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Abstract Background Transposition of the great arteries (TGA) is the most common cyanotic congenital heart defect in neonates but with low prenatal detection rate. This study sought to review the prenatal diagnosis, associated abnormalities, and mid-term postnatal outcomes of fetuses with TGA and investigate the integrated prenatal and postnatal management for TGA neonates. Methods A total of 134 infants prenatally diagnosed with TGA in Guangdong Provincial People’s Hospital, China, from January 2009 to December 2022 were included in the study. The prenatal ultrasound data and neonatal records were reviewed to assess the accuracy of prenatal diagnosis. Univariate and multivariate logistic and Cox analyses were used to identify risk factors associated with prognosis in such individuals. Results The population originated from 40 cities in 10 provinces in China, with integrated antenatal and postnatal management rate reaching 94.0% (126/134) and a high accuracy rate (99.3%) of prenatal primary diagnosis. The median period of follow-up was 1.6 [interquartile range (IQR) 0.1–4.3] years. There were 3 (2.2%) postnatal deaths, 118 (88.1%) patients undergoing arterial switch operation (ASO), 3 (2.2%) undergoing Rastelli operations and 5 (3.7%) doing stage operations. Of 118 patients receiving ASO, the major morbidity occurred in 64 patients (54.2%), and right ventricular outflow tract obstruction (RVOTO) in 31 (26.3%). In the multivariate logistic analysis, gestational ages at birth (OR = 0.953, 95% CI 0.910–0.991; p = 0.025) and cardiopulmonary bypass (CPB) time (OR = 1.010, 95% CI 1.000–1.030; p = 0.038) were identified as independent risk factors associated with major morbidity. In the Cox multivariate analysis, aortic cross-clamping time (HR = 1.030, 95% CI 1.000–1.050; p = 0.017) was identified as independent risk factor associated with RVOTO. Conclusion Earlier gestational ages at birth and longer CPB time are significantly associated with increased morbidity. Integrated prenatal and postnatal management is recommended for patients with prenatal diagnosis of TGA.

Abstract Recently, various cancer types have been identified to express a distinct subset of Interferon-stimulated genes (ISGs) that mediate therapy resistance. The mechanism through which cancer cells maintain prolonged Interferon stimulation effects to coordinate resistance remains unclear. Our research demonstrated that aberrant upregulation of TAGLN2 is associated with gastric cancer progression, and inhibiting its expression renders gastric cancer cells more susceptible to chemotherapy and radiation. We uncovered a novel role for TAGLN2 in the upregulation of resistance signature ISGs by enhancing YBX1-associated ssDNA aggregation and cGAS-STING pathway activation. TAGLN2 modulates YBX1 by recruiting c-Myc and SOX9 to YBX1 promoter region and directly interacting with AKT-YBX1, thereby enhancing YBX1 phosphorylation and nuclear translocation. Significantly, targeted downregulation of key proteins, inhibition of the TAGLN2-YBX1-AKT interaction (using Fisetin or MK2206) or disruption of the cGAS-STING pathway substantially reduced ssDNA accumulation, subsequent ISGs upregulation, and therapy resistance. The combination of Cisplatin with MK2206 displayed a synergistic effect in the higher TAGLN2-expressing xenograft tumors. Clinical analysis indicated that a derived nine-gene set effectively predicts therapeutic sensitivity and long-term prognosis in gastric cancer patients. These findings suggest that TAGLN2, YBX1 and induced ISGs are novel predictive markers for clinical outcomes, and targeting this axis is an attractive therapeutic sensitization strategy.

Abstract Background ST-elevation myocardial infarction (STEMI) is a common acute ischemia heart disease that causes serious damage to human health worldwide. Even though morbidity and mortality have significantly decreased by percutaneous coronary intervention (PCI), an additional cardiac protection strategy is still required. Acupuncture therapy has presented a dominant cardiac protection in many studies lately. Thus, we aim to evaluate the effect and safety of acupuncture as an adjunctive therapy in STEMI patients after PCI through a randomized controlled trial. Methods/Design This study describes a protocol of multicenter, double-blinded, parallel-controlled, randomized controlled trial. Ninety-six patients with STEMI aged 18–85 years who undergoing PCI will be recruited from the Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, The Affiliated Third Hospital of Chengdu Traditional Chinese Medicine University/Chengdu Pidu District Hospital of Traditional Chinese Medicine, and Zhaotong Municipal Hospital of Traditional Chinese Medicine. Participants will be randomly assigned (1:1 ratio) to the verum acupuncture plus basic therapy (i.e., treatment) group or the sham acupuncture plus basic therapy (i.e., control) group. These participants will be treated for 5 days and then will be followed up for 24 weeks. Any adverse events will be recorded throughout the study to evaluate safety. Discussion The present study aims to investigate the effect and safety of acupuncture for patients with STEMI after PCI and set up standardized treatment programs for acupuncture of these patients. Trial registration This study was registered in the Chinese Clinical Trial Registry (Registration ID: [ChiCTR2400081117]), on February 22, 2024.

Abstract Background The aging society has resulted in enormous demand for long-term care services. However, ageism is a common phenomenon in long-term care facilities, which not only hinders the quality of care for the recipients but also negatively influences caregivers’ well-being. In this paper, we first applied the Fraboni Scale of Ageism (FSA) to evaluate its reliability and construct validity among Chinese long-term caregivers in nursing homes. This study could contribute to assessing the prevalence of ageism in Chinese long-term caregivers, prompting facilities and the government to recognize the issue of ageism and explore necessary interventions to reduce ageism in long-term caregivers. Methods This is a cross-sectional study. We recruited 392 long-term caregivers using a convenience sampling strategy in nursing homes from two cities in Chinese central and northern regions. Parameters included the demographic characteristics, Cronbach’s alpha coefficients, and intraclass correlation coefficient. The construct validity was conducted by exploratory factor analysis and confirmatory factor analysis. Results The Cronbach’s alpha of FSA (Chinese version) was 0.856 and ICC was 0.871. The factor analysis identified 3 principal factors, explaining 43.95% of the total variance. The 3-factor model was confirmed to fit by confirmatory factor analysis. Conclusions The findings confirm that the FSA is easy to use and has good psychometric properties. This study will contribute to improving the condition of ageism, thereby improving the quality of care for the elderly and retention of professional talents in the LTC system.

Abstract Pregnane X receptor (PXR) has been reported to regulate glycolipid metabolism. The dysfunction of intestinal barrier contributes to metabolic disorders. However, the role of intestinal PXR in metabolic diseases remains largely unknown. Here, we show that activation of PXR by tributyl citrate (TBC), an intestinal-selective PXR agonist, improves high fat diet (HFD)-induced obesity. The metabolic benefit of intestinal PXR activation is associated with upregulation of β-1,3 galactosyltransferase 5 (B3galt5). Our results reveal that B3galt5 mainly expresses in the intestine and is a direct PXR transcriptional target. B3galt5 knockout exacerbates HFD-induced obesity, insulin resistance and inflammation. Mechanistically, B3galt5 is essential to maintain the integrity of intestinal mucus barrier. B3galt5 ablation impairs the O-glycosylation of mucin2, destabilizes the mucus layer, and increases intestinal permeability. Furthermore, B3galt5 deficiency abolishes the beneficial effect of intestinal PXR activation on metabolic disorders. Our results suggest the intestinal-selective PXR activation regulates B3galt5 expression and maintains metabolic homeostasis, making it a potential therapeutic strategy in obesity.

We provide the simultaneous traceable measurements of microwave electric fields at two different frequencies by the electromagnetically induced transparency (EIT) and Autler–Townes (AT) splitting. A static magnetic field working together with a linearly polarized probe and coupling light prepares Rydberg atoms in Zeeman sublevels with maximal |mJ| in an atomic vapor cell. Using the EIT-AT splitting of these two maximal |mJ| states, the microwave electric fields at two different frequencies are simultaneously measured, in which their frequency difference can be adjustable within the linear range of magnetic field-induced level shifts. The proposed method provides a promising prospect for calibrating multiple microwave frequencies simultaneously in the future.

Gastric cancer (GC) is a major cause of cancer-related mortality worldwide. Despite the widespread recognition of tumor immunotherapy in treating unresectable GC, challenges, including ineffective immunotherapy and drug resistance, persist. Therefore, understanding the regulatory mechanisms of PD-L1, particularly in the context of super-enhancers (SEs) and zinc finger protein 36 ring finger protein-like 1 (ZFP36L1) RNA-binding protein, is crucial. In this study, we performed H3K27ac Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing, investigated the heterogeneity of SEs between two GC subtypes with differential growth patterns, and revealed the immune escape signatures driven by ZFP36L1-SE in infiltrative GC through SEs inhibitors treatment. The regulation of ZFP36L1 to PD-L1 was evaluated by quantitative PCR, western blot, flow cytometry, and immunohistochemistry. Furthermore, we explored its regulatory mechanisms using a combination of molecular biology techniques, including luciferase reporter assay, GST/RNA pull-down, chromatin immunoprecipitation (ChIP)/RIP experiments, and in vivo functional assays. We demonstrated that ZFP36L1, driven by an SE, enhances IFN-γ-induced PD-L1 expression, with SPI1 identified as the specific transcription factor binding to ZFP36L1-SE. Mechanistically, ZFP36L1 binds to the adenylate uridylate-rich element in the 3ʹ untranslated region (3ʹUTR) of HDAC3 mRNA, exacerbating its mRNA decay, and thereby facilitating PD-L1 abnormal transcriptional activation. Collectively, our findings provide mechanistic insights into the role of the SPI1-ZFP36L1-HDAC3-PD-L1 signaling axis in orchestrating immune escape mechanisms in GC, thereby offering valuable insights into the potential targets for immune checkpoint therapy in GC management.

BackgroundAcute kidney injury (AKI) is common in cirrhotic patients, especially in the intensive care unit (ICU), and is often associated with poor prognosis. Albumin is often used for plasma volume expansion, but its efficacy in cirrhotic patients with AKI [excluding hepatorenal syndrome (HRS)] is debated. This study aimed to assess the impact of albumin therapy on prognosis in ICU patients with cirrhosis and non-HRS AKI.MethodsA retrospective analysis was conducted using the MIMIC-IV 2.2 database. The primary endpoint was 28-day mortality. Inverse probability of treatment weighting (IPTW) was used to balance baseline characteristics between the albumin and non-albumin groups.ResultsA total of 1,623 patients were included, with 586 receiving albumin. After IPTW, the sample sizes were 1,713 in the non-albumin group and 1,490 in the albumin group. Albumin administration was associated with higher rates of AKI recovery at 48 h but did not improve 28-day mortality in the overall cohort. Further analysis revealed that using 5% albumin concentration was associated with improved 28-day mortality (HR 0.68; 95% CI 0.49–0.95; p = 0.025), whereas 25% albumin did not show benefit. In patients with high bilirubin levels, albumin treatment significantly reduced 28-day mortality. However, albumin therapy may increase 28-day mortality in certain subgroups, including patients with chronic kidney disease and baseline albumin levels >3.3 g/dL.ConclusionAlthough albumin therapy improved 28-day mortality in some cases, it may also increase mortality in certain subgroups. The use of albumin in critically ill patients with cirrhosis and AKI should be approached with greater consideration of its risks and benefits.

Epilepsy, a complex neurological condition marked by recurring seizures, is increasingly recognized for its intricate relationship with mitochondria, the cellular powerhouses responsible for energy production and calcium regulation. This review offers an in-depth examination of the interplay between epilepsy, mitochondrial function, and aging. Many factors might account for the correlation between epilepsy and aging. Mitochondria, integral to cellular energy dynamics and neuronal excitability, perform a critical role in the pathophysiology of epilepsy. The mechanisms linking epilepsy and mitochondria are multifaceted, involving mitochondrial dysfunction, reactive oxygen species (ROS), and mitochondrial dynamics. Mitochondrial dysfunction can trigger seizures by compromising ATP production, increasing glutamate release, and altering ion channel function. ROS, natural byproducts of mitochondrial respiration, contribute to oxidative stress and neuroinflammation, critical factors in epileptogenesis. Mitochondrial dynamics govern fusion and fission processes, influence seizure threshold and calcium buffering, and impact seizure propagation. Energy demands during seizures highlight the critical role of mitochondrial ATP generation in maintaining neuronal membrane potential. Mitochondrial calcium handling dynamically modulates neuronal excitability, affecting synaptic transmission and action potential generation. Dysregulated mitochondrial calcium handling is a hallmark of epilepsy, contributing to excitotoxicity. Epigenetic modifications in epilepsy influence mitochondrial function through histone modifications, DNA methylation, and non-coding RNA expression. Potential therapeutic avenues targeting mitochondria in epilepsy include mitochondria-targeted antioxidants, ketogenic diets, and metabolic therapies. The review concludes by outlining future directions in epilepsy research, emphasizing integrative approaches, advancements in mitochondrial research, and ethical considerations. Mitochondria emerge as central players in the complex narrative of epilepsy, offering profound insights and therapeutic potential for this challenging neurological disorder.

Mounting evidence suggests that insect hormones associated with growth and development also participate in pathogen defense. We have discovered a previously undescribed midgut transcriptional control pathway that modulates the availability of 20-hydroxyecdysone (20E) in a worldwide insect pest (Plutella xylostella), allowing it to defeat the major virulence factor of an insect pathogen Bacillus thuringiensis (Bt). A reduction of the transcriptional inhibitor (PxDfd) increases the expression of a midgut microRNA (miR-8545), which in turn represses the expression of a newly identified ecdysteroid-degrading glucose dehydrogenase (PxGLD). Downregulation of PxGLD reduces 20E degradation to increase 20E titer and concurrently triggers a transcriptional negative feedback loop to mitigate 20E overproduction. The moderately elevated 20E titer in the midgut activates a MAPK signaling pathway to increase Bt tolerance/resistance. These findings deepen our understanding of the functions attributed to these classical insect hormones and help inform potential future strategies that can be employed to control insect pests.

Grain refinement is a crucial technique for enhancing the mechanical properties and corrosion resistance of magnesium alloys. In this study, the addition of 0.3 wt% CaO and 0.3 wt% CaCO3 successfully refined the AM60 alloy, resulting in a significant reduction in the average grain size from 326 μm to 96 μm (when adding CaCO3). The refined grain size of the as-cast AM60 alloy led to an increase in both tensile strength and yield strength to 118.2 MPa and 72.6 MPa, representing a respective increase of 35% and 23% compared to the alloy without the refiner. As results of EBSD, it is verified that the basal slip system (0001) has a higher Schmid factor after adding CaO, which indicates that this system has higher activity. The substitution reaction between CaO and Mg can produce synergistic effects from the solute effect of Ca and the nucleating effect of residual CaO, which play an important role in grain refinement. Due to the fine grain size and diffuse distribution of the second phase in the AM60-CaCO3 alloy and the thermal decomposition of CaCO3, which consumes the aluminum element in the matrix, the content of the β-phase (Mg17Al12) is reduced. Consequently, this reduces the electric coupling effect between the β-phase and the magnesium matrix. The AM60-CaCO3 alloy exhibited the most superior corrosion resistance, achieving a corrosion rate of only 1.01 mm y−1, representing a 48.9% reduction in corrosion rate compared to the AM60 alloy.

Induced pluripotent stem cells (iPSCs) can be personalized and differentiated into neural stem cells (NSCs), thereby effectively providing a source of transplanted cells for spinal cord injury (SCI). To further improve the repair efficiency of SCI, we designed a functional neural network tissue based on TrkC-modified iPSC-derived NSCs and a CBD-NT3-modified linear-ordered collagen scaffold (LOCS). We confirmed that transplantation of this tissue regenerated neurons and synapses, improved the microenvironment of the injured area, enhanced remodeling of the extracellular matrix, and promoted functional recovery of the hind limbs in a rat SCI model with complete transection. RNA sequencing and metabolomic analyses also confirmed the repair effect of this tissue from multiple perspectives and revealed its potential mechanism for treating SCI. Together, we constructed a functional neural network tissue using human iPSCs-derived NSCs as seed cells based on the interaction of receptors and ligands for the first time. This tissue can effectively improve the therapeutic effect of SCI, thus confirming the feasibility of human iPSCs-derived NSCs and LOCS for SCI repair and providing a valuable direction for SCI research.

Abstract Background The population aging trend and the shortage of elderly care workers require the long-term care profession to become more attractive. However, the professional attractiveness among long-term care workers has yet to be extensively studied. This study aims to identify the factors that influence the attractiveness of the long-term care profession for nursing home (NH) care workers.. Methods A cross-sectional study was conducted in more than 50 NHs. Perception of professional attractiveness among long-term care workers and potential associated factors were measured using the Attractive Work Questionnaire (AWQ) and structural instruments including the Fraboni Scale of Ageism (FSA) and the Maslach Burnout Inventory (MBI). A multiple linear regression method was employed to explore the influence of potential independent variables on professional attractiveness. Results The overall response rate was 99%. The results showed the score of professional attractiveness (185.37 ± 20.034), as well as the scores of each component (99.26 ± 11.258 for work condition, 30.13 ± 3.583 for work content, and 55.99 ± 7.074 for job satisfaction). Findings of multiple linear regression analysis indicated that age(β = 0.129, p

Drug repurposing offers an efficient approach to therapeutic development. In this study, our bioinformatic analysis first predicted an association between obesity and lansoprazole (LPZ), a commonly prescribed drug for gastrointestinal ulcers. We went on to show that LPZ treatment increased energy expenditure and alleviated the high-fat diet-induced obesity, insulin resistance, and hepatic steatosis in mice. Treatment with LPZ elicited thermogenic gene expression and mitochondrial respiration in primary adipocytes, and induced cold tolerance in cold-exposed mice, suggesting the activity of LPZ in promoting adipose thermogenesis and energy metabolism. Mechanistically, LPZ is an efficient inhibitor of adipose phosphocholine phosphatase 1 (PHOSPHO1) and produces metabolic benefits in a PHOSPHO1-dependent manner. Our results suggested that LPZ may stimulate adipose thermogenesis by inhibiting the conversion of 2-arachidonoylglycerol-lysophosphatidic acid (2-AG-LPA) to 2-arachidonoylglycerol (2-AG) and reduce the activity of the thermogenic-suppressive cannabinoid receptor signaling. In summary, we have uncovered a novel therapeutic indication and mechanism of LPZ in managing obesity and its related metabolic syndrome, and identified a potential metabolic basis by which LPZ improves energy metabolism.

Sulfation is a crucial and prevalent conjugation reaction involved in cellular processes and mammalian physiology. 3′-Phosphoadenosine 5′-phosphosulfate (PAPS) synthase 2 (PAPSS2) is the primary enzyme to generate the universal sulfonate donor PAPS. The involvement of PAPSS2-mediated sulfation in adenomatous polyposis coli (APC) mutation-promoted colonic carcinogenesis has not been reported. Here, we showed that the expression of PAPSS2 was decreased in human colon tumors along with cancer stages, and the lower expression of PAPSS2 was correlated with poor prognosis in advanced colon cancer. Gut epithelial-specific heterozygous Apc deficient and Papss2-knockout (ApcΔgut-HetPapss2Δgut) mice were created, and the phenotypes were compared to the spontaneous intestinal tumorigenesis of ApcΔgut-Het mice. ApcΔgut-HetPapss2Δgut mice were more sensitive to gut tumorigenesis, which was mechanistically accounted for by the activation of Wnt/β-catenin signaling pathway due to the suppression of chondroitin sulfation and inhibition of the farnesoid X receptor (FXR)-transducin-like enhancer of split 3 (TLE3) gene regulatory axis. Chondroitin sulfate supplementation in ApcΔgut-HetPapss2Δgut mice alleviated intestinal tumorigenesis. In summary, we have uncovered the protective role of PAPSS2-mediated chondroitin sulfation and bile acids–FXR–TLE3 activation in the prevention of gut carcinogenesis via the antagonization of Wnt/β-catenin signaling. Chondroitin sulfate may be explored as a therapeutic agent for Papss2 deficiency-associated colonic carcinogenesis.

Gastrointestinal (GI) cancers represent a significant global health challenge, driving relentless efforts to identify innovative diagnostic and therapeutic approaches. Recent strides in microbiome research have unveiled a previously underestimated dimension of cancer progression that revolves around the intricate metabolic interplay between GI cancers and the host's gut microbiota. This review aims to provide a comprehensive overview of these emerging metabolic interactions and their potential to catalyze a paradigm shift in precision diagnosis and therapeutic breakthroughs in GI cancers. The article underscores the groundbreaking impact of microbiome research on oncology by delving into the symbiotic connection between host metabolism and the gut microbiota. It offers valuable insights into tailoring treatment strategies to individual patients, thus moving beyond the traditional one-size-fits-all approach. This review also sheds light on novel diagnostic methodologies that could transform the early detection of GI cancers, potentially leading to more favorable patient outcomes. In conclusion, exploring the metabolic interactions between host gut microbiota and GI cancers showcases a promising frontier in the ongoing battle against these formidable diseases. By comprehending and harnessing the microbiome's influence, the future of precision diagnosis and therapeutic innovation for GI cancers appears more optimistic, opening doors to tailored treatments and enhanced diagnostic precision.

ObjectiveThis study aimed to investigate the diagnostic utility of the modified lung ultrasound score (MLUS) in distinguishing between Mycoplasma pneumonia and viral pneumonia in children and evaluate their severity.MethodsA prospective collection of 137 suspected cases of community-acquired pneumonia in children admitted to the Quanzhou Maternity and Children's Hospital in Quanzhou City, Fujian Province, from January 2023 to December 2023 constituted the study cohort. All patients underwent lung ultrasound examinations, and MLUS scores were assigned based on ultrasound findings, including pleural lines, A-lines, B-lines, and lung consolidations. Based on the pathogenic results, the patients were categorized into the Mycoplasma pneumonia (74 cases) and viral pneumonia (63 cases) groups. The severity was classified as mild (110 cases) or severe (27 cases). The diagnostic value of MLUS for Mycoplasma pneumonia and viral pneumonia in children was analyzed.Results(1) MLUS scores were significantly different between the Mycoplasma pneumonia (15, 10–21) and viral pneumonia (8, 5–16) groups (P = 0.002). ROC curve analysis indicated that using a cut-off value of 11, MLUS exhibited a sensitivity of 70.3%, specificity of 58.7%, and an area under curve (AUC) of 0.653 for diagnosing Mycoplasma pneumonia. Furthermore, large-area lung consolidation on ultrasound images demonstrated good diagnostic performance for predicting Mycoplasma pneumonia, with an AUC of 0.763, a sensitivity of 71.6%, and a specificity of 81.0%. (2) MLUS scores were significantly different between the mild pneumonia (10.5, 5–17) and severe pneumonia (21, 16–29) groups (P

Background & Aims: Currently, there is limited knowledge on the clinical profile of drug-induced liver injury (DILI) in Chinese children. We aimed to assess the clinical characteristics, suspected drugs, and outcomes associated with pediatric DILI in China. Methods: This nationwide, multicenter, retrospective study, conducted between 2012 and 2014, analyzed 25,927 cases of suspected DILI at 308 medical centers using the inpatient medical register system. Utilizing the Roussel Uclaf causality assessment method score, only patients with scores ≥6 or diagnosed with DILI by three experts after scoring

Objectives The blood urea nitrogen to creatinine (BUN/Cr) ratio is associated with early neurological deterioration in acute ischaemic stroke (AIS). However, the predictive value of the BUN/Cr ratio for the AIS prognosis remains unclear. Therefore, we evaluated the correlation between the BUN/Cr ratio and the 3-month outcome in patients with AIS, further testing their dose–response relationship.Design This retrospective cohort study enrolled patients with AIS who were admitted between 1 January 2013 and 31 May 2022. Poor clinical outcome was defined as 3-month Modified Rankin Scale (mRS) >2. Cox proportional HR was used to evaluate the correlation between the BUN/Cr ratio and 3-month outcome. Restricted cubic spline and robust locally weighted regression analyses were conducted to determine the dose–response relationship between the BUN/Cr ratio and the 3-month outcome.Results A total of 4952 eligible patients were included in the study. The patients were divided into three groups according to the tertiles of BUN/Cr ratio (T1, 0.093). After logistic regression adjustment for demographic and clinical characteristics, the BUN/Cr ratio was found to be independently associated with the 3-month outcome in patients with AIS. The restricted cubic spline and locally regression smoothing scatterplot graph showed a strong dose–response relationship between the BUN/Cr ratio and the 3-month outcome in patients with AIS.Conclusion A dose–response relationship was observed between the BUN/Cr ratio and the 3-month outcome in patients with AIS, suggesting that the BUN/Cr ratio could serve as a reliable predictor for the AIS prognosis.

Background & Aims: Hepatic recompensation may be achieved in patients with decompensated cirrhosis due to chronic hepatitis B (CHB) upon effective suppression of viral replication by nucleos(t)ide analogues (NAs). However, the optimal timing and predictors of recompensation and the subsequent clinical course of patients with CHB with vs. without recompensation are not well-defined. Methods: This study was a retrospective extension of a multi-centre prospective cohort, focusing on patients with CHB and decompensated cirrhosis treated with entecavir. We followed patients beyond treatment week 120 until a second decompensation event or June 2023. We identified the optimal timing and predictors of recompensation by week 120, evaluated durability of recompensation in patients fulfilling recompensation criteria by week 120 and examined late recompensation in those who did not fulfil it by week 120. Results: At treatment week 24, serum albumin ≥34 g/L predicted recompensation by week 120. The Brec-PAS model offered good predictive ability for recompensation by week 120. Of the 283 patients who finished 120 weeks of therapy, 175 were followed beyond week 120 (median follow-up: 240 weeks). Among the 106 patients achieving recompensation by week 120, 92 (86.8%) maintained recompensation for another 120 (72-168) weeks. Among the 69 patients without recompensation by week 120, 40.6% attained late recompensation during the subsequent 120 (72-168) weeks. Additionally, hepatocellular carcinoma incidence was lower in the recompensated group (5.0% vs. 16.13%, p = 0.002). Conclusions: A serum albumin ≥34 g/L at treatment week 24 predicted recompensation by week 120. Recompensation achieved by week 120 of NA treatment is maintained in >80% of patients in the long term. Some patients may achieve recompensation only after >120 weeks of NA treatment. The incidence of hepatocellular carcinoma was reduced but not completely abolished after recompensation. Impact and implications: Our research provides a meaningful contribution to understanding the long-term prognosis of recompensation in patients with chronic hepatitis B and decompensated cirrhosis, as well as to evaluating the predictive value of serum albumin levels, offering a comprehensive view of clinical outcomes after recompensation. The significance of early biomarkers in guiding therapeutic decisions is highlighted, shedding light on the continued benefits and possible risks after recompensation. This enhances the capability for more precise prognostic evaluations and informed therapeutic strategies. For healthcare providers, these insights afford a detailed perspective on patient monitoring and intervention planning, underscoring the need for ongoing assessment past the initial recompensation phase.

Abstract Background There are a variety of determinants that are key to functional disability of older adults. However, little is known regarding the relationship between cognitive frailty and disability among older people. The aims of this study were to examine the associations between cognitive frailty and its six components with instrumental activities of daily living (IADL) functioning in community-dwelling older adults. Methods A total of 313 community-dwelling older adults (aged ≥ 65 years) were recruited from eight community centers in central China. Cognitive frailty was operationalized using the Mini-Mental State Examination for the evaluation of cognitive status and the Fried criteria for the evaluation of physical frailty. The outcome was functional disability assessed by the IADL scale. The association between cognitive frailty, as well as its components, and IADL limitations was identified by conducting binary logistic regression analysis. Results The prevalence of cognitive frailty was 8.9% in this study. The results showed that cognitive frailty (OR = 22.86) and frailty without cognitive impairment (OR = 8.15) were associated with IADL limitations. Subdimensions of cognitive frailty, exhaustion, weakness, low physical activity and cognitive impairment components were independently associated with IADL limitations. Conclusion Cognitive frailty was associated with a higher prevalence of disability. Interventions for improving cognitive frailty should be developed to prevent IADL disability among community-dwelling older adults in China.

It is well known that distillation learning has the ability to enhance the performance of a light (student) model by transferring knowledge from a heavy (teacher) model, without incurring additional computational and storage costs. This article proposes an improved decoupled knowledge distillation (DKD) strategy for hyperspectral image (HSI) classification. A spatial feature blurring (SFB) module is designed to improve the classification performance of the student network when using DKD strategy. The SFB module utilizes randomly initialized 2-D standard normal distribution tensors to blur the spatial features of HSI, which increases the complexity of the data. This aligns with the characteristics of DKD, which transfers more useful knowledge under the condition of sample complexity. To effectively transfer knowledge, this article proposes a robust teacher network named the dual-branch spatial transformer-spectral transformer (DBSTST) network. This network describes the spatial and spectral long-range dependencies of HSI, addressing the limitations of convolutional neural networks in capturing only local features due to their fixed receptive fields. More specifically, the DBSTST network adopts spatial transformer-spectral transformer, which is composed of a parallel spatial-spectral multihead self-attention (PS2MHSA) module, aiming to describe pixel-level spatial long-range dependencies and spectral correlations in HSI. Simultaneously, the introduction of spatial-spectral positional embedding into PS2MHSA enhances positional awareness. We demonstrated the effectiveness of our proposed method on four publicly available HSI datasets. The student network achieves classification performance improvement and surpasses some other networks. Moreover, when compared with state-of-the-art classification methods, the DBSTST network also exhibits significant improvements in classification performance.

Abstract Gastric cancer (GC) remains a predominant form of malignant tumor globally, necessitating innovative non-surgical therapeutic approaches. This investigation aimed to delineate the expression landscape of macrophage-associated genes in GC and to evaluate their prognostic significance and influence on immunotherapeutic responsiveness. Utilizing the CellMarker2.0 database, we identified 69 immune cell markers with prognostic relevance in GC, including 12 macrophage-specific genes. A Weighted Gene Co-Expression Network Analysis (WGCNA) isolated 3,181 genes correlated with these macrophage markers. The Cancer Genome Atlas (TCGA-STAD) dataset was employed as the training set, while data from the GSE62254 served as the validation cohort. 13 genes were shortlisted through LASSO-Cox regression to formulate a prognostic model. Multivariable Cox regression substantiated that the calculated risk score serves as an imperative independent predictor of overall survival (OS). Distinct macrophage infiltration profiles, pathway associations, treatment susceptibilities, and drug sensitivities were observed between high- and low-risk groups. The preliminary validation of ANXA5 in predicting the survival rates of GC patients at 1 year, 3 years, and 5 years, as well as its expression levels were higher and role in promoting tumor angiogenesis in GC through immunohistochemistry and angiogenesis experiments. In summary, macrophage-related genes were potentially a novel crosstalk mechanism between macrophages and endothelial cells in the tumor microenvironment, and the interplay between inflammation and angiogenesis might have also offered new therapeutic targets, providing a new avenue for personalized treatment interventions.

The analysis of the Global NFavigation Satellite System (GNSS) time series provides valuable information for geodesy and geodynamics researcFh. Precise data analysis strategies are crucial for accurately obtaining the linear velocity of GNSS stations, enabling high-precision applications of GNSS time series. This study investigates the impact of different stochastic noise models on velocity estimations derived from GNSS time series, specifically under conditions of environmental loading correction and common mode error (CME) removal. By comparing data from various data centers, we find that post-correction, different analysis strategies exhibit high consistency in their noise characteristics and velocity estimation results. Across various analysis strategies, the optimal noise models were predominantly Power Law with White Noise (PLWN) and Fractional Noise with White Noise (FNWN), with the optimal noise models including COMB/JPL, COMB/SOPAC, and COMB/NGL for approximately 50% of the datasets. Most of the stations (approximately 80%) showed velocity differences below 0.3 mm/year and velocity estimation uncertainties below 0.1 mm/year. Nonetheless, variations in amplitudes and periodic signals persisted due to differences in the processing of raw GNSS observations. For instance, the NGL and JPL datasets, which were processed using GipsyX 2.1 software, showed higher amplitudes of the 5.5-day periodic signal. These findings provide a solid empirical foundation for advancing data analysis methods and enhancing the reliability of GNSS time series results in future research.

Abstract PARP inhibitors (PARPi)‐based synthetic lethal therapy demonstrates limited efficacy for most cancer types that are homologous recombination (HR) proficient. To potentiate the PARPi application, a nanocarrier based on 5‐azacytidine (AZA)‐conjugated polymer (PAZA) for the codelivery of AZA and a PARP inhibitor, BMN673 (BMN) is developed. AZA conjugation significantly decreased the nanoparticle (NP) size and increased BMN loading. Molecular dynamics simulation and experimental validations shed mechanistic insights into the self‐assembly of effective NPs. The small PAZA NPs demonstrated higher efficiency of tumor targeting and penetration than larger NPs, which is mediated by a new mechanism of active targeting that involves the recruitment of fibronectin from serum proteins following systemic administration of PAZA NPs. Furthermore, it is found that PAZA carrier sensitize the HR‐proficient nonsmall cell lung cancer (NSCLC) to BMN, a combination therapy that is more effective at a lower AZA/BMN dosage. To investigate the underlying mechanism, the tumor immune microenvironment and various gene expressions by RNAseq are explored. Moreover, the BMN/PAZA combination increased the immunogenicity and synergized with PD‐1 antibody in improving the overall therapeutic effect in an orthotopic model of lung cancer (LLC).

Abstract Polyunsaturated fatty acids (PUFAs) are essential nutrients for all living organisms. PUFA synthesis is mediated by Δ12 desaturases in plants and microorganisms, whereas animals usually obtain PUFAs through their diet. The whitefly Bemisia tabaci is an extremely polyphagous agricultural pest that feeds on phloem sap of many plants that do not always provide them with sufficient PUFAs. Here, a plant‐derived Δ12 desaturase gene family BtFAD2 is characterized in B. tabaci and it shows that the BtFAD2‐9 gene enables the pest to synthesize PUFAs, thereby significantly enhancing its fecundity. The role of BtFAD2‐9 in reproduction is further confirmed by transferring the gene to Drosophila melanogaster, which also increases the fruit fly's reproduction. These findings reveal an extraordinary evolutionary scenario whereby a phytophagous insect acquired a family of plant genes that enables it to synthesize essential nutrients, thereby lessening its nutritional dependency and allowing it to feed and reproduce on many host plants.

Deep neural networks have recently been extensively utilized for Polarimetric synthetic aperture radar (PolSAR) image classification. However, this heavily relies on extensive labeled data which is both costly and labor-intensive. To lower the collection of labeling data and enhance the classification performance, a novel multichannel semi-supervised active learning (MSSAL) method is proposed for PolSAR image classification. First, a multichannel strategy-based committee model with cooperative representation classification is presented to explore more effective information in the limited training data. Second, a loss prediction (LP) module is designed to identify the most informative pixels, and an ensemble learning (EL) strategy is designed to select the pixels with the highest confidence. Then, the deep neural network is fine-tuned with the obtaining target pixels through LP and EL in each iteration. Finally, the trained deep model predicts labels for all unlabeled data, outputting the final classification results. The proposed method is evaluated on three real-world PolSAR datasets, demonstrating superior performance to other PolSAR image classification methods with limited labeled samples.

Abstract Introduction A pan-genotypic and effective treatment regimen for patients with chronic hepatitis C virus (HCV) infection remains an unmet medical need in China. Alfosbuvir is a novel potent HCV NS5B polymerase inhibitor in development for the treatment of chronic HCV infection. We conducted a phase 3 study to evaluate the efficacy and safety of alfosbuvir in combination with daclatasvir in Chinese patients with HCV infection. Methods All patients received 600 mg alfosbuvir tablets plus 60 mg daclatasvir tablets once daily for 12 weeks. The primary endpoint was sustained virological response 12 weeks after the end of treatment (SVR12). A follow-up visit was done at week 4 and 12, and those who achieved SVR12 were followed up at post-treatment week 24. Results Of the 326 patients who received at least one dose of the study drug, 320 (98.2% [95% confidence interval (CI): 96.5%–99.5%]) achieved sustained virological response at post-treatment week 12 (SVR12), which was superior to the historical SVR12 rate of 88% (p

Abstract Background Although breastfeeding is strongly recommended, the breastfeeding rate of preterm infants in China remains significantly low. In addition to the global structural challenges to breastfeeding and the physiological immaturity of preterm infants, Chinese mothers of preterm infants face unique challenges of maternal-infant separation after birth. Moreover, little is known about Chinese mothers’ specific needs in coping with the difficulties posed by these challenges. This study utilized the Behaviour Change Wheel to investigate the breastfeeding needs of Chinese preterm mothers that may facilitate its practice in the future. Method A qualitative descriptive design was implemented in Wuhan in 2022. Based on purposeful sampling, 13 preterm mothers were recruited from a NICU in a Grade III Class A hospital in Wuhan, China. Face-to-face semi-structured interviews were conducted to collect data using the interview guide developed by the Theoretical Domains Framework. Theoretical Thematic Analysis was used to review the data in 6 steps to identify themes. Results Five major themes emerged: (1) capability: ability to interpret infants’ cues and identify problems, and need for breastfeeding knowledge and skills training; (2) physical opportunity: cleanliness and quietness in household environment, private lactation spaces and breastfeeding tools in workplaces and hospitals; (3) social opportunity: family support, peer support, and authoritative support from healthcare providers; (4) reflective motivation: information on health impacts of breastfeeding; (5) automatic motivation: maternal-infant bonding, free of aversive stimulus. Conclusion Preterm mothers’ needs to enable breastfeeding were diverse, including increasing their capability, physical and social opportunities, and reflective and automatic motivation. People, resources and environments associated with these needs should be engaged together to stablish a conducive structural environment for breastfeeding. The policy change for “zero separation” and implementation of kangaroo care should also be implemented in Chinese neonatal intensive care units. Future studies are needed to design effective interventions according to mothers’ specific needs.

The bean flower thrip Megalurothrips usitatus (Bagnall) is a severe pest on cowpeas and causes a 20–30% reduction in cowpeas in Hainan, China, with even complete crop failure in severe cases. Spinetoram is currently the most important pesticide against M. usitatus in cowpea production. In the main producing areas of cowpeas in Hainan, however, the efficacy of spinetoram against M. usitatus is not well known. In the present study, we employed the maximum dose bioassay to evaluate the efficacy of the mortality rates of adult thrips at F0 in spinetoram, freshly collected from 212 field populations of M. usitatus collected from 20 villages in the Yazhou District of Hainan. Our results showed that the mortality rates of these thrip populations exposed to spinetoram were from 3.31% to 100%. Among them, the mortality rates of 66.98% (142/212) of the populations exceeded 80%, while that of 33.96% (72/212) of the populations surpassed 90%. Only a small proportion of 0.47% (1/212) the populations exhibited a mortality rate below 10%, and 4.72% (10/212) displayed rates below 50%. Furthermore, significant differences were also observed in the mortality rates of thrips among different villages. Taken together, the maximum dosage bioassay method is a rapid and easily implemented approach providing valuable insights into the field efficacy of insecticides and offers guidance in determining the optimal dosage required in the field. Spinetoram is still effective against M. usitatus in the main producing areas of cowpeas in Hainan, but caution should be exercised in its combined use with other methods to reduce potential resistance.

Objective: Respiratory viral diseases have posed a persistent threat to public health due to their high transmissibility. Influenza virus and SARS-Cov-2 are both respiratory viruses that have caused global pandemics. A zero-COVID-19 strategy is a public health policy imposed to stop community transmission of COVID-19 as soon as it is detected. In this study, we aim to examine the epidemiological characteristics of seasonal influenza in the past five years before and after the emergence of COVID-19 in China and observe the possible impact of the strategy on influenza. Methods: Data from two data sources were retrospectively analyzed. A comparison on influenza incidence rate between Hubei and Zhejiang provinces was conducted based on data from the Chinese Center for Disease Control and Prevention (CDC). Then a descriptive and comparative analysis on seasonal influenza based on data from Zhongnan Hospital of Wuhan University and Hangzhou Ninth People`s Hospital before and after the outbreak of SARS-CoV-2 was conducted. Results: From 2010–2017, both provinces experienced relatively low influenza activity until the 1st week of 2018, when they reached peak incidence rates of 78.16/100000PY, 34.05/100000PY respectively. Since then, influenza showed an obvious seasonality in Hubei and Zhejiang until the onset of COVID-19. During 2020 and 2021, there was a dramatic decline in influenza activity compared to 2018 and 2019. However, influenza activity seemed to rebound at the beginning of 2022 and surged in summer, with positive rates of 20.52% and 31.53% in Zhongnan Hospital of Wuhan University and Hangzhou Ninth People`s Hospital respectively as of the time writing this article. Conclusions: Our results reinforce the hypothesis that zero-COVID-19 strategy may impact the epidemiological pattern of influenza. Under the complex pandemic situation, implementation of NPIs could be a beneficial strategy containing not only COVID-19 but also influenza.

Background/Aims Existing hepatocellular carcinoma (HCC) prediction models are derived mainly from pretreatment or early on-treatment parameters. We reassessed the dynamic changes in the performance of 17 HCC models in patients with chronic hepatitis B (CHB) during long-term antiviral therapy (AVT). Methods Among 987 CHB patients administered long-term entecavir therapy, 660 patients had 8 years of follow-up data. Model scores were calculated using on-treatment values at 2.5, 3, 3.5, 4, 4.5, and 5 years of AVT to predict three-year HCC occurrence. Model performance was assessed with the area under the receiver operating curve (AUROC). The original model cutoffs to distinguish different levels of HCC risk were evaluated by the log-rank test. Results The AUROCs of the 17 HCC models varied from 0.51 to 0.78 when using on-treatment scores from years 2.5 to 5. Models with a cirrhosis variable showed numerically higher AUROCs (pooled at 0.65–0.73 for treated, untreated, or mixed treatment models) than models without (treated or mixed models: 0.61–0.68; untreated models: 0.51–0.59). Stratification into low, intermediate, and high-risk levels using the original cutoff values could no longer reflect the true HCC incidence using scores after 3.5 years of AVT for models without cirrhosis and after 4 years of AVT for models with cirrhosis. Conclusions The performance of existing HCC prediction models, especially models without the cirrhosis variable, decreased in CHB patients on long-term AVT. The optimization of existing models or the development of novel models for better HCC prediction during long-term AVT is warranted.

Many populations of the two-spotted spider mite, Tetranychus urticae Koch, have developed high levels of resistance to the pesticide abamectin in China and other countries. This study developed a near-isogenic line to understand better the inheritance, cross-resistance, and fitness costs associated with abamectin resistance in the field population of T. urticae in China. We introduced the trait that confers extremely high abamectin resistance in a field-collected population of T. urticae into a susceptible laboratory strain (IPP-SS) to generate an abamectin-resistant near-isogenic line (NIL-Aba). This process was carried out through multiple backcrossing to IPP-SS and via parthenogenesis and abamectin screening. Compared with IPP-SS, the NIL-Aba strain had a 25 147-fold resistance to abamectin and a high level of cross-resistance to bifenthrin (288.17-fold), an intermediate level to emamectin benzoate (42.57-fold), and low levels to bifenazate, chlorfenapyr, cyflumetofen, cyenopyrafen, and cyetpyrafen with resistance ranging from 3.18- to 9.31-fold. But it had no cross-resistance to profenofos. The resistance to abamectin in NIL-Aba was autosomal, incompletely dominant, and polygenic. Based on two sex life table parameters, no fitness cost was found in NIL-Aba. Establishing the NIL-Aba strain provides a reliable basis for an in-depth study of abamectin resistance in T. urticae. New information on toxicological characteristics and fitness cost should facilitate the management of abamectin resistance in field populations of T. urticae.

Neonicotinoid insecticides, which target insect nicotinic acetylcholine receptors (nAChRs), have been widely and intensively used to control the whitefly, Bemisia tabaci, a highly damaging, globally distributed, crop pest. This has inevitably led to the emergence of populations with resistance to neonicotinoids. However, to date, there have been no reports of target-site resistance involving mutation of B. tabaci nAChR genes. Here we characterize the nAChR subunit gene family of B. tabaci and identify dual mutations (A58T&R79E) in one of these genes (BTβ1) that confer resistance to multiple neonicotinoids. Transgenic D. melanogaster, where the native nAChR Dβ1 was replaced with BTβ1A58T&R79E, were significantly more resistant to neonicotinoids than flies where Dβ1 were replaced with the wildtype BTβ1 sequence, demonstrating the causal role of the mutations in resistance. The two mutations identified in this study replace two amino acids that are highly conserved in >200 insect species. Three-dimensional modelling suggests a molecular mechanism for this resistance, whereby A58T forms a hydrogen bond with the R79E side chain, which positions its negatively-charged carboxylate group to electrostatically repulse a neonicotinoid at the orthosteric site. Together these findings describe the first case of target-site resistance to neonicotinoids in B. tabaci and provide insight into the molecular determinants of neonicotinoid binding and selectivity.

Abstract Bioinsecticides and transgenic crops based on the bacterial pathogen Bacillus thuringiensis (Bt) can effectively control diverse agricultural insect pests, nevertheless, the evolution of resistance without obvious fitness costs has seriously eroded the sustainable use of these Bt products. Recently, it has been discovered that an increased titer of juvenile hormone (JH) favors an insect host (Plutella xylostella) to enhance fitness whilst resisting the Bt pathogen, however, the underlying regulatory mechanisms of the increased JH titer are obscure. Here, the involvement of N6‐methyladenosine (m6A) RNA modification in modulating the availability of JH in this process is defined. Specifically, it is found that two m6A methyltransferase subunit genes, PxMettl3 and PxMettl14, repress the expression of a key JH‐degrading enzyme JH esterase (JHE) to induce an increased JH titer, mitigating the fitness costs associated with a robust defense against the Bt pathogen. This study identifies an as‐yet uncharacterized m6A‐mediated epigenetic regulator of insect hormones for maintaining fitness during pathogen defense and unveils an emerging Bt resistance‐related m6A methylation atlas in insects, which further expands the functional landscape of m6A modification and showcases the pivotal role of epigenetic regulation in host‐pathogen interactions.

ObjectivePrevious studies have shown that emotional disorders are negatively associated with heart rate variability (HRV), but the potential causal relationship between genetic susceptibility to emotional disorders and HRV remains unclear. We aimed to perform a Mendelian randomization (MR) study to investigate the potential association between emotional disorders and HRV.MethodsThe data used for this study were obtained from publicly available genome-wide association study datasets. Five models, including the inverse variance weighted model (IVW), the weighted median estimation model (WME), the weighted model-based method (WM), the simple model (SM) and the MR-Egger regression model (MER), were utilized for MR. The leave-one-out sensitivity test, MR pleiotropy residual sum and outlier test (MR-PRESSO) and Cochran's Q test were used to confirm heterogeneity and pleiotropy.ResultsMR analysis revealed that genetic susceptibility to broad depression was negatively correlated with HRV (pvRSA/HF) (OR = 0.380, 95% CI 0.146-0.992; p = 0.048). However, genetic susceptibility to irritability was positively correlated with HRV (pvRSA/HF, SDNN) (OR = 2.017, 95% CI 1.152-3.534, p = 0.008) (OR = 1.154, 95% CI 1.000-1.331, p = 0.044). Genetic susceptibility to anxiety was positively correlated with HRV (RMSSD) (OR = 2.106, 95% CI 1.032-4.299; p = 0.041). No significant directional pleiotropy or heterogeneity was detected. The accuracy and robustness of these findings were confirmed through a sensitivity analysis.ConclusionsOur MR study provides genetic support for the causal effects of broad depression, irritable mood, and anxiety on HRV.

Summary: In nasopharyngeal carcinoma (NPC), the TGF-β/Smad pathway genes are altered with inactive TGF-β signal, but the mechanisms remain unclear. RNA-sequencing results showed that FLOT2 negatively regulated the TGF-β signaling pathway via up-regulating CD109 expression. qRT-PCR, western blot, ChIP, and dual-luciferase assays were used to identify whether STAT3 is the activating transcription factor of CD109. Co-IP immunofluorescence staining assays were used to demonstrate the connection between FLOT2 and STAT3. In vitro and in vivo experiments were used to detect whether CD109 could rescue the functional changes of NPC cells resulting from FLOT2 alteration. IHC and Spearman correlation coefficients were used to assay the correlation between FLOT2 and CD109 expression in NPC tissues. Our results found that FLOT2 promotes the development of NPC by inhibiting TGF-β signaling pathway via stimulating the expression of CD109 by stabilizing STAT3, which provides a potential therapeutic strategy for NPC treatment.

Abstract Congenital heart disease (CHD) is one of the leading causes of mortality among birth defects, and due to significant variations in the whole heart and great vessel, automatic CHD segmentation using CT images has been always under-researched. Even though some segmentation algorithms have been developed in the literature, none perform very well under the complex structure of CHD. To deal with the challenges, we take advantage of deep learning in processing regular structures and graph algorithms in dealing with large variations and propose a framework combining both the whole heart and great vessel segmentation in complex CHD. We benefit from deep learning in segmenting the four chambers and myocardium based on the blood pool, and then we extract the connection information and apply graph matching to determine the categories of all the vessels. Experimental results on 68 3D CT images covering 14 types of CHD illustrate our framework can increase the Dice score by 12% on average compared with the state-of-the-art whole heart and great vessel segmentation method in normal anatomy. We further introduce two cardiovascular imaging specialists to evaluate our results in the standard of the Van Praagh classification system, and achieves well performance in clinical evaluation. All these results may pave the way for the clinical use of our method in the incoming future.

Drug-induced liver injury (DILI) is a relatively rare but important adverse event for a variety of commonly used drugs, herbal and dietary supplements, illegal drugs and novel agents. The actual epidemiology of DILI is difficult to evaluate and varies between different countries. Many risk factors have been identified for DILI but the exact and detailed mechanisms of DILI still remain largely unknown. DILI has been typically classified as direct or idiosyncratic, but indirect injury has been recognized as the third type of DILI. It is difficult to predict and prevent DILI due to the lack of acute diagnosis tools. Many novel serum biomarkers have been identified for DILI and need further study in the clinic. For management, discontinuation of suspicious drugs is the first and important step. Effective drugs treatment is limited but novel drugs have been explored. Novel drugs, such as immune checkpoint inhibitors and monoclonal antibodies, have emerging as important causative agents of DILI. This paper reviewed the epidemiology, risk factors, pathogenesis, clinical presentation, causative agents, diagnosis and management of DILI.

Abstract Purpose The integral conceptual model of frailty (ICFM) integrates physical, psychological, social aspects of individuals and stresses that frailty is a dynamic state evolving over time. This study aimed to validate the ICMF among community-dwelling older adults in China. Methods The study recruited 341 older community-dwelling adults by convenient sampling method between June 1 and August 30, 2019 in Hubei province, China. The data was collected by questionnaire-based survey. Frailty was assessed by the Chinese version of the Tilburg Frailty Index. Participants were assessed for life-course determinants, disease and adverse health outcomes. Hierarchical regression analyses, Bootstrap method and the structural equation model were conducted in data analysis. Results Both linear and logistic hierarchical regression models were statistically significant. Life-course determinants, disease, and three domains of frailty together explained 35.6% to 50.6% of the variance of disability and all domains of quality of life. The mediation effect of frailty between disease and all adverse outcomes was significant, excluding hospitalization. The structural equation model guided by the ICMF fits the data well. Conclusions The ICMF is valid among community-dwelling older adults in China. Therefore, the multidimensional concept of frailty should be widely used in Chinese communities.

Abstract Sudden sensorineural hearing loss (SSNHL) is a multifactorial emergency disease. Until now, the etiology of SSNHL is still unknown. Previous studies regarding the etiology of SSNHL are clinical studies depending on clinical data collection and analysis. Due to the insufficient sample size or various selective bias in clinical studies, the results of these studies may be inaccurate. This prospective case–control study aimed at exploring the possible etiology and risk factors of SSNHL. We enrolled 255 SSNHL patients and 255 sex-, age- and residence-matched non-SSNHL subjects in the control group. Our study shows that there was no significant difference in the prevalence of comorbidities including hypertension and diabetes, as well as the incidence of smoking and drinking habits between the case and control groups (P > 0.05). In addition, the peripheral blood white blood cell count, neutrophil count, platelet-to-lymphocyte ratio (PLR) and fibrinogen level of the case group were significantly higher than those in the control group (P

Background: The impact of dominant ventricular morphology on Fontan patient outcomes remain controversial. This study evaluates long-term results of right ventricle (RV) dominance versus left ventricle (LV) dominance in Fontan circulation without hypoplastic left heart syndrome (HLHS). Methods: We retrospectively examined 323 Fontan operations from our center. To minimize pre- and intra-Fontan heterogeneity, 42 dominant RV patients were matched with 42 dominant LV patients using propensity score matching, allowing for a comparative analysis of outcomes between groups. Results: The mean follow-up was 8.0 ± 4.6 years for matched RV dominant and 6.5 ± 4.7 years for matched LV dominant group (p > 0.05), showing no significant difference. The cumulative incidence of moderate or greater atrioventricular valve regurgitation was also comparable between the two groups (p > 0.05). Similarly, 10-year freedom from death or transplantation following the Fontan operation was 84% ± 7% in the matched dominant RV group, similar to 81% ± 7% in the matched dominant LV group (p > 0.05). The 10-year freedom from Fontan failure was 78% ± 8% in the matched dominant RV group, also similar to 75% ± 8% in the matched dominant LV group (p >0.05). Multivariate analysis did not identify RV dominance as a risk factor for Fontan failure (p > 0.05). Conclusions: In the pre- and intra-Fontan context, RV dominance demonstrated similar and comparable long-term outcomes compared to LV dominance in non-HLHS Fontan circulation.

Hexavalent chromium is a common pollutant in the environment. Long-term exposure to hexavalent chromium can cause damage to multiple organs. The kidney is one of the main organs that metabolizes heavy metal toxicity, and the accumulation of Cr (VI) in the body can lead to serious damage to kidney function. Studies have shown that ginseng polysaccharides have the function of preventing cisplatin-induced endoplasmic reticulum stress, inflammatory response, and apoptosis in renal cells, but their efficacy and mechanisms against hexavalent chromium-induced nephrotoxicity need to be explored. The aim of this study was to explore the efficacy and mechanism of ginseng polysaccharide against hexavalent chromium-induced nephrotoxicity. The results of pharmacodynamic experiments showed that ginseng polysaccharide could significantly reduce the kidney index, urea nitrogen (BUN), and serum creatinine (Cre) values of K2Cr2O7-treated mice. The results of mechanistic experiments showed that ginseng polysaccharides could alleviate oxidative stress, apoptosis, and biofilm damage in renal tissues caused by Cr (VI). Lipidomic correlation analysis showed that ginseng polysaccharides could protect the organism by regulating the expression of differential lipids. This study opens new avenues for the development of alternative strategies for the prevention of kidney injury caused by hexavalent chromium.

Background: Both systemic-to-pulmonary shunt and right ventricle-pulmonary artery (RV-PA) connection are extensively applied to initially rehabilitate the pulmonary artery in pulmonary atresia with the ventricle septal defect (PA/VSD). However, which of these options is the most ideal for promoting pulmonary artery development and improving outcomes remains controversial. Methods: A total of 109 PA/VSD patients undergoing initial rehabilitative surgery at Guangdong Provincial People’s Hospital from 2010 to 2020 were enrolled in this study. A series of clinical data were collected to compare the perioperative and postoperative outcomes between systemic-to-pulmonary and RV-PA connection. Results: The mean duration of follow-up was 61.1 months in the systemic-to-pulmonary shunt group and 70.3 months in the RV-PA connection group (p > 0.05). The RV-PA connection technique resulted in a significantly higher PaO2, lower red blood cells (RBC), lower hemoglobin, and lower hematocrit (Hct) (p < 0.05). The cumulative incidence curve estimated a cumulative complete repair rate of 56 ± 7% after 5 years in the RV-PA connection group, significantly higher than 36 ± 7% after 5 years in the systemic-to-pulmonary shunt group (p < 0.05). The Kaplan-Meier curve revealed a similar estimated survival rate between the two groups (p = 0.73). The RV-PA connection was identified as an independent predictor for complete repair in the multivariable analysis (HR = 2.348, 95% CI = 1.131–4.873). Conclusions: The RV-PA connection is a more ideal initial rehabilitative technique than systemic-to-pulmonary shunt in treating PA/VSD as a consequence of comparable probability of survival but improved definitive complete repair rate.

BackgroundRecently, heart failure (HF) and inflammatory bowel disease (IBD) have been considered to be related diseases with increasing incidence rates; both diseases are related to immunity. This study aims to analyze and identify immune-related gene (IRG) markers of HF and IBD through bioinformatics and machine learning (ML) methods and to explore their immune infiltration characteristics.MethodsThis study used gene expressiondata (GSE120895, GSE21610, GSE4183) from the Gene Expression Omnibus (GEO) database to screen differentially expressed genes (DEGs) and compare them with IRGs from the ImmPort database to obtain differentially expressed immune-related genes (DIRGs). Functional enrichment analysis of IRGs was performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, three machine models and protein–protein interactions (PPIs) were established to identify diagnostic biomarkers. The receiver operating characteristic (ROC) curves were applied to evaluate the diagnostic value of the candidate biomarkersin the validation set (GSE1145, GSE36807) and obtain their correlations with immune cells through the Spearman algorithm. Finally, the CIBERSORT algorithm was used to evaluate the immune cell infiltration of the two diseases.ResultsThirty-four DIRGs were screened and GO and KEGG analysis results showed that these genes are mainly related to inflammatory and immune responses. CCL2, CXCR2 and S100A9 were identified as biomarkers.The immune correlation results indicated in both diseases that CCL2 is positively correlated with mast cell activation, CXCR2 is positively correlated with neutrophils and S100A9 is positively correlated with neutrophils and mast cell activation. Analysis of immune characteristics showed that macrophages M2, macrophages M0 and neutrophils were present in both diseases.ConclusionsCCL2, CXCR2 and S100A9 are promising biomarkers that will become potential immunogenetic biomarkers for diagnosing comorbidities of HF and IBD. macrophages M2, macrophages M0, neutrophil-mediated inflammation and immune regulation play important roles in the development of HF and IBD and may become diagnostic and therapeutic targets.

BackgroundThere is a lack of evidence guiding the surgical timing selection in pulmonary atresia with ventricular septal defect. This study aims to compare the long-term outcomes of different initial rehabilitative surgical ages in patients with pulmonary atresia with ventricular septal defect (PAVSD).MethodsFrom January 2011 to December 2020, a total of 101 PAVSD patients undergoing the initial rehabilitative surgery at our center were retrospectively reviewed. Receiver-operator characteristics curve analysis was used to identify the cutoff age of 6.4 months and therefore to classify the patients into two groups. Competing risk models were used to identify risk factors associated with complete repair. The probability of survival and complete repair were compared between the two groups using the Kaplan-Meier curve and cumulative incidence curve, respectively.ResultsThe median duration of follow-up was 72.76 months. There were similar ΔMcGoon ratio and ΔNakata index between the two groups. Multivariate analysis showed that age ≤6.4 months (hazard ratio (HR) = 2.728; 95% confidence interval (CI):1.122–6.637; p = 0.027) and right ventricle-to-pulmonary artery connection (HR = 4.196; 95% CI = 1.782–9.883; p = 0.001) were associated with increased probability of complete repair. The cumulative incidence curve showed that the estimated complete repair rates were 64% ± 8% after 3 years and 69% ± 8%% after 5 years in the younger group, significantly higher than 28% ± 6% after 3 years and 33% ± 6% after 5 years in the elder group (p 6.4 months, PAVSD patients at the age ≤6.4 months had an equal pulmonary vasculature development, a similar probability of survival but an improved probability of complete repair.

Chemosensory proteins (CSPs) perform several functions in insects. This study performed the gene expression, ligand-binding, and molecular docking assays on the EforCSP3 identified in the parasitoid wasp Encarsia formosa, to determine whether EforCSP3 functions in olfaction, especially in host location and host preference. The results showed that EforCSP3 was highly expressed in the female head, and its relative expression was much higher in adults than in other developmental stages. The fluorescence binding assays suggested that the EforCSP3 exhibited high binding affinities to a wide range of host-related volatiles, among which dibutyl phthalate, 1-octene, β-elemene, and tridecane had the strongest binding affinity with EforCSP3, besides α-humulene and β-myrcene, and should be assessed as potential attractants. Protein structure modeling and molecular docking predicted the amino acid residues of EforCSP3 possibly involved in volatile binding. α-Humulene and β-myrcene attracted E. formosa in a previous study and exhibited strong binding affinities with EforCSP3 in the current study. In conclusion, EforCSP3 may be involved in semiochemical reception by E. formosa.

Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in the United States. Tyrosine sulfation, catalyzed by the tyrosylprotein sulfotransferase 2 (TPST2), is a post-translational modification essential for protein–protein interactions and cellular functions. Solute carrier family 35 member B (SLC35B2) is a key transporter that transports the universal sulfate donor 3’-phosphoadenosine 5’-phosphosulfate into the Golgi apparatus where the protein sulfation occurs. The goal of this study was to determine whether and how the SLC35B2–TPST2 axis of tyrosine sulfation plays a role in PDAC. Methods: Gene expression was analyzed in PDAC patients and mice. Human PDAC MIA PaCa-2 and PANC-1 cells were used for in vitro studies. TPST2-deficient MIA PaCa-2 cells were generated to assess xenograft tumor growth in vivo. Mouse PDAC cells derived from the KrasLSL-G12D/+;Tp53L/+;Pdx1-Cre (KPC) mice were used to generate Tpst2 knockout KPC cells to evaluate tumor growth and metastasis in vivo. Results: High expressions of SLC35B2 and TPST2 were correlated with poor PDAC patient survival. Knocking down SLC35B2 or TPST2, or pharmacologicically inhibiting sulfation, resulted in the inhibition of PDAC cell proliferation and migration in vitro. TPST2-deficient MIA PaCa-2 cells showed inhibited xenograft tumor growth. Orthotopic inoculation of Tpst2 knockout KPC cells in mice showed inhibition of primary tumor growth, local invasion, and metastasis. Mechanistically, the integrin β4 was found to be a novel substrate of TPST2. Inhibition of sulfation destabilizes integrin β4 protein, which may have accounted for the suppression of metastasis. Conclusions: Targeting the SLC35B2–TPST2 axis of tyrosine sulfation may represent a novel approach for therapeutic intervention of PDAC.