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Background: Existing researches have predominantly focused on the implications of dynamic alterations in the triglyceride-glucose (TyG) index and traditional obesity measures for cardiovascular disease (CVD) risk. However, the application of the weight-adjusted waist index (WWI), which incorporates the dynamically changing body composition factors of weight and waist circumference, alongside the TyG index for predicting CVD risk, remains unexplored. This study explores the relationships between baseline TyG-WWI index and its dynamic changes with CVD risk., Methods: Subjects were drawn from the China Health and Retirement Longitudinal Study. Logistic regression analyses were conducted to determine the relationships between baseline and longitudinal changes in the TyG-WWI index and CVD risk, quantified through odds ratios (ORs) and 95% confidence intervals (CIs). The robustness of results was confirmed via subgroup analyses and E-values. Additionally, restricted cubic spline and quartile-based methods evaluated the relationships between baseline and cumulative TyG-WWI indices and CVD risk., Results: Over two survey waves, 613 CVD events were recorded. Analysis using adjusted multivariable models demonstrated a significant relationship between the cumulative TyG-WWI index and increased CVD risk, with an adjusted OR (95% CI) of 1.005 (1.000, 1.009). Class 2 of the TyG-WWI index change showed greater risk of CVD compared to Class 1, with ORs of 1.270 (1.008, 1.605). However, no significant connection was observed between the baseline TyG-WWI index and CVD risk (OR = 1.007, 95% CI: 0.996, 1.019). These findings were corroborated through extensive sensitivity analyses., Competing Interests: Declarations Ethics approval and consent to participate Ethical approval for this program was granted by the Biomedical Ethics Review Board of Peking University, with approval numbers IRB00001052-11015 and IRB00001052-11014. All participants provided informed consent before inclusion in this program. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: High-frequency ventilation (HFV) is commonly used in neonatal intensive care units to provide respiratory support for critically ill neonates. Currently, there is no standardized procedure for weaning from HFV. Two commonly used strategies are transitioning from HFV to conventional mechanical ventilation (CMV) before extubation (HFV-CMV) and extubation after decreasing mean airway pressure during HFV (HFV-HFV). The impact of these strategies on neonatal cerebral oxygenation and hemodynamics remains incompletely understood., Methods: We will conduct a prospective, single-center, randomized controlled trial to investigate the effects of two different HFV weaning strategies (HFV-CMV, HFV-HFV) on neonatal cerebral oxygenation and hemodynamics. The patients enrolled in the trial will be randomly allocated to either the HFV-CMV group or the HFV-HFV group in a 1:1 ratio. The primary outcome will be cerebral oxygen saturation (S c O 2 ) before and after the intervention. Second outcomes are cerebral fractional tissue oxygen extraction, heart rate, blood pressure, and the incidence and severity of intraventricular hemorrhage and periventricular leukomalacia. We hypothesize that HFV-CMV results in positive impact on neonatal cerebral oxygenation compared to HFV-HFV. This study aims to identify a better weaning strategy for HFV and contribute evidence-based data to enhance its clinical application in newborns, potentially improving the care and outcomes for neonates receiving HFV., Discussion: This study aims to assessing the impact of different HFV weaning strategies on neonatal cerebral oxygenation and hemodynamics, as well as the relationship between the duration of HFV under different strategies and neurological complications, to identify better weaning methods for HFV. We hope to contribute evidence-based data to enhance clinical application of HFV in newborns, potentially improving the care and outcomes for neonates receiving HFV., Trial Registration: Chinese Clinical Trial Registry: ChiCTR2400088628. Registered on August 22, 2024, https://www.chictr.org.cn/bin/project/edit?pid=235926 ., Competing Interests: Declarations Ethics approval and consent to participate {24} This study has been approved by the Ethics Committee of West China Second University Hospital of Sichuan University, with the approval number of 2024 (130). Written, informed consent to participate will be obtained from the parent or legal guardian of the neonates participating in the trial. Consent for publication {32} Not applicable. This manuscript does not contain individual personal data from patients. The participant information materials and informed consent form are available from the corresponding author on request. Competing interests {28} The authors declare that they have no competing interests., (© 2024. The Author(s).)

Objective: To investigate the prevalence and risk factors of psychological symptoms and quality of life (QoL) in early patients with inflammatory bowel disease (IBD)., Methods: From September 2021 to May 2022, a unified questionnaire was developed to collect clinical data from early patients with IBD from 42 tertiary care hospitals. The influencing factors of psychological symptoms and poor QoL are screened by logistic regression analysis for constructing model in predicting poor QoL. The consistency index, receiver operating characteristic (ROC) curve, area under the ROC curve (AUC), net reclassification improvement (NRI), integrated discrimination improvement (IDI), calibration curve, and decision curve analysis (DCA) were used to evaluate the performance of the model., Results: A total of 939 early patients with IBD were surveyed, Among them, 20.3% exhibited anxiety, 21.7% had depression, 57.3% experienced sleep disturbance, and 41.9% reported poor QoL. The factors influencing psychological symptoms varied between ulcerative colitis (UC) and Crohn's disease (CD) patients. The QoL was primarily affected by disease activity, income level and depression. The AUC value of the model in the training group was 0.781 (95% CI: 0.748-0.814). The calibration diagram of the model closely matched the ideal curve. Compared to other prediction models, our model showed superior predictive capability, with NRI and IDI values of 0.324 (95%CI:0.196-0.4513) and 0.026 (95%CI:0.014-0.038), respectively. DCA indicated that the nomogram model could provide clinical benefits., Conclusion: Early patients with IBD exhibit a high prevalence of psychological symptoms and poor QoL. The nomogram prediction model we constructed demonstrates high accuracy and performance in predicting QoL in early patients with IBD., Competing Interests: Declarations Ethics approval and consent to participate The study complies with the Declaration of Helsinki. The study was approved by the Institutional Review Board of Renmin Hospital of Wuhan University, and informed consent was obtained from all patients. The clinical research Ethics Review approval number of Renmin Hospital of Wuhan University was WDRY2022-K150. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background and Objectives: This study aimed to employ machine learning techniques to predict the clinical efficacy of acupuncture as an intervention for patients with upper limb motor dysfunction following ischemic stroke, as well as to assess its potential utility in clinical practice., Methods: Medical records and digital subtraction angiography (DSA) imaging data were collected from 735 ischemic stroke patients with upper limb motor dysfunction who were treated with standardized acupuncture at two hospitals. Following the initial screening, 314 patient datasets that met the inclusion criteria were selected. We applied three deep-learning algorithms (YOLOX, FasterRCNN, and TOOD) to develop the object detection model. Object detection results pertaining to the cerebral vessels were integrated into a clinical efficacy prediction model (random forest). This model aimed to classify patient responses to acupuncture treatment. Finally, the accuracies and discriminative capabilities of the prediction models were assessed., Results: The object detection model achieved an optimal recognition rate, The mean average precisions of YOLOX, TOOD, and FasterRCNN were 0.61, 0.7, and 0.68, respectively. The prediction accuracy of the clinical efficacy model reached 93.6%, with all three-treatment response classification area under the curves (AUCs) exceeding 0.95. Feature extraction using the prediction model highlighted the significant influence of various cerebral vascular stenosis sites within the internal carotid artery (ICA) on prediction outcomes. Specifically, the initial and C1 segments of the ICA had the highest predictive weights among all stenosis sites. Additionally, stenosis of the middle cerebral, anterior cerebral, and posterior cerebral arteries exerted a notable influence on the predictions. In contrast, the stenosis sites within the vertebral artery exhibited minimal impact on the model's predictive abilities., Conclusions: Results underscore the substantial predictive influence of each cerebral vascular stenosis site within the ICA, with the initial and C1 segments being pivotal predictors., (© 2024. The Author(s).)

Osteomyelitis (OM) is an inflammatory disease of bone infection and destruction characterized by dysregulation of bone homeostasis. Staphylococcus aureus (SA) has been reported to be the most common pathogen causing infectious OM. Recent studies have demonstrated that N6-methyladenosine (m6A) regulators are associated with the development of OM. However, the molecular mechanism of m6A modifications in OM remains unclear. Here, we investigated the function of methyltransferase-like 3 (METTL3)-mediated m6A modification in OM development. In this study, human bone mesenchymal stem cells (hBMSCs) were treated with staphylococcal protein A (SpA), a vital virulence factor of SA, to construct cell models of OM. Firstly, we found that METTL3 was upregulated in OM patients and SpA-induced hBMSCs, and SpA treatment suppressed osteogenic differentiation and induced oxidative stress and inflammatory injury in hBMSCs. Functional experiments showed that METTL3 knockdown alleviated the inhibition of osteogenic differentiation and the promotion of oxidative stress and inflammation in SpA-treated hBMSCs. Furthermore, METTL3-mediated m6A modification upregulated miR-320a expression by promoting pri-miR-320a maturation, and the mitigating effects of METTL3 knockdown on SpA-mediated osteogenic differentiation, oxidative stress and inflammatory responses can be reversed by miR-320 mimic. In addition, we demonstrated that phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) was a downstream target of miR-320a, upregulation of PIK3CA alleviated miR-320a-induced inhibition of osteogenic differentiation, and upregulation of oxidative stress and inflammatory responses during SpA infection. Finally, we found that silencing METTL3 alleviated OM development by regulating the miR-320a/PIK3CA axis. Taken together, our data demonstrated that the METTL3/m6A/miR-320a/PIK3CA axis regulated SpA-mediated osteogenic differentiation, oxidative stress, and inflammatory responses in OM, which may provide a new therapeutic strategy for OM patients., (© 2024. The Author(s).)

Background: Lysosomal homeostasis and functions are essential for the survival of neural cells. Impaired lysosomal biogenesis and acidification in Alzheimer's disease (AD) pathogenesis leads to proteolytic dysfunction and neurodegeneration. However, the key regulatory factors and mechanisms of lysosomal homeostasis in AD remain poorly understood., Methods: ROCK1 expression and its co-localization with LAMP1 and SQSTM1/p62 were detected in post-mortem brains of healthy controls and AD patients. Lysosome-related fluorescence probe staining, transmission electron microscopy and immunoblotting were performed to evaluate the role of ROCK1 in lysosomal biogenesis and acidification in various neural cell types. The interaction between ROCK1 and TFEB was confirmed by surface plasmon resonance and in situ proximity ligation assay (PLA). Moreover, we performed AAV-mediated ROCK1 downregulation followed by immunofluorescence, enzyme-linked immunosorbent assay (ELISA) and behavioral tests to unveil the effects of the ROCK1-TFEB axis on lysosomes in APP/PS1 transgenic mice., Results: ROCK1 level was significantly increased in the brains of AD individuals, and was positively correlated with lysosomal markers and Aβ. Lysosomal proteolysis was largely impaired by the high abundance of ROCK1, while ROCK1 knockdown mitigated the lysosomal dysfunction in neurons and microglia. Moreover, we verified ROCK1 as a previously unknown upstream kinase of TFEB independent of m-TOR or GSK-3β. ROCK1 elevation resulted in abundant extracellular Aβ deposition which in turn bound to Aβ receptors and activated RhoA/ROCK1, thus forming a vicious circle of AD pathogenesis. Genetically downregulating ROCK1 lowered its interference with TFEB, promoted TFEB nuclear distribution, lysosomal biogenesis and lysosome-mediated Aβ clearance, and eventually prevented pathological traits and cognitive deficits in APP/PS1 mice., Conclusion: In summary, our results provide a mechanistic insight into the critical role of ROCK1 in lysosomal regulation and Aβ clearance in AD by acting as a novel upstream serine kinase of TFEB., (© 2024. The Author(s).)

Background: Mannitol is frequently utilized to achieve intracranial brain relaxation during the retrosigmoid approach for auditory brainstem implantation (ABI). Hypertonic saline (HS) is an alternative for reducing intracranial pressure; however, its application during ABI surgery remains under-investigated. We aimed to compare the efficacy and safety between HS and mannitol for maintaining brain relaxation., Methods: This single-center retrospective cohort study included pediatric patients undergoing ABI surgery from September 2020 to January 2022 who received only 4.54% HS or 20% mannitol for brain relaxation. The analysis involved initial doses, subsequent doses, and dosing intervals of the two hyperosmolar solutions, as well as the time elapsed from meningeal opening to the first ABI electrode placement attempt. Additionally, the analysis encompassed electrolyte testing, hemodynamic variables, urine output, blood transfusion, second surgeries, adverse events, intensive care unit length of stay, and 30-day mortality., Results: We analyzed 68 consecutive pediatric patients; 26 and 42 in the HS and mannitol groups, respectively. The HS group exhibited a reduced rate of supplementary use (7.7% vs. 31%) and lower total urine volume. Perioperative outcomes, mortality, and length of intensive care unit stay did not exhibit significant between-group differences, despite transient increases in blood sodium and chloride observed within 2 h after HS infusion., Conclusions: In pediatric ABI surgery, as an osmotherapy for cerebral relaxation, 4.54% HS demonstrated a lower likelihood of necessitating additional supplementation than 20% mannitol. Furthermore, the diuretic effect of HS was weak and the increase in electrolyte levels during surgery was temporary and slight., (© 2024. The Author(s).)

Background: Monitoring symptoms is crucial for the early detection of disease progression and timely intervention, which is essential for reducing severe cases and mortality rates in rapidly spreading pandemics, such as COVID-19. Therefore, during infectious disease pandemics, the rapid development of real-time symptom monitoring platforms is essential. This study aimed to explore the urgent development process of an electronic system for patient-reported outcome monitoring in emergency situations., Methods: The development of the electronic patient-reported outcome COVID-19 symptom monitoring platform (ePRO-CoV-SM) included the following steps: (1) modifying an electronic patient-reported outcome symptom-reporting platform to assess patients with COVID-19 and validating its feasibility and sensitivity for longitudinal symptom measurement; (2) updating the system to accommodate the newly emerged severe acute respiratory syndrome coronavirus 2 BA.2.2 variant; and (3) applying it in real-world settings. Literature review, expert consultation, and subject-group discussions were used to develop symptom items. Response rate and missing item rate were used as validation indicators for ePRO-CoV-SM., Results: The ePRO-CoV-SM (2.0) consists of a core set of symptom items, a WeChat mini program, an online project design backend, a management and communication front, and a database. During the 2020 verification, the response rate of ePRO symptom monitoring reached 89.47% and the item missing rate was 0.33%, the monitoring revealed that a considerable number of asymptomatic patients were experiencing undesirable symptoms during the isolation period. In its real-world application in 2022, the response rate was 85.93% and the item missing rate was 4.84%, the monitoring found the symptom burden was higher in the younger group (18-40 years old) than in the older group (40-67 years old), and over 30% of patients reported symptoms such as cough (36.08%), dry mouth (35.67%), sleep disorders (32.27%), appetite loss (32.17%), and sputum (30.79%) during the isolation period., Conclusions: Electronic patient-reported outcome measurement was demonstrated to be sensitive and feasible for monitoring symptoms in patients with COVID-19. By integrating smartphone-based data collection with real-time online data transmission and secure data storage using Secure Sockets Layer encryption, an electronic platform for monitoring critical symptoms can be rapidly established in emergency situations., (© 2024. The Author(s).)

Background: Neonatal septic shock represents a critical and life-threatening condition that necessitates immediate and personalized interventions. Prior research endeavors have been undertaken to inform the optimization of neonatal septic shock management, yet substantial heterogeneity prevails in the selection, measurement, and reporting of outcomes across relevant studies. The heterogeneity in outcome selections and measures impedes the comparability of results and the synthesis of evidence, thus contributing to suboptimal utilization of research findings. This protocol presents the methodology for identifying and developing a Core Outcome Set for Neonatal Septic Shock Management (COS-NSS), intended for use in both research and routine clinical practice. A rigorous four-stage approach will be employed to develop the COS-NSS. In Stage 1, a scoping review will be conducted to compile a list of currently reported outcomes for neonatal septic shock management. Stage 2 will involve an expert stakeholder meeting using a semi-structured discussion approach to elucidate all identified outcomes and outcome domains, as well as to gather any additional outcomes. Moving to Stage 3, a two-round e-Delphi survey involving a wide variety of stakeholders will be undertaken to elicit diverse perspectives on the level of importance assigned to each proposed outcome. Finally, in Stage 4, the results of the Delphi study will be discussed in a consensus meeting to determine and agree on the final list of outcomes that will constitute the COS-NSS., Discussion: The stagewise approach integrates research evidence with multi-stakeholder perspectives to establish standardized outcomes that would improve consistency across neonatal septic shock trials. The development and uptake of the COS-NSS will facilitate effective comparison of studies, allowing for study synthesis and generation of high-quality evidence, thus ultimately fostering enhanced medical care for neonates suffering from septic shock., Trial Registration: Core Outcome Measures in Effectiveness Trials (COMET) Initiative database registration: 2766 . Registered on July 19th, 2023., (© 2024. The Author(s).)

Background: As an efficient and high-quality additive in agriculture and forestry production, silicon (Si) plays an important role in alleviating heavy metal stress and improving plant growth. However, the alleviating effect of aluminum (Al) toxicity by Si in Eucalyptus is still incomplete., Results: Here, a study was conducted using two Al concentrations (0 and 4.5 mM) with four Si concentrations (0, 0.5, 1, and 1.5 mM) to investigate plant growth, tolerance and antioxidant defense system in four Eucalyptus species (Eucalyptus tereticornis, Eucalyptus urophylla, Eucalyptus grandis, and Eucalyptus urophylla × Eucalyptus grandis). The results showed that the stress induced by 4.5 mM Al increased oxidative damage, disturbed the balance of enzymatic and non-enzymatic antioxidant systems, and negatively affected plant growth and tolerance quality in the four Eucalyptus species. However, the addition of 0.5 mM and 1 mM Si alleviated the effects of Al toxicity on plant growth and improved plant growth quality by strengthening stress tolerance. Besides, adding Si significantly facilitated the synergistic action of enzymatic and non-enzymatic antioxidant defenses, increased the removal of reactive oxygen species, reduced lipid peroxidation, and oxidative stress, and promoted the phytoremediation rate of the four Eucalyptus species by 18.7 ~ 34.8% compared to that in the absence of Si., Conclusions: Silicon can alleviate the effect of Al toxicity by enhancing the antioxidant capacity and improving plant growth and tolerance quality. Hence, the application of Si is an effective method for the phytoremediation of Eucalyptus plantations in southern China., (© 2024. The Author(s).)

The therapeutic approach to thymic cysts remains a subject of controversy. Predicted biomarkers for identifying thymic cysts and thymoma (THYM) are crucial. In this research, patients diagnosed with thymic cysts (MTC, n = 6) and thymoma (B1, n = 6; B3, n = 6) were enrolled. Proteins of superior quality were subjected to TMT labeling and UPLC-MS, and differentially expressed proteins (DEPs) were identified. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interactive network analyses were applied to the DEPs. Some key differentially expressed genes(DEGs) were corroborated through GEPIA 32. The pan-cancer expression levels of key DEGs remarkably linked with prognosis were determined utilizing The University of ALabama at Birmingham CANcer data analysis Portal (UALCAN). Eventually, 49 DEPs were identified in the B1 vs. MTC comparison (17 upregulated and 32 downregulated), 27 in the B3 vs. MTC comparison (8 upregulated and 19 downregulated), and 38 in the B3 vs. B1 comparison (9 upregulated and 29 downregulated). IL13RA1 (down), galectin-3 binding protein (LGALS3BP)(up), PRCSH (down), C3 (down), MXRA5 (down), TNN (down), CFHR1 (down), SUN3 (down) were jointly altered in both B1 vs. NZ and B3 vs. NZ. GEPIA validated that LGALS3BP was significantly upregulated in thymoma patients. In conclusion, LGALS3BP might be an essential biomarker to identify thymoma from the thymic cyst., (© 2024. The Author(s).)

Background: Volatile organic compounds (VOCs) released by plants can act as signaling molecules mediating ecological interactions. Therefore, the study of VOCs mediated intra- and interspecific interactions with downstream plant physiological responses is critical to advance our understanding of mechanisms underlying information exchange in plants. Here, we investigated how plant-emitted VOCs affect the performance of an interspecific neighboring plant via induced shifts in root exudate chemistry with implications for root-associated microbiota recruitment., Results: First, we showed that VOCs emitted by potato-onion plants stimulate the growth of adjacent tomato plants. Then, we demonstrated that this positive effect on tomato biomass was attributed to shifts in the tomato rhizosphere microbiota. Specifically, we found potato-onion VOCs to indirectly affect the recruitment of specific bacteria (e.g., Pseudomonas and Bacillus spp.) in the tomato rhizosphere. Second, we identified and validated the compound dipropyl disulfide as the active molecule within the blend of potato-onion VOCs mediating this interspecific plant communication. Third, we showed that the effect on the tomato rhizosphere microbiota occurs via induced changes in root exudates of tomato plants caused by exposure to dipropyl disulfide. Last, Pseudomonas and Bacillus spp. bacteria enriched in the tomato rhizosphere were shown to have plant growth-promoting activities., Conclusions: Potato-onion VOCs-specifically dipropyl disulfide-can induce shifts in the root exudate of adjacent tomato plants, which results in the recruitment of plant-beneficial bacteria in the rhizosphere. Taken together, this study elucidated a new mechanism of interspecific plant interaction mediated by VOCs resulting in alterations in the rhizosphere microbiota with beneficial outcomes for plant performance. Video Abstract., (© 2024. The Author(s).)

Excessive production of reactive oxygen species (ROS) around titanium implants under diabetic conditions causes persistent inflammation, leading to poor osseointegration and even implant failure. Surface modification is an effective way to promote ROS clearance, alleviate inflammation, and stimulate bone formation. In this study, a multifunctional coating is fabricated by introducing cerium (Ce)-containing mesoporous bioactive glass nanoparticles (Ce-MBGNs) onto the titanium surface via an electrophoretic deposition method. The incorporation of Ce-MBGNs remarkably improves surface hydrophilicity by increasing the surface areas. The bioactive ions are appropriately released, thereby promoting mesenchymal stem cell proliferation and differentiation under diabetic conditions. The conversion between Ce(III) and Ce(IV) endows Ce-MBGNs coating with antioxidative nanoenzymes properties to scavenge diabetes-induced ROS, resulting in macrophage polarization towards the anti-inflammatory phenotype. The therapeutic effect of Ce-MBGNs-modified titanium implants is also verified in diabetic rats by inhibiting inflammatory responses and accelerating early osseointegration. Taken together, the findings reveal that the ROS-scavenging and immunomodulation activity of the Ce-MBGNs coating contributes to enhanced osseointegration, and provides a novel implant surface for diabetic patients., (© 2024. The Author(s).)

Background: The association between malnutrition and outcomes of heart transplantation (HTx) has not been well studied. The purpose of this article was to evaluate the prognostic value of three different nutrition indices in HTx, including CONUT (Controlling Nutritional Status), NRI (Nutritional Risk Index) and GNRI (Geriatric Nutritional Risk Index)., Methods: A total of 438 patients who underwent THx from January 2015 to December 2020 were included in this study. The nutritional status of the patients was evaluated by CONUT, NRI and GNRI. Kaplan-Meier (KM) curves were constructed to compare the difference in overall survival (OS) between the normal and malnutrition groups in each index. Cox regression analysis was used to identify the independent risk factors of OS. The predictive power was compared by time-dependent ROC and time-dependent ccurves. Logistic regression model was used to evaluate the relationship between these three nutrition indices and postoperative clinical events., Results: 336 (76.7%), 183 (43.8%), and 190 (43.4%) patients had malnutrition according to CONUT, NRI and GNRI calculations. 102 (23.3%) patients had died at the end of follow-up. After adjustment for confounding variables, multivariate Cox analysis showed that CONUT [HR 1.286 (95%CI 1.166 ~ 1.419); p < 0.001], NRI [HR 0.942 (95%CI 0.923 ~ 0.962); p < 0.001] and GNRI [HR 0.959 (95%CI 0.939 ~ 0.979); p < 0.001] were all independent predictors for OS. The predictive power of CONUT score was higher than that of NRI (p = 0.045) and GNRI (p < 0.001). Regarding the postoperative complications, multivariate logistic regression model showed that malnutrition assessed by CONUT [HR 1.156 (95%CI 1.032 ~ 1.294); p = 0.012] and NRI [HR 1.543 (95%CI 1.008 ~ 2.362); p = 0.046] was independent risk factors for posttransplant infections., Conclusion: Poor nutritional status, as assessed by CONUT, NRI and GNRI, was associated with an increased risk of mortality after HTx. CONUT displayed the highest predictive power compared to the other two indices. CONUT and NRI were also independently associated with posttransplant infections., (© 2024. The Author(s).)

Background: A growing body of evidence supports the comorbidity between depression (DEP) and obesity, yet the genetic mechanisms underlying this association remain unclear. Our study explored the shared genetic architecture and causal associations of DEP with BMI., Methods: We investigated the multigene overlap and genetic correlation between DEP (N > 1.3 million) and BMI (N = 806,834) based on genome-wide association studies (GWAS) and using the bivariate causal mixture model and linkage disequilibrium score regression (LDSC). The causal association was explored by bi-directional Mendelian randomization (MR). Common risk loci were identified through cross-trait meta-analyses. Stratified LDSC and multi-marker gene annotation analyses were applied to investigate single-nucleotide polymorphisms enrichment across tissue types, cell types, and functional categories. Finally, we explored shared functional genes by Summary Data-Based Mendelian Randomization (SMR) and further detected differential expression genes (DEG) in brain tissues of individuals with depression and obesity., Results: We found a positive genetic correlation between DEP and BMI (r g = 0.19, P = 4.07 × 10 -26 ), which was more evident in local genomic regions. Cross-trait meta-analyses identified 16 shared genetic loci, 5 of which were newly identified, and they had influence on both diseases in the same direction. MR analysis showed a bidirectional causal association between DEP and BMI, with comparable effect sizes estimated in both directions. Combined with gene expression information, we found that genetic correlations between DEP and BMI were enriched in 6 brain regions, predominantly in the nucleus accumbens and anterior cingulate cortex. Moreover, 6 specific cell types and 23 functional genes were found to have an impact on both DEP and BMI across the brain regions. Of which, NEGR1 was identified as the most significant functional gene and associated with DEP and BMI at the genome-wide significance level (P < 5 × 10 -8 ). Compared with healthy controls, the expression levels of NEGR1 gene were significant lower in brain tissues of individuals with depression and obesity., Conclusions: Our study reveals shared genetic basis underpinnings between DEP and BMI, including genetic correlations and common genes. These insights offer novel opportunities and avenues for future research into their comorbidities., (© 2024. The Author(s).)

Background and Objectives: Cauda equina syndrome with retention (CESR) is a severe lumbar condition characterized by painless urine retention due to cauda equina nerve injury. The standard treatment, posterior lumbar interbody fusion (PLIF), often yields suboptimal results. This study aims to compare the clinical safety and efficacy of a novel technique, capsule lumbar interbody fusion (CLIF), with PLIF in CESR patients, hypothesizing that CLIF can enhance neurological recovery by reducing nerve tension., Methods: A single-center, retrospective study was conducted on 83 patients with CESR due to lumbar disc herniation, who underwent either PLIF (n = 44) or CLIF (n = 39). Patients were assessed preoperatively and at 3, 12, and 24 months postoperatively using the Oswestry Disability Index (ODI), Visual Analogue Scale (VAS), International Consultation on Incontinence Questionnaire Short Form (ICI-Q-SF), and Rintala score. Urodynamic studies and nerve tension measurements were also performed. Statistical analysis included t tests, Mann-Whitney U tests, and Spearman's correlation., Results: Both groups showed significant postoperative improvements, but the CLIF group had superior outcomes. At 12 months, the CLIF group had lower VAS scores (1.15 ± 0.84 vs. 1.68 ± 0.60, p = 0.001) and ODI scores (23.31 ± 7.51 vs. 28.30 ± 8.26, p = 0.005). At 24 months, the CLIF group continued to show better results with ODI scores (15.97 ± 6.43 vs. 22.11 ± 6.41, p < 0.001) and higher ODI recovery rates (60.41 ± 17.6% vs. 44.71 ± 18.99%, p < 0.001). The CLIF group also had better ICI-Q-SF scores (2.13 ± 1.23 vs. 3.02 ± 1.45, p = 0.004) and Rintala scores (17.97 ± 1.43 vs. 16.59 ± 1.54, p < 0.001). Lower postoperative nerve tension in the CLIF group correlated with these improved outcomes., Conclusions: CLIF demonstrated superior efficacy over PLIF in treating CESR, with significant improvements in pain relief, functional recovery, and bladder and bowel function. This study highlights the potential of CLIF as a more effective surgical option for CESR, emphasizing its importance in improving patient outcomes and reducing the burden of CESR on patients and society., (© 2024. The Author(s).)

Background: Long COVID, also known as post-acute sequelae of COVID-19 (PASC), is a poorly understood condition with symptoms across a range of biological domains that often have debilitating consequences. Some have recently suggested that lingering SARS-CoV-2 virus particles in the gut may impede serotonin production and that low serotonin may drive many Long COVID symptoms across a range of biological systems. Therefore, selective serotonin reuptake inhibitors (SSRIs), which increase synaptic serotonin availability, may be used to prevent or treat Long COVID. SSRIs are commonly prescribed for depression, therefore restricting a study sample to only include patients with depression can reduce the concern of confounding by indication., Methods: In an observational sample of electronic health records from patients in the National COVID Cohort Collaborative (N3C) with a COVID-19 diagnosis between September 1, 2021, and December 1, 2022, and a comorbid depressive disorder, the leading indication for SSRI use, we evaluated the relationship between SSRI use during acute COVID-19 and subsequent 12-month risk of Long COVID (defined by ICD-10 code U09.9). We defined SSRI use as a prescription for SSRI medication beginning at least 30 days before acute COVID-19 and not ending before SARS-CoV-2 infection. To minimize bias, we estimated relationships using nonparametric targeted maximum likelihood estimation to aggressively adjust for high-dimensional covariates., Results: We analyzed a sample (n = 302,626) of patients with a diagnosis of a depressive condition before COVID-19 diagnosis, where 100,803 (33%) were using an SSRI. We found that SSRI users had a significantly lower risk of Long COVID compared to nonusers (adjusted causal relative risk 0.92, 95% CI (0.86, 0.99)) and we found a similar relationship comparing new SSRI users (first SSRI prescription 1 to 4 months before acute COVID-19 with no prior history of SSRI use) to nonusers (adjusted causal relative risk 0.89, 95% CI (0.80, 0.98))., Conclusions: These findings suggest that SSRI use during acute COVID-19 may be protective against Long COVID, supporting the hypothesis that serotonin may be a key mechanistic biomarker of Long COVID., (© 2024. The Author(s).)

Nocardia farcinica is the most pathogenic Nocardia, which is easy to disseminate. It can be caused by trauma, and even lead to severe lung or central nervous system infection. This report covers a case of Nocardia brain abscess in an HIV patient, who underwent resection of the brain abscess, followed by anti-infective therapy with sulfamethoxazole and meropenem, and eventually made a good recovery. The mortality rate of Nocardia farcinica brain abscess has been attributed to the severity of the underlying disease, the difficulty in identifying the pathogen, and its inherent resistance to antibiotics, leading to inappropriate or late initiation of treatment. Medication should follow the principle of sufficient dosage and sufficient course of treatment., (© 2024. The Author(s).)

Objective: The purpose of this study was to compare the analgesic effects of intercostal nerve block (ICNB) and local anesthetic infiltration (LAI) on postoperative pain and recovery following thoracoscopic resection of pulmonary bullae., Methods: A total of 160 patients undergoing thoracoscopic pulmonary bullae resection were randomly assigned to receive either ICNB (n = 80) or LAI (n = 80). An experienced anesthesiologist administered ultrasound guided ICNB at the T4 and T7 levels with 5 mL of 0.375% ropivacaine hydrochloride for the ICNB group. Instead, the LAI group received 10 mL of the same concentration of ropivacaine hydrochloride at the same concentration used for ICNB for infiltration anesthesia at the incision sites. Out of the initial cohort, 146 patients completed the study (ICNB group, n = 71; LAI group, n = 75). The collected data included preoperative clinical characteristics, visual analog scale (VAS) scores for pain at various time points post-surgery (6, 12, 24, 48, and 72 h). Additionally, the Quality of Recovery-15 (QoR-15) questionnaire was administered 24 h after surgery, and sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI)., Results: No significant differences were found in drainage volume, use of additional analgesics, duration of chest tube placement, or hospital stay between the two groups. However, the ICNB group had significantly lower VAS scores and QoR-15 scores 24 h postoperatively (p < 0.05), indicating better pain management and recovery. The ICNB group also reported better sleep quality, as reflected by lower PSQI scores., Conclusion: ICNB provides superior analgesia compared to LAI after thoracoscopic resection of pulmonary bullae, significantly improving postoperative recovery., (© 2024. The Author(s).)

Background: Oral mucositis (OM) is a prevalent and painful complication in patients undergoing anticancer treatment, which significantly impacts patients' quality of life (QoL) and adherence to therapy. The use of oral probiotics as a preventive strategy for OM has shown promise, but the clinical evidence remains inconclusive. This meta-analysis of randomized controlled trials (RCTs) aims to evaluate the efficacy of probiotics in preventing OM caused by radiotherapy and/or chemotherapy., Methods: A comprehensive search of PubMed, EMBASE, Web of Science, Cochrane Library, and ClinicalTrials.gov was conducted up to January 31, 2024, to identify eligible RCTs. The primary outcomes were the incidences of severe OM and all-grade OM. Secondary outcomes included rates of anticancer treatment completion, clinical response, requirement for enteral nutrition, time course of OM, body weight loss, QoL, and adverse events (AEs). Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated., Results: A total of 12 RCTs involving 1,376 patients were included in the quantitative analysis. Probiotics administration significantly reduced the risk of severe OM (RR = 0.61, 95%CI: 0.53-0.72, P < 0.001) and all-grade OM (RR = 0.90, 95%CI: 0.82-0.98, P = 0.016) compared to the control group. Multi-strain probiotics formulations were more effective than single-strain probiotics in preventing severe OM (P = 0.011). There were no significant differences between the probiotics and control groups regarding anticancer treatment completion (RR = 1.03, 95%CI: 0.98-1.08, P = 0.198), clinical response to therapy (RR = 1.05, 95%CI: 0.94-1.17, P = 0.406), or the need for enteral nutrition (RR = 1.28, 95%CI: 0.49-3.35, P = 0.680). AEs related to probiotics were rare, with no serious AEs attributable to probiotics use., Conclusions: Oral probiotics are both safe and effective in preventing and reducing the severity of OM in patients undergoing anticancer therapy. Multi-strain probiotics demonstrate superior efficacy compared to single-strain probiotics. Further research is warranted to confirm these findings and optimize probiotic treatment strategies for cancer patients., (© 2024. The Author(s).)

Demyelination occurs widely in the central nervous system (CNS) neurodegenerative diseases, especially the multiple sclerosis (MS), which with a complex and inflammatory lesion microenvironment inhibiting remyelination. Sirtuin6 (SIRT6), a histone/protein deacetylase is of interest for its promising effect in transcriptional regulation, cell cycling, inflammation, metabolism and longevity. Here we show that SIRT6 participates in the remyelination process in mice subjected to LPC-induced demyelination. Using pharmacological SIRT6 inhibitor or activator, we found that SIRT6 modulated LPC-induced damage in motor or cognitive function. Inhibition of SIRT6 impaired myelin regeneration, exacerbated neurological deficits, and decreased oligodendrocyte precursor cells (OPCs) proliferation and differentiation, whereas activation of SIRT6 reversed behavioral performance in mice, demonstrating a beneficial effect of SIRT6. Importantly, based on RNA sequencing analysis of the corpus callosum tissues, it was further revealed that SIRT6 took charge in regulation of glial activation during remyelination, and significant alterations in CHI3L1 were obtained, a glycoprotein specifically secreted by astrocytes. Impaired proliferation and differentiation of OPCs could be induced in vitro using supernatants from reactive astrocyte, especially when SIRT6 was inhibited. Mechanistically, SIRT6 regulates the secretion of CHI3L1 from reactive astrocytes by histone-H3-lysine-9 acetylation (H3K9Ac). Adeno-associated virus-overexpression of SIRT6 (AAV-SIRT6-OE) in astrocytes improved remyelination and functional recovery after LPC-induced demyelination, whereas together with AAV-CHI3L1-OE inhibits this therapeutic effect. Collectively, our data elucidate the role of SIRT6 in remyelination and further reveal astrocytic SIRT6/CHI3L1 as the key regulator for improving the remyelination environment, which may be a potential target for MS therapy., (© 2024. The Author(s).)

Background: The distribution of body fat and metabolic health may contribute to the onset of metabolic syndrome (MetS), but the associations between body fat anthropometric indices (AIs) and mortality in individuals with MetS remain unclear., Methods: Participants aged 18 years or older with MetS were recruited from the NHANES 1999-2018. The body fat anthropometric indices included the a body shape index (ABSI), body roundness index (BRI), cardiometabolic index (CMI), visceral adiposity index (VAI), waist triglyceride index (WTI), lipid accumulation product (LAP), atherogenic index of plasma (AIP), and triglyceride‒glucose (TyG) index. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) criteria. Mortality data were obtained from the National Death Index through December 31, 2019., Results: Data were collected from 8,379 individuals with MetS, with a median follow-up of 8.5 years, of whom 1,698 died from all causes and 568 from the CCD. The random survival forest (RSF) analysis indicated that the ABSI had the strongest predictive power for both all-cause mortality and CCD mortality among the eight body fat AIs. After adjusting for multiple variables, the ABSI was found to be linearly and positively associated with all-cause and CCD mortality in individuals with MetS. Participants in the highest quartile of ABSI had an increased risk of all-cause (HR = 1.773 [1.419-2.215]) and CCD (HR = 1.735 [1.267-2.375]) mortality compared with those in the lowest quartile. Furthermore, the ABSI predicted areas under the curve (AUCs) of 0.735, 0.723, 0.718, and 0.725 for all-cause mortality at 3, 5, 10, and 15 years, respectively, and 0.774, 0.758, 0.725, and 0.715 for CCD mortality, respectively., Conclusion: Among eight body fat AIs, the ABSI exhibited the strongest predictive power for mortality in individuals with MetS. Higher ABSI values significantly increased all-cause mortality and CCD mortality in participants with MetS., (© 2024. The Author(s).)

Background: Lung cancer accounts for a significant proportion of cancer-related deaths in China, with the majority of the cases being classified as non-small cell lung cancer (NSCLC). The study aimed to investigate the expression of serum SNHG22 in patients with NSCLC, and its molecular mechanism and prognostic potential in NSCLC., Methods: Admitted 125 NSCLC patients were selected for the study, along with 125 healthy individuals in the same period. The levels of SNHG22 and miR-128-3p were quantified via RT-qPCR. Correlations between the SNHG22 level and the pathological characteristics of the NSCLC patients were investigated through the application of the chi-square test. The targeting relationship between SNHG22 and miR-128-3p was predicted by online database and confirmed by luciferase activity. The prognostic ability of SNHG22 in NSCLC was assessed by Kaplan-Meier curves and multivariate Cox analysis., Results: SNHG22 was upregulated in NSCLC and directly targeted miR-128-3p. The rate of overall survival is lower in patients with high-SNHG22 group compared to those with low-SNHG22 group. Silencing SNHG22 impaired the functionality of cells, which was restored by miR-128-3p inhibitor. SNHG22 stands as an independent predictor of poor prognosis in NSCLC patients., Conclusion: The overexpression of SNHG22 in NSCLC is related to lymph node metastasis, TNM stage and patient survival, which is expected to be a prognostic predictor of NSCLC patients., (© 2024. The Author(s).)

Background: The comorbidity of tuberculosis (TB) and diabetes mellitus (DM) is a significant global public health issue. This study aims to explore the recurrence risk and related factors of active pulmonary TB, specifically focusing on the impact of DM., Methods: A retrospective cohort study was conducted in Lianyungang City, Jiangsu Province, Eastern China by recruiting 12,509 individuals with newly diagnosed pulmonary TB between 2011 and 2019. The Cox proportional hazards models were performed to identify risk factors of recurrence and assess the association between DM and recurrence. The hazard ratio (HR) and 95% confidence interval (CI) were used to estimate the strength of the association., Results: After a median follow-up period of 5.46 years, we observed 439 recurrent cases (incident recurrence rate: 6.62 per 1000 person-years). Males (HR: 1.30, 95% CI: 1.03-1.64), patients aged ≥ 60 years (HR: 1.39, 95% CI: 1.15-1.70), DM (HR: 2.40, 95% CI: 1.68-3.45), and etiologic positivity in the initial episode (HR: 2.42, 95% CI: 2.00-2.92) had a significantly increased risk of recurrence., Conclusions: Recurrence of pulmonary TB patients who have completed treatment, especially those who also suffer from DM, should be a concern. Enhanced follow-up and targeted surveillance of these high-risk groups are needed., (© 2024. The Author(s).)

Background: Studies have shown that Averrhoa carambola L. possesses therapeutic potential for diabetes and related complications. However, the specific beneficial effects and molecular mechanisms of 2-dodecyl-6-meth-oxycyclohexa-2,5-diene-1,4-dione (DMDD) isolated from Averrhoa carambola L. on diabetic nephropathy (DN) require further investigation., Methods: 80 C57BL/6 J male mice were subjected to a 1-week adaptive feeding, followed by a high-fat diet and intraperitoneal injection of 100 mg/kg streptozotocin (STZ) to construct an in vivo DN model. Additionally, human renal proximal tubular epithelial cells (HK-2) induced by high glucose (HG) were used as an in vitro DN model. The expression levels of epithelial-mesenchymal transition (EMT), endoplasmic reticulum stress (ERS), and autophagy-related proteins in renal tubular cells were detected by Western Blot, flow cytometry, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA) staining. Transcriptome analysis revealed was conducted to elucidate the specific mechanism of by which DMDD mitigates DN by inhibiting ERS and autophagy. HK-2 cells were transfected with IRE1α overexpression lentivirus to reveal the role of IRE1α overexpression in HG-induced HK-2., Results: The experimental data showed that DMDD significantly reduced blood glucose levels and improved renal pathological alterations in DN mice. Additionally, DMDD inhibited the calcium (Ca 2+ ) pathway, manifested by decreased autophagosome formation and downregulation of LC3II/I, Beclin-1, and ATG5 expression. Moreover, in HG-induced HK-2 cells, DMDD suppressed the overexpression of GRP78, CHOP, LC3II/I, Beclin1, and ATG5. Notably, IRE1α overexpression significantly increased autophagy incidence; however, DMDD treatment subsequently reduced the expression of LC3II/I, Beclin1, and ATG5., Conclusion: DMDD effectively inhibits excessive ERS and autophagy, thereby reducing renal cell apoptosis through the IRE1α pathway and Ca 2+ pathway., (© 2024. The Author(s).)

Background: The cell development atlas of transition stage from late Carnegie to fetal development (7-9 weeks) remain unclear. It can be seen that the early period of human embryos (7-9 weeks) is a critical research gap. Therefore, we employed single‑cell RNA sequencing to identify cell types and elucidate differentiation relationships., Results: The single‑cell RNA sequencing analysis determines eighteen cell clusters in human embryos during the 7-9 weeks period. We uncover two distinct pathways of cellular development and differentiation. Initially, mesenchymal progenitor cells differentiated into osteoblast progenitor cells and neural stem cells, respectively. Neural stem cells further differentiated into neurons. Alternatively, multipotential stem cells differentiated into adipocyte, hematopoietic stem cells and neutrophil, respectively. Additionally, COL1A2-(ITGA1 + ITGB1) mediated the cell communication between mesenchymal progenitor cells and osteoblast progenitor cells. NCAM1-FGFR1 facilitated the cell communication between mesenchymal progenitor cells and neural stem cells. Notably, NCAM1-NCAM1 as a major contributor mediated the cell communication between neural stem cells and neurons. Moreover, CGA-FSHR simultaneously mediated the communication between multipotential stem cells, adipocyte, hematopoietic stem cells and neutrophil. Distinct cell clusters activated specific transcription factors such as HIC1, LMX1B, TWIST1, and et al., which were responsible for their specific functions. These coregulators, such as HOXB13, VSX2, PAX5, and et al., may mediate cell development and differentiation in human embryos., Conclusions: We provide the cell development atlas for human embryos (7-9 weeks). Two distinct cell development and differentiation pathways are revealed., (© 2024. The Author(s).)

Objective: This study aimed to evaluate the impact of adding 4 mg estradiol valerate to progesterone for luteal support on pregnancy rates in IVF cycles following a long protocol with reduced luteal serum estradiol levels post-hCG triggering., Design, Setting, and Participants: The prospective randomized controlled trial was conducted at a public tertiary hospital reproductive center with 241 patients who experienced a significant decrease in serum estrogen levels post-oocyte retrieval., Interventions: Participants received either a daily 4 mg dose of estradiol valerate in addition to standard progesterone or standard progesterone alone for luteal support., Results: The ongoing pregnancy rate did not show a significant difference between the E2 group and the control group (56.6% vs. 52.2%, with an absolute rate difference (RD) of 4.4%, 95% CI -0.087 to 0.179, P = 0.262). Similarly, the live birth rate, implantation rate, clinical pregnancy rate, early abortion rate, and severe OHSS rate were comparable between the two groups. Notably, the E2 group had no biochemical miscarriages, contrasting significantly with the control group (0.0% vs. 10.7%, RD -10.7%, 95% CI -0.178 to -0.041, P = 0.000). In the blastocyst stage category, the clinical pregnancy rate was notably higher in the E2 group compared to the control group (75.6% vs. 60.8%, RD 14.9%, 95% CI 0.012 to 0.294, P = 0.016)., Conclusion: Adding 4 mg estradiol valerate to progesterone for luteal support does not affect the ongoing pregnancy rate in embryo transfer cycles using a long protocol with a significant decrease in serum estradiol levels after hCG triggering. However, it may reduce biochemical miscarriages and positively impact clinical pregnancy rates in blastocyst embryo transfer cycles., Trial Registration: ChiCTR1800020342., (© 2024. The Author(s).)

Background: At present, preterm infants with respiratory distress syndrome (RDS) in China present higher mortality and morbidity rates than those in high-income countries. The aim of this nationwide survey was to assess the clinical management of RDS in China., Methods: A nationwide cross-sectional survey to assess adherence to RDS management recommendations was performed. One neonatologist per hospital was randomly selected. The primary outcome was the key care of RDS management., Results: Among the 394 participating hospitals, 88·3% were birthing centres. The number of doctors and nurses per bed were 0·27 and 0·72, respectively. Antenatal corticosteroids (any dose) were administered to 90% of the women at risk of preterm birth at < 34 weeks of gestation (90·0% inborn vs. 50·0% outborn, p < 0·001). The median fraction of inspired oxygen (FiO 2 ) for initial resuscitation was 0·30 for babies born at ≤ 32 weeks of gestation and 0·25 for those born at > 32 weeks. T-piece resuscitators were available in 77·8% of delivery rooms (DRs) (tertiary hospitals: 82·5% vs. secondary hospitals: 63·0%, p < 0·001). Surfactant was used in 51·6% of the DRs. Less invasive surfactant administration (LISA) was used in 49·7% of the hospitals (tertiary hospitals: 55·3% vs. secondary hospitals: 31·5%, p < 0·001). Primary non-invasive ventilation was initiated in approximately 80·0% of the patients. High-frequency oscillation ventilation was primarily reserved for rescue after conventional mechanical ventilation (MV) failure. Caffeine was routinely used during MV in 59·1% of the hospitals. Bedside lung ultrasonography was performed in 54·3% of the health facilities (tertiary hospitals: 61·6% vs. secondary hospitals: 30·4%, p < 0·001). Qualified breast milk banks and Family Integrated Care (FICare) were present in 30·2% and 63·7% of the hospitals, respectively., Conclusions: Significant disparities in resource availability and guidelines adherence were evident across hospitals. Future strategies should address DR facilities and medication access, technical training, staff allocation, and ancillary facility development for a better management of RDS patients in China., (© 2024. The Author(s).)

Background: Primary human hepatocytes (PHHs) are highly valuable for drug-metabolism evaluation, liver disease modeling and hepatocyte transplantation. However, their availability is significantly restricted due to limited donor sources, alongside their constrained proliferation capabilities and reduced functionality when cultured in vitro. To address this challenge, we aimed to develop a novel method to efficiently expand PHHs in vitro without a loss of function., Methods: By mimicking the in vivo liver regeneration route, we developed a two-step strategy involving the de-differentiation/expansion and subsequent maturation of PHHs to generate abundant functional hepatocytes in vitro. Initially, we applied SiPer, a prediction algorithm, to identify candidate small molecules capable of activating liver regenerative transcription factors, thereby formulating a novel hepatic expansion medium to de-differentiate PHHs into proliferative human hepatic progenitor-like cells (ProHPLCs). These ProHPLCs were then re-differentiated into functionally mature hepatocytes using a new hepatocyte maturation condition. Additionally, we investigated the underlying mechanism of PHHs expansion under our new conditions., Results: The novel hepatic expansion medium containing hydrocortisone facilitated the de-differentiation of PHHs into ProHPLCs, which exhibited key hepatic progenitor characteristics and demonstrated a marked increase in proliferation capacity compared to cells cultivated in previously established expansion conditions. Remarkably, these subsequent matured hepatocytes rivaled PHHs in terms of transcriptome profiles, drug metabolizing activities and in vivo engraftment capabilities. Importantly, our findings suggest that the enhanced expansion of PHHs by hydrocortisone may be mediated through the PPARα signaling pathway and regenerative transcription factors., Conclusions: This study presents a two-step strategy that initially induces PHHs into a proliferative state (ProHPLCs) to ensure sufficient cell quantity, followed by the maturation of ProHPLCs into fully functional hepatocytes to guarantee optimal cell quality. This approach offers a promising means of producing large numbers of seeding cells for hepatocyte-based applications., (© 2024. The Author(s).)

Background: Colorectal cancer is the third most common cancer and the second leading cause of cancer death. There are limited therapeutic options for the treatment of locally advanced or metastatic colorectal cancers which fail first-line chemotherapy. Phase I/II studies showed that the combined application of the raltitrexed and irinotecan has significant synergistic effect and acceptable toxicity. However, most of these previous studies have relatively small sample size., Methods: This is a prospective open-label, single-arm, multi-center, Phase II trial. Brief inclusion criteria: patients were aged 18 to 75 years with locally advanced or metastatic colorectal cancer after failure of 5-FU and oxaliplatin therapy. Enrolled patients received raltitrexed (3 mg/m 2 , d1) and irinotecan (180 mg/m 2 , d1) each 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, and the secondary endpoints were disease control rate, objective response rate, overall survival and safety., Results: A total of 108 patients were enrolled between September 2016 and May 2020. The median age was 61 years, ECOG 1 score accounts for 67.6%, the rest were ECOG 0. A total of 502 cycles were completed, with an average of 4.6 cycles and a median of 4 cycles. 108 patients were evaluated, with an objective response rate of 17.6%, and disease control rate of 76.9%. The median follow-up time was 27 months (range:3.1-61.0 m) at data cut-off on March 2023. Median progression-free survival was 4.9 months (95% CI 4.1-5.7) and median overall survival was 13.1 months (95% CI 12.2-15.5). The most common adverse events that were elevated are alanine aminotransferase increased, aspartate aminotransferase increased, fatigue, diarrhoea, neutrocytopenia, thrombocytopenia, hypohemoglobin, and leukocytopenia. Most of the adverse events were Grade I/II, which were relieved after symptomatic treatment, and there were no treatment-related cardiotoxicities and deaths., Conclusions: The combination of raltitrexed and irinotecan as second-line treatment for mCRC could be a reliable option after failure of standard 5-Fu-first-line chemotherapy in locally advanced or metastatic colorectal cancers, especially for patients with 5-FU intolerance (cardiac events or DPD deficiency patients)., Trial Registration: ClinicalTrials.gov identifier: NCT03053167, registration date was 14/2/2017., (© 2024. The Author(s).)

Background: Many studies have demonstrated the association between intestinal microbiota and joint diseases. The "gut-joint axis" also has potential roles in chikungunya virus (CHIKV) infection. Pro-inflammatory arthritis after CHIKV infection might disrupt host homeostasis and lead to dysbacteriosis. This study investigated the characteristics of fecal and gut microbiota, intestinal metabolites, and the changes in gene regulation of intestinal tissues after CHIKV infection using multi-omics analysis to explore the involvement of gut microbiota in the pathogenesis of CHIKV infection., Results: CHIKV infection increases the systemic burden of inflammation in the GI system of infected animals. Moreover, infection-induced alterations in GI microbiota and metabolites may be indirectly involved in the modulation of GI and bone inflammation after CHIKV infection, including the modulation of inflammasomes and interleukin-17 inflammatory cytokine levels., Conclusion: Our results suggest that the GI tract and its microbes are involved in the modulation of CHIKV infection, which could serve as an indicator for the adjuvant treatment of CHIKV infection. Video Abstract., (© 2024. The Author(s).)

Objective: This Study aims to investigate the risk factors of hypoglycemia in neonates through meta-analysis., Method: PubMed, Embase, Cochrane library, and Web of science databases were searched for case-control studies on risk factors for neonatal hypoglycemia. The search was done up to 1st October 2023 and Stata 15.0 was used for data analysis., Results: A total of 12 published studies were included, including 991 neonates in the hypoglycemic group and 4388 neonates in the non-hypoglycemic group. Meta-analysis results suggested caesarean section [OR = 1.90 95%CI (1.23, 2.92)], small gestational age[OR = 2.88, 95%CI (1.59, 5.20)], gestational diabetes [OR = 1.65, 95%CI (1.11, 2.46)], gestational hypertension[OR = 2,79, 95%CI (1.78, 4.35)] and respiratory distress syndrome[OR = 5.33, 95%CI (2.22, 12.84)] were risk factors for neonatal hypoglycemia., Conclusion: Based on the current study, we found that caesarean section, small gestational age, gestational diabetes, gestational hypertension, respiratory distress syndrome are risk factors for neonatal hypoglycemia., Prospero Registration Number: CRD42023472974., (© 2024. The Author(s).)

Background: Cognitive dysfunction caused by infection frequently emerges as a complication in sepsis survivor patients. However, a comprehensive understanding of its pathogenesis remains elusive., Methods: In our in vivo experiments, an animal model of endotoxemia was employed, utilizing the Novel Object Recognition Test and Morris Water Maze Test to assess cognitive function. Various techniques, including immunofluorescent staining, Western blotting, blood‒brain barrier permeability assessment, Limulus Amebocyte Lysate (LAL) assay, and Proximity-ligation assay, were employed to identify brain pathological injury and neuroinflammation. To discern the role of Caspase-11 (Casp11) in hematopoietic or non-hematopoietic cells in endotoxemia-induced cognitive decline, bone marrow chimeras were generated through bone marrow transplantation (BMT) using wild-type (WT) and Casp11-deficient mice. In vitro studies involved treating BV2 cells with E. coli-derived outer membrane vesicles to mimic in vivo conditions., Results: Our findings indicate that the deficiency of Casp11-GSDMD signaling pathways reverses infection-induced cognitive dysfunction. Moreover, cognitive dysfunction can be ameliorated by blocking the IL-1 effect. Mechanistically, the absence of Casp11 signaling significantly mitigated blood‒brain barrier leakage, microglial activation, and synaptic damage in the hippocampal CA3 region, ultimately leading to improved cognitive function., Conclusion: This study unveils the crucial contribution of Casp11 and GSDMD to cognitive impairments and spatial memory loss in a murine sepsis model. Targeting Casp11 signaling emerges as a promising strategy for preventing or treating cognitive dysfunction in patients with severe infections., (© 2024. The Author(s).)

Background: Bread wheat (Triticum aestivum L.) endosperm contains starch and proteins, which determine the final yield, quality, and nutritional value of wheat grain. The preferentially expressed endosperm genes can precisely provide targets in the endosperm for improving wheat grain quality and nutrition using modern bioengineering technologies. However, the genes specifically expressed in developing endosperms remain largely unknown., Results: In this study, 315 preferentially expressed endosperm genes (PEEGs) in the spring wheat landrace, Chinese Spring, were screened using data obtained from an open bioinformatics database, which reveals a unique grain reserve deposition process and special signal transduction in a developing wheat endosperm. Furthermore, transcription and accumulation of storage proteins in the wheat cultivar, XC26 were evaluated. The results revealed that 315 PEEG plays a critical role in storage protein fragment deposition and is a potential candidate for modifying grain quality and nutrition., Conclusion: These results provide new insights into endosperm development and candidate genes and promoters for improving wheat grain quality through genetic engineering and plant breeding techniques., (© 2024. The Author(s).)

Background: Asthma is a common non-communicable disease in children, and airway inflammation is the main pathological change of asthma. Tobacco smoke exposure (TSE) can cause systematic inflammation and oxidative stress, which may further aggravate the progression of asthma. Dietary antioxidants can relieve the inflammation and oxidative stress in human body. This study aims to assess the effect of overall antioxidant capacity of dietary intake, evaluating by dietary antioxidant quality score (DAQS), in the association between TSE and childhood asthma., Methods: Data of this cross-sectional study were extracted from the National Health and Nutrition Examination Surveys (NHANES) 2007-2018. DAQS was calculated based on the daily dietary intake of selenium, zinc, magnesium, vitamin A, C and E. TSE was measured by serum cotinine concentration. The weighted univariate and multivariate logistic regression models were employed to evaluate the role of DAQS in the association between TSE and asthma among children and adolescents. Subgroup analysis was conducted to further evaluate the association based on gender., Results: Totally 11,026 children and adolescents were included, of whom 1,244 (11.28%) had asthma. After adjusted all covariates, TSE was associated with the high odds of childhood asthma (OR = 1.26, 95%CI = 1.05-1.52). Among children exposed to tobacco smoke, those with higher DAQS level (OR = 1.15, 95%CI: 0.88-1.50) had a reduced risk of asthma compared with those children with lower DAQS level (OR = 1.43, 1.08-1.89), especially among girls (OR = 1.42, 95%CI: 0.93-2.17)., Conclusion: High DAQS may have a moderating effect on asthma in children; that is, the higher DAQS, the lower the odds of asthma in children who exposed to tobacco smoke. Our study provides a reference for developing more targeted strategies for prevention and treatment of asthma in children., (© 2024. The Author(s).)

Objective: Colorectal cancer (CRC) is a form of malignancy that exhibits a comparatively elevated occurrence and fatality rate. Given the relatively slower progress in diagnostic and therapeutic approaches for CRC, there is a need to investigate more accurate and efficient biomarkers., Methods: Core regulatory genes were screened using the TCGA database, and the expression of neurexophilin 4 (NXPH4) and its prognostic implications were validated using tissue microarray staining. The assessment of NXPH4 functions involved a range of experiments, including cellular, organoid, and murine models. Furthermore, a regulatory network between m 5 C, NXPH4, and HIF1A was established through several in vitro experiments., Results: The overexpression of NXPH4 is associated with unfavorable prognoses in patients with CRC and hepatocellular carcinoma. Additionally, it facilitates the progression of malignant tumors both in laboratory settings and in living organisms of colorectal carcinoma. Our research also reveals that NXPH4 mRNA can avoid degradation through RNautophagy, relying on an m 5 C-dependent mechanism. Moreover, NXPH4 amplifies the HIF signaling pathway and stabilizes HIF1A by competitively binding to PHD4., Conclusions: NXPH4, regulated by m 5 C, promotes malignant tumor progression and regulates the HIF pathway. Consequently, targeting NXPH4 through molecular therapies could potentially serve as an efficacious therapeutic strategy for the management of CRC exhibiting elevated NXPH4 expression., (© 2024. The Author(s).)

Objective: This study aimed to evaluate the long-term cost-effectiveness of conventional care (CC) and seven first-line targeted therapies marketed in China for the treatment of patients with ankylosing spondylitis (AS)-namely secukinumab, ixekizumab, infliximab, etanercept, adalimumab and golimumab and tofacitinib-from the perspective of the Chinese health care system., Methods: The York model was structured as a 12-week decision tree leading into two Markov models. This study set 1 year as a recurring cycle and a lifetime timeframe for the model. Primary model outcomes included the costs in Chinese yuan (CNY), health outcomes in quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER) under a willingness-to-pay threshold of ¥89,358 (equal to the per capita gross domestic product in China in 2023) per QALY. Parameters in the York model were captured from network meta-analyses and literature including treatment response, short-term disease progression, patient functioning and long-term structural disease progression. Utilities are dependent on indicators such as the BASDAI score, the BASFI score, gender and age. Drug prices were analysed using the median price of the Chinese market from YAOZH net in the basic analysis. Costs and outcomes were discounted at 5.0%. We performed deterministic and probabilistic sensitivity analyses to investigate the robustness of the results. The prices of original drugs and generic drugs were used in the scenario analysis., Results: Compared with CC, the ICER of golimumab was ¥104,217.4/QALY, which is between 1 and 3 times the GDP per capita, while the ICERs of the other six targeted therapies were less than ¥89,358/QALY. The specific economic rank of the targeted therapy was as follows: secukinumab > ixekizumab > tofacitinib > infliximab > etanercept > adalimumab > golimumab. Treatment response rates such as the BASDAI50, changes in the BASDAI/BASFI scores and the discounting rate were key model drivers. According to the scenario analysis, IL-17 inhibitors were still the most economical intervention when original drugs and generic drugs were used., Conclusion: Targeted therapies are cost-effective treatments for AS. Overall, IL-17 inhibitors were the dominant treatment. The choice of the brand-new prices or generic drug prices can greatly affect economics., (© 2024. The Author(s).)

Background: Existing studies have presented limited and disparate findings on the nexus between immune cells, plasma metabolites, and metabolic dysfunction-associated steatotic liver disease (MASLD). The aim of this study was to investigate the causal relationship between immune cells and MASLD. Additionally, we aimed to identify and quantify the potential mediating role of metabolites., Methods: A Mendelian randomization (MR) analysis was conducted using two samples of pooled data from genome-wide association studies on MASLD that included 2568 patients and 409,613 control individuals. Additionally, a mediated MR study was employed to quantify the metabolite-mediated immune cell effects on MASLD., Results: In this study, eight immunophenotypes were linked to the risk of MASLD, and thirty-five metabolites/metabolite ratios were linked to the occurrence of MASLD. Furthermore, a total of six combinations of immunophenotypic and metabolic factors demonstrated effects on the occurrence of MASLD, although the mediating effects of metabolites were not significant., Conclusion: Our study demonstrated that certain immunophenotypes and metabolite/metabolite ratios have independent causal relationships with MASLD. Furthermore, we identified specific metabolites/metabolite ratios that are associated with an increased risk of MASLD. However, their mediating role in the causal association between immunophenotypes and MASLD was not significant. It is important to consider immune and metabolic disorders among patients with MASLD in clinical practice., (© 2024. The Author(s).)

Background: The prevalence of non-alcoholic fatty liver disease (NAFLD) keeps increasing annually worldwide. Non-invasive assessment tools for evaluating the risk and severity of the disease are still limited. Insulin resistance (IR) and abdominal obesity (ABO) are closely related to NAFLD., Methods: A retrospective large-scale, population-based study was conducted based on the data from the 2017-2018 cycle of the National Health and Nutrition Examination Survey (NHANES). Three ABO indices, namely lipid accumulation product (LAP), visceral obesity index (VAI), waist circumference-triglyceride index (WTI), and three IR indices, including triglyceride glucose index (TyG), homeostasis model assessment of insulin resistance (HOMA-IR) and metabolic score for insulin resistance (METS-IR), were analyzed and compared for their relationships with NAFLD based on weighted multivariable logistic regression, spearman correlation heatmap, smooth curve fittings. The area under the curve (AUC) of receiver-operating characteristic (ROC) curve was used to evaluate the diagnostic capability of these indices for NAFLD. Differences among the AUCs were calculated and compared by Delong test., Results: In total, 3095 participants were included in our study among which 1368 adults were diagnosed with NAFLD. All six indices presented positive associations with NAFLD. There was a claw-shaped curve between HOMA-IR, VAI, LAP and NAFLD while a smooth semi-bell curve was observed in TyG, METS-IR and WTI. LAP and HOMA-IR had the best diagnostic capability for NAFLD (LAP: AUC = 0.8, Youden index = 0.48; HOMA-IR: AUC = 0.798, Youden index = 0.472) while VAI (AUC = 0.728, Youden index = 0.361) showed the lowest predictive value. The correlation heat map indicated positive correlations between all six indices and liver function, hepatic steatosis and fibrosis severity. In the NAFLD group, IR indicators presented a stronger association with alanine aminotransferase (ALT) compared with ABO indices., Conclusions: All six indices can screen NAFLD withLAP and HOMA-IR being possibly optimal predictors. IR indices may be more sensitive to identify acute hepatic injury in NAFLD patients than ABO indices., (© 2024. The Author(s).)

Background: Diabetes can cause chronic microvascular complications such as diabetic retinopathy (DR) and diabetic nephropathy (DN). DR and DN can lead to or exacerbate diabetic macular edema (DME). Hemodialysis (HD) is the main treatment method for patients with end-stage kidney disease (ESKD) secondary to DN., Purpose: The aim of this prospective cohort study was to determine the immediate effect of single HD session on retinal and choroidal thickness in DR patients with ESKD and the features of DR and the prevalence of DME in these patients who have received long-term HD., Methods: Eighty-five eyes of 44 DR patients with ESKD who underwent long-term HD were examined by swept-source optical coherence tomography angiography (SS-OCTA). Based on OCTA images, the characteristics of DR and the prevalence of DME in these patients were analyzed. Changes in central retinal thickness (CRT), central retinal volume (CRV), subfoveal choroidal thickness (SFCT) and subfoveal choroidal volume (SFCV) within 30 min before and after single HD session were compared. CRT, CRV, SFCT and SFCV were compared before single HD session and before the next single HD session., Results: There was no significant difference in the average CRT (251.69 ± 39.21 μm vs. 251.46 ± 39.38 μm, P = 0.286) or CRV (0.15 ± 0.62 μm vs. 0.15 ± 0.63 μm, P = 0.324) between before and after single HD session. After single HD session, SFCT (243.11 ± 77.15 μm vs. 219.20 ± 72.84 μm, P < 0.001) and SFCV (0.15 ± 0.10 μm vs. 0.13 ± 0.90 μm, P < 0.001) significantly decreased. There was no statistically significant difference in CRT (251.69 ± 39.21 μm vs. 251.11 ± 38.47 μm, P = 0.206), CRV (0.15 ± 0.62 μm vs. 0.15 ± 0.61 μm, P = 0.154), SFCT (243.11 ± 77.15 μm vs. 245.41 ± 76.23 μm, P = 0.108), or SFCV (0.15 ± 0.10 μm vs. 0.16 ± 0.10 μm, P = 0.174) before HD and before the next single HD session. On en face OCTA images, eighty-five eyes (100%) had retinal nonperfusion areas, foveal avascular zone (FAZ) enlargement, and abnormal retinal microvasculature. Based on cross-sectional OCTA images, retinal neovascularization (RNV) was confirmed in 42 eyes (49.41%), and intraretinal microvascular abnormalities (IRMAs) were detected in 85 eyes (100%). Seventeen eyes (20%) still had DME, all of which were cystoid macular edema (CME). Among eyes with DME, the epiretinal membrane (ERM) was present in 7 eyes (8.24%)., Conclusions: For DR patients with ESKD who have undergone long-term HD, the choroidal thickness still changes significantly before and after single HD session, which may be related to short-term effects such as reduced blood volume and plasma osmotic pressure caused by single HD session. Although macular features seem to have stabilized in DR patients undergoing long-term dialysis, the DR of patients with ESKD should still be given attention., (© 2024. The Author(s).)

Background: The objective of this study is to illustrate the changes in the choroidal vasculature in individuals with diffuse chorioretinal atrophy (DCA, early-stage myopic maculopathy) and investigate the association between them., Methods: This study included 1418 highly myopic eyes from 720 participants aged 18 - 60 years from the Wenzhou High Myopia Cohort Study. These participants underwent comprehensive ophthalmic assessments. Myopic maculopathy classification followed the Meta-PM system, with pathological myopia defined as myopic maculopathy of DCA or severer. Eyes with myopic maculopathy categorized as no macular lesions (C0), tessellated fundus (C1), and DCA (C2) were enrolled in the analysis. Choroidal images were obtained from swept-source optical coherence tomography (SS-OCT), and the images were processed with a deep learning-based automatic segmentation algorithm and the Niblack auto-local threshold algorithm., Results: DCA was detected in 247 eyes (17.4%). In comparison to eyes with C0, those with C2 exhibited significant reductions in choroidal thickness (ChT), luminal area (LA), and stromal area (SA) across all evaluated regions (all P < 0.001). An increase in choroidal vascular index (CVI) was observed in all regions, except for the nasal perifoveal (N2) and inferior perifoveal (I2) regions (all P < 0.01). Multivariable logistic regression analysis revealed a negative association between the presence of DCA and increases in choroidal LA and SA (odds ratio ≤ 0.099, P < 0.001). Multivariable linear regression analysis showed that the mean deviation of the visual field test was positively associated with LA and SA at the vertical meridian (B = 1.512, P < 0.001 for LA; B = 1.956, P < 0.001 for SA). Furthermore, the receiver operating characteristic curve analyses showed the optimal ChT to diagnose pathological myopia was 82.4 µm in the N2 region, the LA was 0.076 mm 2 and the SA was 0.049 mm 2 , with area under the curves of 0.916, 0.908, and 0.895, respectively., Conclusions: The results of this study indicated that both the presence of DCA and visual function impairment were associated with reductions in choroidal perfusion and stromal components. Moreover, we established threshold values for choroidal parameters in diagnosing pathological myopia, offering valuable references for clinical diagnosis and management., (© 2024. The Author(s).)

Purpose: To investigate the prevalence of insomnia among nurses with long COVID-19, analyze the potential risk factors and establish a nomogram model., Methods: Nurses in Ningbo, China, were recruited for this study. General demographic information and insomnia, burnout, and stress assessment scores were collected through a face-to face questionnaire survey administered at a single center from March to May 2023. We used LASSO regression to identify potential factors contributing to insomnia. Then, a nomogram was plotted based on the model chosen to visualize the results and evaluated by receiver operating characteristic curves and calibration curves., Results: A total of 437 nurses were recruited. 54% of the nurses had insomnia according to the Insomnia Severity Index (ISI) score. Eleven variables, including family structure, years of work experience, relaxation time, respiratory system sequelae, nervous system sequelae, others sequelae, attitudes toward COVID-19, sleep duration before infection, previous sleep problems, stress, and job burnout, were independently associated with insomnia. The R-squared value was 0.464, and the area under the curve was 0.866. The derived nomogram showed that neurological sequelae, stress, job burnout, sleep duration before infection, and previous sleep problems contributed the most to insomnia. The calibration curves showed significant agreement between the nomogram models and actual observations., Conclusion: This study focused on insomnia among nurses with long COVID-19 and identified eleven risk factors related to nurses' insomnia. A nomogram model was established to illustrate and visualize these factors, which will be instrumental in future research for identifying nurses with insomnia amid pandemic normalization and may increase awareness of the health status of healthcare workers with long COVID-19., (© 2024. The Author(s).)