activities. Previous research has explored differences in the brain structures related to the navigational abilities of drivers compared to non-drivers. However, it remains unclear whether changes occur in the structures associated with low-level sensory and higher-order cognitive abilities in drivers. Methods Gray matter volume, assessed via voxel-based morphometry analysis of T1-weighted images, is considered a reliable indicator of structural changes in the brain. This study employs voxel-based morphological analysis to investigate structural differences between drivers (n = 22) and non-drivers (n = 20). Results The results indicate that, in comparison to non-drivers, drivers exhibit significantly reduced gray matter volume in the middle occipital gyrus, middle temporal gyrus, supramarginal gyrus, and cerebellum, suggesting a relationship with driving-related experience. Furthermore, the volume of the middle occipital gyrus, and middle temporal gyrus, is found to be marginally negative related to the years of driving experience, suggesting a potential impact of driving experience on gray matter volume. However, no significant correlations were observed between driving experiences and frontal gray matter volume. Conclusion These findings suggest that driving skills and experience have a pronounced impact on the cortical areas responsible for low-level sensory and motor processing. Meanwhile, the influence on cortical areas associated with higher-order cognitive function appears to be minimal.

Abstract Background Diabetic peripheral neuropathy (DPN) is a common complication of Type 2 diabetes mellitus (T2DM), which frequently results in disabling neuropathic pain and lower‐limb amputation. The identification of noninvasive biomarkers for DPN may help early detection and individualized treatment of DPN. Methods In this study, we identified differentially expressed genes (DEGs) between DPN and the control based on blood‐source (GSE95849) and tissue‐source gene expression profiles (GSE143979) from the Gene Expression Omnibus (GEO) database using limma, edgeR, and DESeq2 approaches. KEGGG and GO functional enrichments were performed. Hub genes and their correlation with infiltrating immune cells were analyzed. Real‐time quantitative polymerase chain reaction (RT‐qPCR) was used to quantify hub gene expression. Results In total, 144 DEGs between DPN and the control were identified. Functional enrichment revealed that the DEGs were mainly enriched in immune‐related pathways like the Fc epsilon receptor Ig signaling pathway. By protein–protein interaction (PPI) network analysis, FCER1G, SYK, ITGA4, F13A1, MS4A2, and PTK2B were screened as hub genes with higher expression in DPN patients, among which half were immune genes (FCER1G, PTK2B, and SYK). RT‐qPCR demonstrated that mRNA expression of FCER1G, PTK2B, and SYK was significantly increased in patients with DPN compared with both diabetic nonperipheral neuropathy (DNN) and normal subjects. The area under the receiver operating characteristic (ROC) curve of FCER1G, PTK2B, and SYK was 0.84, 0.81, and 0.73, respectively, suggesting their great advantages as diagnostic biomarkers to predict the progression of neuropathy in T2DM. Further analysis indicated that the expression of FCER1G, PTK2B, and SYK was negatively correlated with the cell proportion of significantly altered resting natural killer cells, T follicular helper cells, and activated mast cells, but positively correlated with monocytes. Conclusions Our findings demonstrated FCER1G, PTK2B, and SYK are potential diagnostic biomarkers and therapeutic targets for DPN, which provides new insight into DPN pathogenesis and therapies.

Type 2 diabetes mellitus (T2DM) is associated with liver dysfunction and intestinal dysbiosis. Bioactive peptides (BAPs) have been reported to ameliorate T2DM by preventing oxidative damage to the liver. Bacillus amyloliquefaciens fmb50 produces the lipopeptide surfactin with a wide range of biological activities. The effects of surfactin on T2DM, on the other hand, have not been studied. In the present study, 80 mg/kg body weight surfactin supplementation lowered fasting blood glucose (FBG) levels by 21.05 % and insulin resistance (IR) by 18.18 % compared with those in the T2DM group, reduced inflammation, and increased antioxidant activity in mice with T2DM induced by a high-fat diet (HFD) and streptozotocin (STZ). According to further research, surfactin administration reduced Firmicutes-to-Bacteroidetes ratios while increasing Bifidobacterium abundance by 20 times and the level of the tight junction protein Occludin by 18.38 % and ZO-1 by 66.60 %. Furthermore, surfactin also improved hepatic glucose metabolism by activating the adenosine monophosphate-activated protein kinase (AMPK) signalling pathway, increasing glycogen synthesis and glucose transporter 2 (GLUT2) protein expression while reducing glucose-6-phosphatase (G6Pase) protein expression. In addition, the increased Bifidobacterium abundance indirectly reduced the liver burden of the metabolic products indole, cresol and amine produced by saprophytic bacteria. All of these findings revealed that surfactin not only ameliorated HFD/STZ-induced gut dysbiosis and preserved intestinal barrier integrity but also enhanced hepatic glucose metabolism and detoxification function in T2DM mice. The gut microbiota appeared to be important in controlling glucose metabolism, IR, fat accumulation, inflammation and antioxidation, according to Spearman’s correlation coefficients. All data indicated that surfactin alleviated hyperglycaemia in mice with T2DM induced by HFD/STZ.

Abstract Background Prolonged treatment of HER2+ breast cancer with lapatinib (LAP) causes cellular senescence and acquired drug resistance, which often associating with poor prognosis for patients. We aim to explore the correlation between cellular senescence and LAP resistance in HER2+ breast cancer, screen for molecular marker of reversible senescence, and construct targeted nanobubbles for ultrasound molecular imaging to dynamically evaluate LAP resistance. Methods and Results In this study, we established a new cellular model of reversible cellular senescence using LAP and HER2+ breast cancer cells and found that reversible senescence contributed to LAP resistance in HER2+ breast cancer. Then, we identified ecto‐5′‐nucleotidase (NT5E) as a marker of reversible senescence in HER2+ breast cancer. Based on this, we constructed NT5E‐targeted nanobubbles (NT5E‐FITC‐NBs) as a new molecular imaging modality which could both target reversible senescent cells and be used for ultrasound imaging. NT5E‐FITC‐NBs showed excellent physical and imaging characteristics. As an ultrasound contrast agent, NT5E‐FITC‐NBs could accurately identify reversible senescent cells both in vitro and in vivo. Conclusions Our data demonstrate that cellular senescence‐based ultrasound‐targeted imaging can identify reversible senescence and evaluate LAP resistance effectively in HER2+ breast cancer cells, which has the potential to improve cancer treatment outcomes by altering therapeutic strategies ahead of aggressive recurrences.

Abstract Background Notwithstanding that the past decade has witnessed unprecedented medical progress, gastric cancer (GC) remains a leading cause of cancer death, highlighting the need for effective prognostic markers. The Memorial Sloan Kettering Prognostic Score (MPS) has been validated as a valuable prognostic tool for patients with metastatic pancreatic adenocarcinoma (mPDAC). This study aimed to assess the prognostic value of the MPS in advanced GC. Methods Data from 367 patients were analyzed in the present study. The MPS for each patient was calculated based on the sum of scores based on the neutrophil‐to‐lymphocyte ratio and serum albumin levels. Multivariate analyses were performed to identify the independent clinicopathological parameters associated with overall survival (OS). Further subgroup analyses based on clinicopathological features were conducted. Results Patients with MPS 0 (n = 161), MPS 1 (n = 158), and MPS 2 (n = 48) exhibited significantly different OS, with a median survival duration of 20.7 (95%CI: 12.2–29.2), 14.9 (95%CI: 12.5–17.3), and 12.7 (95%CI: 9.3–16.0) months, respectively (p

Abstract. Background:. Immune checkpoint inhibitors (ICIs) are standard treatments for advanced non-small cell lung cancer (NSCLC); however, evidence regarding their relative efficacy and safety is lacking. This study compared the efficacy and safety of all currently available ICI treatments in patients with advanced NSCLC to identify optimal treatment regimens. Methods:. PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase databases were systematically searched for randomized controlled trials (RCTs) published up to August 8, 2022. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes included objective response rate (ORR) and adverse events (AEs). Results:. Forty RCTs involving 22,526 patients were selected, and a total of 26 treatment regimens were identified. Treatment with anti-programmed cell death protein-1 (anti-PD-1) provided superior OS compared with anti-programmed death ligand 1 (anti-PD-L1) treatment. ICIs plus platinum-based chemotherapy (PBC) were superior to ICIs treatment alone, although the addition of PBC increased treatment toxicity. Cemiplimab ranked first for OS and lowest for any-grade AEs in advanced NSCLC patients without PD-L1 selection. Regarding grade ≥3 AEs, the toxicity of ICI monotherapy or ICI-ICI combination was consistently lower than that of the other treatments. For patients without PD-L1 selection, cemiplimab showed the best OS, pembrolizumab plus docetaxel (Pem-DXT) showed the best PFS, and atezolizumab plus bevacizumab and PBC (Atezo-Beva-PBC) showed the best ORR. Pembrolizumab plus PBC and Atezo-Beva-PBC were the most likely optimal treatments for OS and PFS in patients with PD-L1 expression

BackgroundThe current guideline recommended the use of intravenous thrombolysis (IVT) before Endovascular thrombectomy (EVT), but the effectiveness and safety of tenecteplase compare to alteplase in patients before EVT remain uncertain.MethodsWe searched PubMed, Embase, Web of Science, and the Cochrane Library to identify eligible articles from inception until September 16, 2023. The primary outcome was functional independence (mRS 0–2) at 90 days. Secondary outcomes included excellent outcome (mRS 0–1) at 90 days, all-cause mortality at follow-up, successful reperfusion (TICI 2b–3) after the end of EVT, symptomatic intracranial hemorrhage (sICH) or any intracranial hemorrhage (aICH). The PROSPERO registration number is CRD42023470419.ResultsEight randomized controlled trials (RCTs) were included involving 2,836 acute ischemic stroke (AIS) patients. Compared to EVT alone, tenecteplase (0.25 mg/kg and 0.4 mg/kg) + EVT and 0.9 mg/kg alteplase + EVT were significant difference associated with higher successful reperfusion (TICI 2b–3) after the end of EVT (RR = 2.31; 95% CI 1.15–4.63; RR = 2.31; 95% CI 1.00–5.33; RR = 1.05; 95% CI 1.01–1.09). And compared to 0.25 mg/kg tenecteplase + EVT, alteplase (0.6 mg/kg and 0.9 mg/kg) + EVT were significant difference associated with lower successful reperfusion (TICI 2b–3) after the end of EVT (RR = 0.45; 95% CI 0.22–0.90; RR = 0.45; 95% CI 0.23–0.91). The risk of aICH (RR = 1.50; 95% CI 1.07–2.09) was significantly higher for 0.6 mg/kg alteplase + EVT than EVT alone. There was no significant difference in functional independence (mRS 0–2), excellent outcome (mRS 0–1), all-cause mortality or sICH among the different IVT strategies (0.25 mg/kg or 0.4 mg/kg tenecteplase and 0.6 mg/kg or 0.9 mg/kg alteplase) before EVT.ConclusionThe use of alteplase before EVT may potentially improve the successful reperfusion after EVT compared to tenecteplase. Due to the insufficient sample size, more high-quality RCTs are needed to confirm effectiveness and safety of tenecteplase compare to alteplase in patients before EVT.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier: CRD42023470419.

Background Among patients with advanced/metastatic triple-negative breast cancer (TNBC) with high/positive programmed death-ligand 1 (PD-L1) expression, a superior survival outcome has been demonstrated with immune checkpoint inhibitors (ICIs). However, it remains unclear whether ICIs are beneficial for patients with low PD-L1 levels. Here, we derived survival data for subgroups with low PD-L1-expressing and conducted a pooled analysis.Methods After a systematic search of Embase, PubMed, MEDLINE, and CENTRAL from inception until May 18, 2023, randomized controlled trials (RCTs) reporting progression-free survival (PFS), overall survival (OS), or duration of response (DOR) for metastatic TNBC treated with ICI-based regimens were included. Kaplan-Meier curves were extracted for the intention-to-treat population and high PD-L1 subgroups. KMSubtraction was used when survival curves were not provided for subgroups with low PD-L1 expression. A pooled analysis of survival data was then conducted.Results A total of 3022 patients were included in four RCTs: Impassion130, Impassion131, KEYNOTE-119, and KEYNOTE-355. Unreported low PD-L1-expressing subgroups were identified, including PD-L1 immune cell (IC)

Elucidating the intricate neural mechanisms underlying brain functions requires integrative brain dynamics modeling. To facilitate this process, it is crucial to develop a general-purpose programming framework that allows users to freely define neural models across multiple scales, efficiently simulate, train, and analyze model dynamics, and conveniently incorporate new modeling approaches. In response to this need, we present BrainPy. BrainPy leverages the advanced just-in-time (JIT) compilation capabilities of JAX and XLA to provide a powerful infrastructure tailored for brain dynamics programming. It offers an integrated platform for building, simulating, training, and analyzing brain dynamics models. Models defined in BrainPy can be JIT compiled into binary instructions for various devices, including Central Processing Unit, Graphics Processing Unit, and Tensor Processing Unit, which ensures high-running performance comparable to native C or CUDA. Additionally, BrainPy features an extensible architecture that allows for easy expansion of new infrastructure, utilities, and machine-learning approaches. This flexibility enables researchers to incorporate cutting-edge techniques and adapt the framework to their specific needs.

ObjectiveThis study aimed to evaluate the glymphatic system in childhood absence epilepsy (CAE) using diffusion tensor image analysis along the paravascular space (DTI-ALPS) index. Methods: Forty-two CAE patients and 50 age- and gender-matched healthy controls (HC) were included in this study. All participants underwent scanning using a Siemens 3.0 T magnetic resonance scanner, and the DTI-ALPS index was calculated. The study compared the differences of DTI-ALPS index between CAE patients and the healthy controls. Additionally, this study also assessed the relationship between the DTI-ALPS index and clinical characteristics such as age, seizure frequency, and duration of epilepsy.ResultsThe DTI-ALPS index was lower in CAE patients compared to the healthy controls (1.45 ± 0.36 vs. 1.66 ± 0.30, p