Search

Abstract It remains that intracranial infection has an alarming mortality and morbidity. Klebsiella pneumoniae (KP) have increasingly been isolated in ventriculitis and meningitis episodes. Intracranial infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) account for high mortality. To understand its clinical impact and related risk factors accurately are crucial in the management of bacterial intracranial infection. The retrospective study aimed to delineate the clinical risk of death from intracranial infection and analyze the risk factors. A total of 176 Klebsiella pneumoniae intracranial infectious patients were available to divide into CRKP group and carbapenem-susceptive Klebsiella Pneumoniae (CSKP) group. We performed survival analysis and estimate the time-varying effects of CRKP and CSKP infection on 30-day mortality. Infectious patients caused by CSKP was associated with lower mortality than CRKP group. The risk factors associated with death from intracranial infection caused by Klebsiella pneumoniae included SOFA scores, ventilator therapy, CRKP, and heart failure. Longer hospital stays are independently associated with lower mortality rates. Intracranial infection caused by CRKP was associated with excess mortality. Complex comorbidities mean higher mortality. Active supportive treatment is required for complicated patients with intracranial infections caused by carbapenem-resistant Klebsiella pneumoniae.

Abstract Soil salinization, a prevalent form of environmental stress, leads to significant soil desertification and impacts agricultural productivity by altering the internal soil environment, slowing cellular metabolism, and modifying cellular architecture. This results in a marked reduction in both the yield and diversity of crops. Maize, which is particularly susceptible to salt stress, serves as a critical model for studying these effects, making the elucidation of its molecular responses essential for crop improvement strategies. This study focuses on the phytochrome-interacting factor 3 (PIF3), previously known for its role in freezing tolerance, to assess its function in salt stress tolerance. Utilizing two transcript variants of maize ZmPIF3 (ZmPIF3.1 and ZmPIF3.2), we engineered Arabidopsis transgenic lines to overexpress these variants and analyzed their phenotypic, physiological, biochemical, and transcriptomic responses to salt stress. Our findings reveal that these transgenic lines displayed not only enhanced salt tolerance but also improved peroxide decomposition and reduced cellular membrane damage. Transcriptome analysis indicated significant roles of hormonal and Ca2+ signaling pathways, along with key transcription factors, in mediating the enhanced salt stress response. This research underscores a novel role for ZmPIF3 in plant salt stress tolerance, offering potential avenues for breeding salt-resistant crop varieties.

Abstract Transcription, RNA splicing, RNA translation, and post-translational protein modification are fundamental processes of gene expression. Epigenetic modifications, such as DNA methylation, RNA modifications, and protein modifications, play a crucial role in regulating gene expression. The methyltransferase-like protein (METTL) family, a constituent of the 7-β-strand (7BS) methyltransferase subfamily, is broadly distributed across the cell nucleus, cytoplasm, and mitochondria. Members of the METTL family, through their S-adenosyl methionine (SAM) binding domain, can transfer methyl groups to DNA, RNA, or proteins, thereby impacting processes such as DNA replication, transcription, and mRNA translation, to participate in the maintenance of normal function or promote disease development. This review primarily examines the involvement of the METTL family in normal cell differentiation, the maintenance of mitochondrial function, and its association with tumor formation, the nervous system, and cardiovascular diseases. Notably, the METTL family is intricately linked to cellular translation, particularly in its regulation of translation factors. Members represent important molecules in disease development processes and are associated with patient immunity and tolerance to radiotherapy and chemotherapy. Moreover, future research directions could include the development of drugs or antibodies targeting its structural domains, and utilizing nanomaterials to carry miRNA corresponding to METTL family mRNA. Additionally, the precise mechanisms underlying the interactions between the METTL family and cellular translation factors remain to be clarified.

Abstract Circular RNAs (circRNAs) are a class of endogenous noncoding RNAs characterized by their lack of 5′ caps and 3′ poly(A) tails. These molecules have garnered substantial attention from the scientific community. A wide range of circRNA types has been found to be expressed in various tissues of the human body, exhibiting unique characteristics such as high abundance, remarkable stability, and tissue-specific expression patterns. These attributes, along with their detectability in liquid biopsy samples such as plasma, position circRNAs an ideal choice as cancer diagnostic and prognostic biomarkers. Additionally, several studies have reported that the functions of circRNAs are associated with tumor proliferation, metastasis, and drug resistance. They achieve this through various mechanisms, including modulation of parental gene expression, regulation of gene transcription, acting as microRNA (miRNA) sponges, and encoding functional proteins. In recent years, a large number of studies have focused on synthesizing circRNAs in vitro and delivering them to tumor tissue to exert its effects in inhibit tumor progression. Herein, we briefly discuss the biogenesis, characteristics, functions, and detection of circRNAs, emphasizing their clinical potential as biomarkers for cancer diagnosis and prognosis. We also provide an overview the recent techniques for synthesizing circRNAs and delivery strategies, and outline the application of engineered circRNAs in clinical cancer therapy.

Abstract Background Leiomyosarcoma is a tumor that can develop in any organ that contains smooth muscles. Although leiomyosarcoma is common, its epididymal localization is quite rare. Case presentation A 79-year-old male Chinese Han patient presented with mild pain in the right groin and scrotum for 3 years concomitant with right scrotal swelling. Ultrasonography and magnetic resonance imaging of the scrotum showed a irregular and heterogeneous mass that was extratesticular. Right high orchiectomy was performed, and pathological examination of the resected specimen confirmed the diagnosis of leiomyosarcoma of the epididymis with surgical margins clear of tumor. Conclusion Epididymal leiomyosarcoma is rare and difficult to diagnose preoperatively. The final diagnosis of epididymal leiomyosarcoma requires histologic examination. Resection must be extensive and complete. The effect of chemotherapy and radiation on the epididymal leiomyosarcoma remains unclear. Recurrence is common, so follow-up is necessary.

Abstract Background Painful diabetic neuropathy (PDN) is closely linked to inflammation, which has been demonstrated to be associated with pyroptosis. Emerging evidence has implicated TANK-binding kinase 1 (TBK1) in various inflammatory diseases. However, it remains unknown whether activated TBK1 causes hyperalgesia via pyroptosis. Methods PDN mice model of type 1 or type 2 diabetic was induced by C57BL/6J or BKS-DB mice with Lepr gene mutation. For type 2 diabetes PDN model, TBK1-siRNA, Caspase-1 inhibitor Ac-YVAD-cmk or TBK1 inhibitor amlexanox (AMX) were delivered by intrathecal injection or intragastric administration. The pain threshold and plantar skin blood perfusion were evaluated through animal experiments. The assessments of spinal cord, dorsal root ganglion, sciatic nerve, plantar skin and serum included western blotting, immunofluorescence, ELISA, and transmission electron microscopy. Results In the PDN mouse model, we found that TBK1 was significantly activated in the spinal dorsal horn (SDH) and mainly located in microglia, and intrathecal injection of chemically modified TBK1-siRNA could improve hyperalgesia. Herein, we described the mechanism that TBK1 could activate the noncanonical nuclear factor κB (NF-κB) pathway, mediate the activation of NLRP3 inflammasome, trigger microglia pyroptosis, and ultimately induce PDN, which could be reversed following TBK1-siRNA injection. We also found that systemic administration of AMX, a TBK1 inhibitor, could effectively improve peripheral nerve injury. These results revealed the key role of TBK1 in PDN and that TBK1 inhibitor AMX could be a potential strategy for treating PDN. Conclusions Our findings revealed a novel causal role of TBK1 in pathogenesis of PDN, which raises the possibility of applying amlexanox to selectively target TBK1 as a potential therapeutic strategy for PDN.

Abstract Rapid urbanization has led to increasingly prominent urban heat island phenomena and social inequality. It is urgent to quantify the threshold area of urban parks from multiple perspectives to maximize the cooling effect and improve the equity of park cooling services. Using 33 urban parks in Harbin City as research objects, four indices, i.e., park cooling intensity (PCI), park cooling distance (PCD), park cooling area (PCA), and park cooling efficiency (PCE), were used to explore the park cooling effect and the threshold value of efficiency (TVoE) of the size. The OD (origin–destination) matrix model was constructed to assess the spatial accessibility from the community to the cooling range. The Gini coefficient was used to assess the equity of cooling range accessibility. The relative contribution of each influencing factor to the cooling indicator was quantified through regression modeling. The results showed that the average PCI was 3.27 ℃, the average PCD was 277 m, the average PCA was 115.35 ha, and the average PCE was 5.74. Gray space area was the dominant factor for PCI, PCD, and PCA (relative contributions of 100%, 31%, and 19%, respectively). Park area was the dominant factor for PCE (relative contribution of 28%). The TVoE of park sizes based on PCA and PCE were calculated as 82.37 ha and 2.56 ha, respectively. 39.2% and 94.01% of communities can reach cooling ranges within 15 min in walk mode and transit mode, respectively. Approximately 18% of neighborhood residents are experiencing severe inequities in cooling range accessibility. This study can guide park design that maximizes cooling effects, as well as inform city planners on more equitable allocation of urban park resources.

Abstract OPFRs are emerging environmental pollutants with reproductive and endocrine toxicity. This study aimed to examine the association between environmental exposure to OPFRs during early pregnancy and GDM. This nested case–control study was based on a birth cohort that was constructed at a maternal and child health hospital, including 74 cases of GDM among 512 pregnant women. The OPFRs, including TBP, TBEP, TCEP, TDCPP, TMCP, TOCP, and TPHP during 10–14 weeks of pregnancy were determined using GC–MS. The association between the OPFRs and GDM was assessed using WQS and BKMR models. The levels of OPFRs were significantly elevated in GDM patients (60) compared with the controls (90). The WQS analysis showed that mixtures of the OPFRs were significantly associated with GDM (OR 1.370, 95% CI 1.036–1.810, P = 0.027), and TBP, TPHP, and TMCP were the major contributors to the mixed exposure effect. In the BKMR model, individual exposure to TBP, TPHP, and TMCP, and the interaction of TMCP with TBP and TPHP were significantly associated with GDM. Environmental exposure to OPFRs is positively associated with GDM. These findings provide evidence for the adverse effects of OPFR exposure on the health of pregnant women.

Abstract The TBS is a new method for clinicians to assess the bone quality. It is directly related to the mechanical strength of bone and helps predict fracture risk. The present analysis aimed to investigate the associations between serum PTH levels and TBS by analyzing data from the National Health and Nutrition Examination Survey (NHANES). A total of 3516 participants from the NHANES 2005–2006 were included in this cross-sectional study. The independent variable was serum PTH, and the outcome variable was TBS. The associations of serum PTH levels with TBS were examined using multivariable linear regression models. After adjusting for covariates, there was a negative association between serum PTH level and TBS (β = − 0.0034; 95% confidence interval, − 0.0050 to − 0.0017). However, in the subgroup analysis stratified by gender, race, and age, this association became negative only in Non-Hispanic White (β = − 0.0047, 95% CI: − 0.0071 to − 0.0048) and young people (age

Abstract Bloodstream infections caused by multidrug-resistant organisms such as Klebsiella pneumoniae are a significant challenge in managing hematological malignancies. This study aims to characterize the epidemiology of Klebsiella pneumoniae bloodstream infections specifically in patients with hematological malignancies, delineate the patterns of initial antibiotic therapy, assess the prevalence of resistant strains, identify risk factors for these resistant strains, and evaluate factors influencing patient outcomes. A retrospective analysis was conducted at a single center from January 2017 to December 2020, focusing on 182 patients with hematological malignancies who developed Klebsiella pneumoniae bloodstream infections. We compared the 30-day mortality rates between patients receiving appropriate and inappropriate antibiotic treatments, including the effectiveness of both single-drug and combination therapies. Kaplan–Meier survival analysis and multivariate logistic and Cox regression were used to identify factors influencing mortality risk. The 30-day all-cause mortality rate was 30.2% for all patients. The 30-day all-cause mortality rates were 77.2% and 8.8% in patients who received inappropriate initial treatment and appropriate initial treatment (p

Abstract Antitumor therapies based on adoptively transferred T cells or oncolytic viruses have made significant progress in recent years, but the limited efficiency of their infiltration into solid tumors makes it difficult to achieve desired antitumor effects when used alone. In this study, an oncolytic virus (rVSV-LCMVG) that is not prone to induce virus-neutralizing antibodies was designed and combined with adoptively transferred T cells. By transforming the immunosuppressive tumor microenvironment into an immunosensitive one, in B16 tumor-bearing mice, combination therapy showed superior antitumor effects than monotherapy. This occurred whether the OV was administered intratumorally or intravenously. Combination therapy significantly increased cytokine and chemokine levels within tumors and recruited CD8+ T cells to the TME to trigger antitumor immune responses. Pretreatment with adoptively transferred T cells and subsequent oncolytic virotherapy sensitizes refractory tumors by boosting T-cell recruitment, down-regulating the expression of PD-1, and restoring effector T-cell function. To offer a combination therapy with greater translational value, mRNA vaccines were introduced to induce tumor-specific T cells instead of adoptively transferred T cells. The combination of OVs and mRNA vaccine also displays a significant reduction in tumor burden and prolonged survival. This study proposed a rational combination therapy of OVs with adoptive T-cell transfer or mRNA vaccines encoding tumor-associated antigens, in terms of synergistic efficacy and mechanism.

Objective To evaluate the safety and feasibility of transumbilical single-port laparoscopic uterine artery embolization combined with incision and embryo retrieval in the treatment of cesarean scar pregnancy. Methods Eleven patients with cesarean scar pregnancy who underwent transumbilical single-hole laparoscopic uterine artery embolization combined with incision and embryo retrieval were recruited in the study group， and ten patients who underwent multi-hole laparoscopic uterine artery embolization combined with incision and embryo retrieval were assigned into the control group. Baseline data and perioperative clinical data were compared between two groups. Results No significant differences were found in age， number of pregnancies， number of cesarean sections， time interval from last cesarean section， clinical classification， number of days of menopause， and the presence or absence of symptoms of vaginal bleeding between two groups （all P > 0.05）. No significant differences were observed in operation time， intraoperative bleeding and postoperative retention time of catheterization between two groups （all P > 0.05）. In the study group， postoperative numeric rating scale （NRS） score was significantly lower and the length of hospital stay was significantly shorter compared with those in the control group （both P < 0.05）. Conclusions Compared with traditional multi-port laparoscopic uterine artery embolization combined with incision and embryo retrieval， transumbilical single-port laparoscopic uterine artery embolization combined with incision and embryo retrieval is a feasible and safe procedure， which can alleviate postoperative pain， shortern the length of hospital stay and yield better cosmetic results.

Abstract Establish a new classification system of distal radius fracture based on computed tomographic (CT), and evaluate its reliability and reproducibility preliminarily, and provide a new theoretical reference for clinicians to use the clinical classification system. The imaging data and clinical data of 204 inpatients with distal radius fracture during 6 years from January 1, 2014 to January 1, 2019 in orthopaedic department were analyzed retrospectively and classified based on CT. Three observers evaluated the image data of 48 randomly selected cases based on CT at different time nodes of T1 and T2. Cohen's kappa was used to calculate the consistency. At the last follow-up, patients' Disabilities of the Arm, Shoulder and Hand (DASH), Patient Rated Wrist Evaluation (PRWE), and VAS scores were collected. Among 204 cases, there were 12 cases of type 1, including 6 cases of type 1-D, 4 cases of type 1-V and 2 cases of type 1-R. There were 6 cases of type 2, including 2 cases of type 2-DV, 2 cases of type 2-DR and 2 cases of type 2-VR. There were 186 cases of type 3, including 32 cases of type 3–0, 127 cases of type 3–1 and 27 cases of type 3–2. There was no significant difference in DASH, PRWE and VAS scores among all types (P > 0.05). The results of interobserver reproducibility were kappa = 0.985, ICC = 0.984 in the first evaluation, kappa = 0.986, ICC = 0.986 in the second evaluation. The results of intraobserver reproducibility were O1 = 0.991, O2 = 0.991, O3 = 0.989 respectively. The new classification system of distal radius fracture based on CT has theoretical and practical significance for incision selection, fracture reduction and internal fixation. 123 classification system is clear, comprehensive, easy to understand and remember. Moreover, it has higher interobserver reliability and intraobserver reproducibility than other systems reported at present.

Abstract The transpedicular procedure has been widely used in spinal surgery. The determination of the best entry point is the key to perform a successful transpedicular procedure. Various techniques have been used to determine this point, but the results are variable. This study was carried out to determine the posterior endpoint of the lumbar pedicle central axis on the standard anterior–posterior (AP) fluoroscopic images. Computer-aided design technology was used to determine the pedicle central axis and the posterior endpoint of the pedicle central axis on the posterior aspect of the vertebra. The standard AP fluoroscopic image of the lumbar vertebral models by three-dimensional printing was achieved. The endpoint projection on the AP fluoroscopic image was determined in reference to the pedicle cortex projection by the measurements of the angle and distance on the established X–Y coordinate system of the radiologic image. The projection of posterior endpoint of the lumbar pedicle central axis were found to be superior to the X-axis of the established X–Y coordinate system and was located on the pedicle cortex projection on the standard AP fluoroscopic image of the vertebra. The projection point was distributed in different sectors in the coordinate system. It was located superior to the X-axis by 18° to 26° at L1, while they were located superior to the X-axis by 12° to 14° at L2 to L5. The projections of posterior endpoints of the lumbar pedicle central axis were located in different positions on the standard AP fluoroscopic image of the vertebra. The determination method of the projection point was helpful for selecting an entry point for a transpedicular procedure with a fluoroscopic technique.

Abstract Background Sequencing the mitochondrial genome has been increasingly important for the investigation of primary mitochondrial diseases (PMD) and mitochondrial genetics. To overcome the limitations originating from PCR-based mtDNA enrichment, we set out to develop and evaluate a PCR-independent approach in this study, named Pime-Seq (PCR-independent mtDNA enrichment and next generation Sequencing). Results By using the optimized mtDNA enrichment procedure, the mtDNA reads ratio reached 88.0 ± 7.9% in the sequencing library when applied on human PBMC samples. We found the variants called by Pime-Seq were highly consistent among technical repeats. To evaluate the accuracy and reliability of this method, we compared Pime-Seq with lrPCR based NGS by performing both methods simultaneously on 45 samples, yielding 1677 concordant variants, as well as 146 discordant variants with low-level heteroplasmic fraction, in which Pime-Seq showed higher reliability. Furthermore, we applied Pime-Seq on 4 samples of PMD patients retrospectively, and successfully detected all the pathogenic mtDNA variants. In addition, we performed a prospective study on 192 apparently healthy pregnant women during prenatal screening, in which Pime-Seq identified pathogenic mtDNA variants in 4 samples, providing extra information for better health monitoring in these cases. Conclusions Pime-Seq can obtain highly enriched mtDNA in a PCR-independent manner for high quality and reliable mtDNA deep-sequencing, which provides us an effective and promising tool for detecting mtDNA variants for both clinical and research purposes.

Abstract Background Humanistic education is an important part of nursing education. Final-year nursing students’ perceptions of nursing humanistic education are under-investigated. This study aimed to examined final-year nursing students’ perceptions of nursing humanistic education in both school and hospital. Methods This was a cross-sectional descriptive study conducted from May to June 2022 among 107 final-year nursing students with a self-designed questionnaire. Results Final-year nursing students recognized the importance of humanistic education, scoring above 4.0 on a 1–5 scale, while their initiative to enhance humanistic qualities was relatively low. Students’ satisfaction with the number of humanities courses offered was only 3.7 ± 0.862. Moreover, 62.6% of students believed there was a need to enhance humanistic environmental development including corridor culture. The “monotonous teaching format” (63.6%) and “teaching methods” (64.5%) have emerged as focal points that students identified as needing attention and improvement. Conclusions In the future, nursing humanistic education can be enhanced by increasing the proportion of humanities, improving teaching methods, stimulating students’ learning motivation, and strengthening the construction of humanistic environment.

Abstract The disintegration of red-bed soft rock exhibits a strong correlation with various geological disasters. However, the investigation into the evolutionary mechanisms underlying disintegration breakage has not yet received extensive exploration. In order to comprehensively examine the disintegration characteristics of red-bed soft rock, the slake durability tests were conducted to red-bed soft rocks of varying burial depths. Subsequently, an investigation was carried out to examine the disintegration characteristics and the evolution of disintegration parameters, including the coefficient of uniformity (Cu), coefficient of curvature (Cc), disintegration rate (DRE), disintegration ratio (Dr), and fractal dimension (D), throughout the disintegration process. Finally, employing the energy dissipation theory, an energy dissipation model was developed to predicate the disintegration process of samples at various burial depths. The findings demonstrate a decrease in the abundance of large particles and a concurrent increase in the abundance of small particles as the number of drying-wetting cycles increases. Furthermore, as the number of drying-wetting cycles increases, a significant alteration is observed in the content of particles larger than 10 mm, whereas the content of particles smaller than 10 mm undergoes only minor changes. The disintegration parameters, including the curvature coefficient, non-uniformity coefficient, disintegration rate, and fractal dimension, exhibit a positive correlation with the number of drying-wetting cycles. Conversely, the disintegration index demonstrates a decreasing trend with the increasing number of cycles. Nevertheless, as the burial depth increases, a notable trend emerges in the disintegration process, characterized by a gradual increase in the content of large particles alongside a progressive decrease in the content of small particles. Concurrently, the curvature coefficient, non-uniformity coefficient, disintegration rate, and fractal dimension exhibit a gradual decline, while the durability index experiences a gradual increase. In addition, based on the principle of energy dissipation, it is revealed that the surface energy increment of red-bed soft rock increases with the increase of the number of drying-wetting cycles, but decreases with the increase of burial depth. Ultimately, by leveraging the outcomes of energy dissipation analyses, a theoretical model is constructed to elucidate the correlation between surface energy and both the number of drying-wetting cycles and burial depth. This model serves as a theoretical reference for predicting the disintegration behavior of samples, offering valuable insights for future research endeavors.

Objectives To identify the barriers and facilitators to the successful implementation of imaging-based diagnostic artificial intelligence (AI)-assisted decision-making software in China, using the updated Consolidated Framework for Implementation Research (CFIR) as a theoretical basis to develop strategies that promote effective implementation.Design This qualitative study involved semistructured interviews with key stakeholders from both clinical settings and industry. Interview guide development, coding, analysis and reporting of findings were thoroughly informed by the updated CFIR.Setting Four healthcare institutions in Beijing and Shanghai and two vendors of AI-assisted decision-making software for lung nodules detection and diabetic retinopathy screening were selected based on purposive sampling.Participants A total of 23 healthcare practitioners, 6 hospital informatics specialists, 4 hospital administrators and 7 vendors of the selected AI-assisted decision-making software were included in the study.Results Within the 5 CFIR domains, 10 constructs were identified as barriers, 8 as facilitators and 3 as both barriers and facilitators. Major barriers included unsatisfactory clinical performance (Innovation); lack of collaborative network between primary and tertiary hospitals, lack of information security measures and certification (outer setting); suboptimal data quality, misalignment between software functions and goals of healthcare institutions (inner setting); unmet clinical needs (individuals). Key facilitators were strong empirical evidence of effectiveness, improved clinical efficiency (innovation); national guidelines related to AI, deployment of AI software in peer hospitals (outer setting); integration of AI software into existing hospital systems (inner setting) and involvement of clinicians (implementation process).Conclusions The study findings contributed to the ongoing exploration of AI integration in healthcare from the perspective of China, emphasising the need for a comprehensive approach considering both innovation-specific factors and the broader organisational and contextual dynamics. As China and other developing countries continue to advance in adopting AI technologies, the derived insights could further inform healthcare practitioners, industry stakeholders and policy-makers, guiding policies and practices that promote the successful implementation of imaging-based diagnostic AI-assisted decision-making software in healthcare for optimal patient care.

Objective To predict birth weight at various potential gestational ages of delivery based on data routinely available at the first antenatal visit.Design Individual participant data meta-analysis.Data sources Individual participant data of four cohorts (237 228 pregnancies) from the International Prediction of Pregnancy Complications (IPPIC) network dataset.Eligibility criteria for selecting studies Studies in the IPPIC network were identified by searching major databases for studies reporting risk factors for adverse pregnancy outcomes, such as pre-eclampsia, fetal growth restriction, and stillbirth, from database inception to August 2019. Data of four IPPIC cohorts (237 228 pregnancies) from the US (National Institute of Child Health and Human Development, 2018; 233 483 pregnancies), UK (Allen et al, 2017; 1045 pregnancies), Norway (STORK Groruddalen research programme, 2010; 823 pregnancies), and Australia (Rumbold et al, 2006; 1877 pregnancies) were included in the development of the model.Results The IPPIC birth weight model was developed with random intercept regression models with backward elimination for variable selection. Internal-external cross validation was performed to assess the study specific and pooled performance of the model, reported as calibration slope, calibration-in-the-large, and observed versus expected average birth weight ratio. Meta-analysis showed that the apparent performance of the model had good calibration (calibration slope 0.99, 95% confidence interval (CI) 0.88 to 1.10; calibration-in-the-large 44.5 g, −18.4 to 107.3) with an observed versus expected average birth weight ratio of 1.02 (95% CI 0.97 to 1.07). The proportion of variation in birth weight explained by the model (R2) was 46.9% (range 32.7-56.1% in each cohort). On internal-external cross validation, the model showed good calibration and predictive performance when validated in three cohorts with a calibration slope of 0.90 (Allen cohort), 1.04 (STORK Groruddalen cohort), and 1.07 (Rumbold cohort), calibration-in-the-large of −22.3 g (Allen cohort), −33.42 (Rumbold cohort), and 86.4 g (STORK Groruddalen cohort), and observed versus expected ratio of 0.99 (Rumbold cohort), 1.00 (Allen cohort), and 1.03 (STORK Groruddalen cohort); respective pooled estimates were 1.00 (95% CI 0.78 to 1.23; calibration slope), 9.7 g (−154.3 to 173.8; calibration-in-the-large), and 1.00 (0.94 to 1.07; observed v expected ratio). The model predictions were more accurate (smaller mean square error) in the lower end of predicted birth weight, which is important in informing clinical decision making.Conclusions The IPPIC birth weight model allowed birth weight predictions for a range of possible gestational ages. The model explained about 50% of individual variation in birth weights, was well calibrated (especially in babies at high risk of fetal growth restriction and its complications), and showed promising performance in four different populations included in the individual participant data meta-analysis. Further research to examine the generalisability of performance in other countries, settings, and subgroups is required.Trial registration PROSPERO CRD42019135045

Abstract Doxorubicin has been used extensively as a potent anticancer agent, but its clinical use is limited by its cardiotoxicity. However, the underlying mechanisms remain to be fully elucidated. In this study, we tested whether NADPH oxidase 2 (Nox2) mediates cardiac sympathetic nerve terminal abnormalities and myocyte autophagy, resulting in cardiac atrophy and dysfunction in doxorubicin-induced heart failure. Nox2 knockout (KO) and wild-type (WT) mice were randomly assigned to receive a single injection of doxorubicin (15 mg/kg, i.p.) or saline. WT doxorubicin mice exhibited the decreases in survival rate, left ventricular (LV) wall thickness and LV fractional shortening and the increase in the lung wet-to-dry weight ratio 1 week after the injections. These alterations were attenuated in Nox2 KO doxorubicin mice. In WT doxorubicin mice, myocardial oxidative stress was increased, myocardial noradrenergic nerve fibers were reduced, myocardial expression of PGP9.5, GAP43, tyrosine hydroxylase and norepinephrine transporter was decreased, and these changes were prevented in Nox2 KO doxorubicin mice. Myocyte autophagy was increased and myocyte size was decreased in WT doxorubicin mice, but not in Nox2 KO doxorubicin mice. Nox2 mediates cardiac sympathetic nerve terminal abnormalities and myocyte autophagy—both of which contribute to cardiac atrophy and failure after doxorubicin treatment.

Abstract Heterogeneous cancer-associated fibroblasts (CAFs) play important roles in cancer progression. However, the specific biological functions and regulatory mechanisms involved in endometrial cancer have yet to be elucidated. We aimed to explore the potential mechanisms of heterogeneous CAFs in promoting endometrial cancer progression. The presence of melanoma cell adhesion molecule (MCAM; CD146) positive CAFs was confirmed by tissue multi-immunofluorescence (mIF), and fluorescence activated cell sorting (FACS). The biological functions were determined by wound healing assays, tuber formation assays and cord formation assays. The effects of CD146+CAFs on endometrial cancer cells were studied in vitro and in vivo. The expression level of interleukin 10 (IL-10) was measured by quantitative real time polymerase chain reaction (qRT-PCR), western boltting and enzyme linked immunosorbent assays (ELISAs). In addition, the transcription factor STAT3 was identified by bioinformatics methods and chromatin immunoprecipitation (ChIP). A subtype of CAFs marked with CD146 was found in endometrial cancer and correlated with poor prognosis. CD146+CAFs promoted angiogenesis and vasculogenic mimicry (VM) in vitro. A xenograft tumour model also showed that CD146+CAFs can facilitate tumour progression. The expression of IL-10 was elevated in CD146+CAFs. IL-10 promoted epithelial-endothelial transformation (EET) and further VM formation in endometrial cancer cells via the janus kinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) signalling pathway. This process could be blocked by the JAK1/STAT3 inhibitor niclosamide. Mechanically, STAT3 can bind to the promoter of cadherin5 (CDH5) to promote its transcription which may be stimulated by IL-10. We concluded that CD146+CAFs could promote angiogenesis and VM formation via the IL-10/JAK1/STAT3 signalling pathway. These findings may lead to the identification of potential targets for antiangiogenic therapeutic strategies for endometrial cancers.

Abstract Background The mitochondria and endoplasmic reticulum (ER) communicate via contact sites known as mitochondria associated membranes (MAMs). Many important cellular functions such as bioenergetics, mitophagy, apoptosis, and calcium signaling are regulated by MAMs, which are thought to be closely related to ischemic reperfusion injury (IRI). However, there exists a gap in systematic proteomic research addressing the relationship between these cellular processes. Methods A 4D label free mass spectrometry-based proteomic analysis of mitochondria associated membranes (MAMs) from the human renal proximal tubular epithelial cell line (HK-2 cells) was conducted under both normal (N) and hypoxia/reperfusion (HR) conditions. Subsequent differential proteins analysis aimed to characterize disease-relevant signaling molecules. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was applied to total proteins and differentially expressed proteins, encompassing Biological Process (BP), Cell Component (CC), Molecular Function (MF), and KEGG pathways. Further, Protein–Protein Interaction Network (PPI) exploration was carried out, leading to the identification of hub genes from differentially expressed proteins. Notably, Mitofusion 2 (MFN2) and BCL2/Adenovirus E1B 19-kDa interacting protein 3(BNIP3) were identified and subsequently validated both in vitro and in vivo. Finally, the impact of MFN2 on MAMs during hypoxia/reoxygenation was explored through regulation of gene expression. Subsequently, a comparative proteomics analysis was conducted between OE-MFN2 and normal HK-2 cells, providing further insights into the underlying mechanisms. Results A total of 4489 proteins were identified, with 3531 successfully quantified. GO/KEGG analysis revealed that MAM proteins were primarily associated with mitochondrial function and energy metabolism. Differential analysis between the two groups showed that 688 proteins in HR HK-2 cells exhibited significant changes in expression level with P-value 1.5 or HR/N

In the realm of pharmaceutical advancement, the transformative prowess of nanotechnology shines through its precision-targeted drug delivery and amplified therapeutic effects. This paper ventures into the realm of radiolabeling techniques for unraveling the intricate choreography of drug kinetics within the bloodstream which encompass the delicate stages of absorption, distribution, metabolism, and excretion. Through the magical lens of the radiolabel, a real-time spectacle unfolds, providing invaluable insights into the safety and efficacy of nanomedicine interventions. Amid the labyrinthine complexities of drug-organism interactions and the lack of universal protocols for nanomedicine preparation, radiolabeling technology has emerged as a guiding constellation. The paper systematically assesses the methods commonly employed for pharmacokinetic studies, delves into the manifold advantages and techniques of radiolabel methods within the nanomedicine landscape, closely examines their application across a spectrum of pharmacokinetic studies and thoughtfully addresses the challenges they may pose. Embark on this illuminating odyssey—a journey that peers into the microcosm of nanomedicine, deciphering its dynamic interplay within the bloodstream through the luminary insights of radiolabeled tracing techniques.

Hemorrhagic shock is a common acute and critical disease caused by trauma in clinic. In particular, local tissue hypoperfusion and cell hypoxia caused by renal ischemia and hypoxia can easily lead to acute kidney injury. In clinical practice, safer, practical, and effective resuscitation methods for patients with hemorrhagic shock are constantly explored to achieve the purpose of better protection of the kidney, such as the applications from colloidal crystal liquid to hypertonic fluid, from normal-pressure resuscitation to low-pressure resuscitation, from correcting blood pressure to restoring oxygen supply to tissue cells, from maintaining hemodynamic stability to inhibiting apoptosis, and from vasoactive drugs to Chinese traditional medicines to enzyme inhibitors. This article reviews the research progress of kidney protection for patients with hemorrhagic shock in recent years.

Abstract Action recognition has been applied in fields such as smart homes, gaming, traffic management, and security monitoring. Motion recognition is helpful for biomechanical analysis, auxiliary training systems, table tennis robots, motion-sensing games, virtual reality and other fields. In our study, we collected data on table tennis skill motion, created the TTMD6 dataset, and analyzed the characteristics of table tennis paddle trajectories. We propose a motion recognition algorithm to recognize paddle trajectories. Other research has used multijoint data to identify actions, while we use only the paddle trajectory to recognize table tennis skill motions, accelerating the speed of motion recognition. Therefore, it is feasible to use paddle trajectories to recognize table tennis skill motions.

Abstract Paraquat (PQ) is an irreplaceable insecticide in many countries for the advantage of fast-acting and broad-spectrum. However, PQ was classified as the most prevailing poisoning substance for suicide with no specific antidote. Therefore, it is imperative to develop more effective therapeutic agents for the treatment of PQ poisoning. In the present study, both the RNA-Seq and the application of various cell death inhibitors reflected that ferroptosis exerts a crucial regulatory role in PQ poisoning. Moreover, we found PQ strengthens lipid peroxidation as evidenced by different experimental approaches. Of note, pretreatment of iron chelation agent DFO could ameliorate the ferroptotic cell death and alleviate the ferroptosis-related events. Mechanistically, PQ treatment intensively impaired mitochondrial homeostasis, enhanced phosphorylation of AMPK, accelerated the autophagy flux and triggered the activation of Nuclear receptor coactivator 4-ferritin heavy chain (NCOA4-FTH) axis. Importantly, the activation of autophagy was observed prior to the degradation of ferritin, and inhibition of autophagy could inhibit the accumulation of iron caused by the ferritinophagy process. Genetic and pharmacological inhibition of ferritinophagy could alleviate the lethal oxidative events, and rescue the ferroptotic cell death. Excitingly, in the mouse models of PQ poisoning, both the administration of DFO and adeno-associated virus-mediated FTH overexpression significantly reduced PQ-induced ferroptosis and improved the pathological characteristics of pulmonary fibrosis. In summary, the current work provides an in-depth study on the mechanism of PQ intoxication, describes a framework for the further understanding of ferroptosis in PQ-associated biological processes, and demonstrates modulation of iron metabolism may act as a promising therapeutic agent for the management of PQ toxicity. Graphical Abstract

Abstract Deafness is a common sensory disorder. In China, approximately 70% of hereditary deafness originates from four common deafness-causing genes: GJB2, SLC26A4, GJB3, and MT-RNR1. A single-tube rapid detection method based on 2D-PCR technology was established for nine mutation sites in the aforementioned genes, and Sanger sequencing was used to verify its reliability and accuracy. The frequency of hotspot mutations in deafness genes was analysed in 116 deaf students. 2D-PCR identified 27 genotypes of nine loci according to the melting curve of the FAM, HEX, and Alexa568 fluorescence channels. Of the 116 deaf patients, 12.9% (15/116) carried SLC26A4 mutations, including c.919-2A > G and c.2168A > G (allele frequencies, 7.3% and 2.2%, respectively). The positivity rate (29.3%; 34/116) was highest for GJB2 (allele frequency, 15.9% for c.235delC, 6.0% for c.299_300delAT, and 2.6% for c.176-191del16). Sanger sequencing confirmed the consistency of results between the detection methods based on 2D-PCR and DNA sequencing. Common pathogenic mutations in patients with non-syndromic deafness in Changzhou were concentrated in GJB2 (c.235delC, c.299_300delAT, and c.176-191del16) and SLC26A4 (c.919-2A > G and c.2168 A > G). 2D-PCR is an effective method for accurately and rapidly identifying deafness-related genotypes using a single-tube reaction, and is superior to DNA sequencing, which has a high cost and long cycle.

Abstract The research attention is increasingly directed towards the effective integration of the 17 United Nations Sustainable Development Goals (SDGs) within the limitations of the real world and amidst intersectoral conflicts. In light of the inextricable relationship between irrigation and energy, the objective of this study is to identify potential avenues for achieving the SDG6 and SDG7 goals of enhancing water use efficiency in agriculture and eradicating energy poverty, respectively. Utilizing data from 30 Chinese provinces from 2002 to 2017, this study explores the dynamic influence of energy poverty on agricultural water efficiency with a system generalized method of moments methodology. The findings suggest that energy poverty may greatly reduce agricultural water efficiency. The heterogeneity study shows that when agricultural water efficiency grows, the negative impacts of energy poverty continue to fade. Based on an assessment of various processes, results suggest that non-farm employment and cropping structure modification is a prominent conduit via which energy poverty negatively influences agricultural water efficiency.

Abstract Understanding and accurately measuring resilience among Chinese civil aviation pilots is imperative, especially concerning the psychological impact of distressing events on their well-being and aviation safety. Despite the necessity, a validated and tailored measurement tool specific to this demographic is absent. Addressing this gap, this study built on the widely used CD-RISC-25 to analyze and modify its applicability to Chinese civil aviation pilots. Utilizing CD-RISC-25 survey data from 231 Chinese pilots, correlational and differential analyses identified items 3 and 20 as incongruent with this population's resilience profile. Subsequently, factor analysis derived a distinct two-factor resilience psychological framework labeled “Decisiveness” and “Adaptability”, which diverged from the structure found in American female pilots and the broader Chinese populace. Additionally, to further accurately identify the measurement characteristics of this 2-factor measurement model, this study introduced Generalized Theory and Item Response Theory, two modern measurement analysis theories, to comprehensively analyze the overall reliability of the measurement and issues with individual items. Results showed that the 2-factor model exhibited high reliability, with generalizability coefficient reaching 0.89503 and dependability coefficient reaching 0.88496, indicating the 2-factor measurement questionnaire can be effectively utilized for relative and absolute comparison of Chinese civil aviation pilot resilience. However, items in Factor 2 provided less information and have larger room for optimization than those in Factor 1, implying item option redesign may be beneficial. Consequently, this study culminates in the creation of a more accurate and reliable two-factor psychological resilience measurement tool tailored for Chinese civil aviation pilots, while exploring directions for optimization. By facilitating early identification of individuals with lower resilience and enabling the evaluation of intervention efficacy, this tool aims to positively impact pilot psychological health and aviation safety in the context of grief and trauma following distressing events.

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to affect vessels and nerves and can be easily visualized in the retina. However, the effect of SARS-CoV-2 on retinal morphology remains controversial. In the present research, we applied Mendelian randomization (MR) analysis to estimate the association between SARS-CoV-2 and changes in the thickness of the inner retina. Methods Two-sample MR analysis was conducted using summary-level data from 3 open genome-wide association study databases concerning COVID-19 infection (2,942,817 participants) and COVID-19 hospitalization (2,401,372 participants); moreover, the dataset of inner retina thickness, including the macular retinal nerve fiber layer (mRNFL) and macular ganglion cell-inner plexiform layer (mGCIPL), included 31,434 optical coherence tomography (OCT) images derived from healthy UK Biobank participants. All the participants were of European ancestry. The inverse variance weighted (IVW) meta-analysis was used as our primary method. Various complementary MR approaches were established to provide robust causal estimates under different assumptions. Results According to our MR analysis, genetically predicted COVID-19 infection was associated with an increased risk of mRNFL and mGCIPL thickness (OR = 1.74, 95% CI 1.20–2.52, P = 3.58 × 10–3; OR = 2.43, 95% CI 1.49–3.96, P = 3.6 × 10–4). The other MR methods produced consistent results. However, genetically predicted COVID-19 hospitalization did not affect the thickness of the inner retina (OR = 1.11, 95% CI 0.90–1.37, P = 0.32; OR = 1.28, 95% CI 0.88–1.85, P = 0.19). Conclusion This work provides the first genetically predictive causal evidence between COVID-19 infection and inner retinal thickness in a European population. These findings will contribute to further understanding of the pathogenesis of COVID-19 and stimulate improvements in treatment modalities.

Abstract Dysregulation of wild-type p53 turnover is a key cause of hepatocellular carcinoma (HCC), yet its mechanism remains poorly understood. Here, we report that WD repeat and SOCS box containing protein 2 (WSB2), an E3 ubiquitin ligase, is an independent adverse prognostic factor in HCC patients. WSB2 drives HCC tumorigenesis and lung metastasis in vitro and in vivo. Mechanistically, WSB2 is a new p53 destabilizer that promotes K48-linked p53 polyubiquitination at the Lys291 and Lys292 sites in HCC cells, leading to p53 proteasomal degradation. Degradation of p53 causes IGFBP3-dependent AKT/mTOR signaling activation. Furthermore, WSB2 was found to bind to the p53 tetramerization domain via its SOCS box domain. Targeting mTOR with everolimus, an oral drug, significantly blocked WSB2-triggered HCC tumorigenesis and metastasis in vivo. In clinical samples, high expression of WSB2 was associated with low wild-type p53 expression and high p-mTOR expression. These findings demonstrate that WSB2 is overexpressed and degrades wild-type p53 and then activates the IGFBP3-AKT/mTOR axis, leading to HCC tumorigenesis and lung metastasis, which indicates that targeting mTOR could be a new therapeutic strategy for HCC patients with high WSB2 expression and wild-type p53.

Senescent chondrocytes or signaling mechanisms leading to senescence are promising new therapeutic approaches for ameliorating cartilage degradation. Herein, we show that the transactive response DNA/RNA-binding protein (TDP-43) regulates chondrocyte senescence and ameliorates cartilage degradation. First, a significant decrease in TDP-43 was observed in 16-month-old mice compared with younger mice. Immunohistochemistry (IHC) analysis of mouse articular cartilage showed that p21, p16, p53, and matrix metalloprotein-13 (MMP13) were increased, but laminB1 and Collagen type II alpha1 1 chain (Col2a1) were decreased in 16-month-old mice. Furthermore, TDP-43 levels were decreased in vivo following D-galactose (D-gal) induction. Therefore, we investigated the role of TDP-43 in the senescent chondrocytes. ATDC5 cells were induced to overexpress TDP-43. Western blot analysis showed increased expression of laminB1, Ki67, and PCNA but decreased expression of p21, p16, p53, and MMP13. Senescence-associated-β-galactosidase (SA-β-Gal) assay, γH2AX staining, and EdU were performed to assess changes in chondrocytes, showing weaker SA-β-Gal and γH2AX staining but stronger EdU and Alican Blue staining. However, TDP-43 deficiency had opposing effects, and similar to D-gal stimulation results. Taken together, our data verified that TDP-43 negatively correlated with senescence markers, positively correlated with cell proliferation markers, and could alleviate cartilage degradation induced by D-gal. This may be an essential mechanism of cellular senescence and cartilage degradation.

Background Single nucleotide polymorphisms (SNPs), as the most abundant form of DNA variation in the human genome, contribute to age-related cataracts (ARC) development. Apoptosis of lens epithelial cells (LECs) is closely related to ARC formation. Insulin-like growth factor 1 (IGF1) contributes to cell apoptosis regulation. Moreover, IGF1 was indicated to exhibit a close association with cataract formation. Afterward, an investigation was conducted to examine the correlation between polymorphisms in IGF1 and the susceptibility to ARC. Methods The present investigation was a case-control study. Venous blood draws were collected from the participants for DNA genotyping. Lens capsule samples were collected to detect mRNA and apoptosis. TaqMan RT-PCR was used to detect IGF1 polymorphism genotypes and qRT PCR was used to detect IGF1 mRNA levels in LECs. LEC apoptosis was evaluated through flow cytometry. The chi-square test was used to compare differences between ARCs and controls of each SNP. Results We found that the G allele frequency in the IGF1-rs6218 was higher in the ARCs than in the controls. Furthermore, it was observed that the rs6218 GG genotype exhibited a positive correlation to elevated levels of IGF1 mRNA in LECs. The IGF1 mRNA in the LECs and the apoptosis of LECs in nuclear type of ARCs (ARNC) was higher than the controls. Conclusion The susceptibility to ARC was related to IGF1-rs6218 polymorphism, and this polymorphism is associated with IGF1 expression at the mRNA level. Moreover, apoptosis in LECs of ARNCs was found to be increased.

Diabetic kidney disease (DKD) is leading causes and one of the fastest growing causes of chronic kidney disease worldwide, and leads to high morbidity and mortality. Emerging evidences have revealed gut microbiota dysbiosis and related metabolism dysfunction play a dominant role in DKD progression and treatment through modulating inflammation. Our previous studies showed that Tangshen Formula (TSF), a Chinese herbal prescription, exhibited anti-inflammatory effect on DKD, but underlying mechanism that involved gut microbiota and related metabolism in aged model remained obscure. Here, BTBR ob/ob mice were used to establish aged DKD model, and 16S rRNA sequence and untargeted metabolomic analyses were employed to investigate the correlation between colonic microbiota and serum metabolism. The aged ob/ob mice exhibited obvious glomerular and renal tubule injury and kidney function decline in kidney, while TSF treatment significantly attenuated these abnormalities. TSF also exhibited potent anti-inflammatory effect in aged ob/ob mice indicating by reduced proinflammatory factor IL-6 and TNF-α, MCP-1 and COX-2 in serum, kidney and intestine, which suggested the involvement of gut microbiota with TSF effect. The 16S rDNA sequencing of the colonic microbiome and untargeted serum metabolomics analysis revealed significant differences in gut microbiota structure and serum metabolomic profiles between WT and ob/ob mice. Notably, TSF treatment reshaped the structure of gut microbiota and corrected the disorder of metabolism especially tryptophan metabolism and arginine biosynthesis. TSF increased Anaeroplasma and Barnesiella genera and decreased Romboutsia, Akkermansia, and Collinsella genera, and further elevated tryptophan, 5-hydroxyindoleacetate, glutamic acid, aspartate and reduced 4-hydroxy-2-quinolinecarboxylic acid, indole-3-acetic acid, xanthurenic acid, glutamine. Further correlation analysis indicated that disturbed gut microbiota was linked to tryptophan metabolism and arginine biosynthesis to regulate inflammation in aged DKD. Our data revealed that TSF attenuated renal inflammation by modulating gut microbiota and related amino acid metabolism in aged DKD model, highlighting gut microbiota and related metabolism functioned as potential therapeutic target for DKD in elderly patients.

Abstract Serum uric acid (SUA) has been discovered to be associated with bone mineral density (BMD), but its relationship with trabecular bone score (TBS) remains unclear. Thus, the aim of our study was to investigate the association between SUA levels and TBS. Our study included 5895 individuals over 20 years old (3061 men and 2834 women) from NHANES 2005–2008. To analyze the association between SUA and TBS, multivariate linear regression models with covariate adjustments were applied. Furthermore, population description, stratified analysis, single factor analysis, smooth curve fitting, interaction analysis, and threshold effect and saturation effect analysis were also conducted. After adjusting for covariates, SUA showed a strong negative relationship with total TBS (β = 0.319; 95% CI 0.145–0.494; P

Abstract This paper proposes the design of a helical hedge flow channel with a high energy loss, which shows promising potential for application in fruit tree root emitters. The aim is to investigate the relationship between the energy loss form in the channel and its influencing factors. The hydraulic performance testing method is employed to analyze the factors that affect energy loss. The main influencing factors are determined using the response surface methodology (RSM) for experimental design. Based on the obtained experimental results, the energy loss form and influencing factors are analyzed, and a prediction model for the energy loss coefficient (ξ) is established. The results indicate that the ξ exhibits a decreasing trend with an increase in the diversion angle (α), a trend of first increasing and then decreasing with an increase in the channel width (b), and an increasing trend with an increase in the number of channel units (n). The effects of the straight section length (l 1), convergence section length (l 2), and bend radius (r) on the ξ can be neglected. The ranking of the geometric parameters' influence on the ξ is as follows: n > b > α > l 1 > r > l 2. The experimental results reveal that the ξ ranges from 19.2 to 234.3. Furthermore, the head loss along the flow channel constitutes merely 0.06–0.47% of the local head loss, The main form of energy loss in the spiral counter flow channel is local head loss. There is a significant linear relationship between α, b, n and the ξ, The established prediction model (R2 = 0.9691) can accurately predict the ξ of the channel.

Abstract The dimension of the void area in pavement is crucial to its structural safety. However, there is no effective method to measure its geometric parameters. To address this issue, a void size extraction algorithm based on the continuous wavelet transform (CWT) method was proposed using ground-penetrating radar (GPR) signal. Firstly, the finite-difference time-domain (FDTD) method was used to investigate the GPR response of void areas with different shapes, sizes, and depths. Next, the GPR signal was processed using the CWT method, and a 3D image based on the CWT result was used to visualize the void area. Based on the differences between the void and normal pavement in the time and frequency domains, the signal with maximum energy from the CWT time–frequency result was extracted and combined to reconstruct the new B-scan image, where void areas have energy concentration phenomenon. Based on this, width and depth of void detection algorithm was proposed to recognize the void area. Finally, the detection algorithm was verified both in numerical model and physical lab model. The results indicated that the CWT time–frequency energy spectrum can be used to enhance the void feature, and the 3D CWT image can clearly visualize the void area with a highlighted energy area. After fully testing and validating in numerical and lab models, our proposed method achieved high accuracy in void width and depth detection, providing a precise method for estimating void dimension in pavement. This method can guide DOT departments to carry out pre-maintenance, thereby ensuring pavement safety.

Abstract Background Emerging metabolomics-based studies suggested links between amino acid metabolism and metabolic dysfunction-associated fatty liver disease (MAFLD) risk; however, whether there exists an aetiological role of amino acid metabolism in MAFLD development remains unknown. The aim of the present study was to assess the causal relationship between circulating levels of amino acids and MAFLD risk. Methods We conducted a two-sample Mendelian randomization (MR) analysis using summary-level data from genome-wide association studies (GWAS) to evaluate the causal relationship between genetically predicted circulating levels of amino acids and the risk of MAFLD. In the discovery MR analysis, we used data from the largest MAFLD GWAS (8434 cases and 770,180 controls), while in the replication MR analysis, we used data from a GWAS on MAFLD (1483 cases and 17,781 controls) where MAFLD cases were diagnosed using liver biopsy. We used Wald ratios or inverse variance-weighted (IVW) methods in the MR main analysis and weighted median and MR-Egger regression analyses in sensitivity analyses. Furthermore, we performed a conservative MR analysis by restricting genetic instruments to those directly involved in amino acid metabolism pathways. Results We found that genetically predicted higher alanine (OR = 1.43, 95% CI 1.13–1.81) and lower glutamine (OR = 0.83, 95% CI 0.73–0.96) levels were associated with a higher risk of developing MAFLD based on the results from the MR main and conservative analysis. The results from MR sensitivity analyses and complementary analysis using liver proton density fat fraction as a continuous outcome proxying for MAFLD supported the main findings. Conclusions Novel causal metabolites related to MAFLD development were uncovered through MR analysis, suggesting future potential for evaluating these metabolites as targets for MAFLD prevention or treatment.

Abstract To construct an injectable fibrin glue system loaded with kaempferol (FG@F) to improve the bioavailability of kaempferol and observe its efficacy in the treatment of intervertebral disc degeneration (IVDD). Kaempferol-loaded fibrin glue was first synthesized in advance. Subsequently, the materials were characterized by various experimental methods. Then, nucleus pulposus cells (NPCs) were stimulated with lipopolysaccharide (LPS) to establish a degenerative cell model, and the corresponding intervention treatment was conducted to observe the effect in vitro. Finally, the tail disc of rats was punctured to establish a model of IVDD, and the therapeutic effect of the material in vivo was observed after intervertebral disc injection. The FG@F system has good injectability, sustained release and biocompatibility. This treatment reduced the inflammatory response associated with IVDD and regulated matrix synthesis and degradation. Animal experimental results showed that the FG@F system can effectively improve needle puncture-induced IVDD in rats. The FG@F system has better efficacy than kaempferol or FG alone due to its slow release and mechanical properties. The drug delivery and biotherapy platform based on this functional system might also serve as an alternative therapy for IVDD.

Prevalence of carbapenem-resistant Klebsiella pneumoniae (CRKP) has compromised antimicrobial efficacy against severe infections worldwide. To monitor global spread, we conducted a comprehensive genomic epidemiologic study comparing sequences from 21 blaOXA-232–carrying CRKP isolates from China with K. pneumoniae sequence type (ST) 15 strains from 68 countries available in GenBank. Phylogenetic and phylogeographic analyses revealed all blaOXA-232–carrying CRKP isolates belonged to ST15 lineage and exhibited multidrug resistance. Analysis grouped 330 global blaOXA-232–carrying ST15 CRKP strains into 5 clades, indicating clonal transmission with small genetic distances among multiple strains. The lineage originated in the United States, then spread to Europe, Asia, Oceania, and Africa. Most recent common ancestor was traced back to 2000; mutations averaged ≈1.7 per year per genome. Our research helps identify key forces driving global spread of blaOXA-232–carrying CRKP ST15 lineage and emphasizes the importance of ongoing surveillance of epidemic CRKP.

Abstract Background Several observational studies have suggested an association between low serum bilirubin levels and Behçet's disease uveitis. However, the causal inference between bilirubin level and juvenile idiopathic arthritis‐associated uveitis (JIAU) remains ambiguous. We investigated the potential causal relationship between serum bilirubin levels and JIAU using a bidirectional two‐sample Mendelian randomization (MR) framework. Methods We systemically integrated summary‐level data from published large‐scale genome‐wide association studies on bilirubin level and JIAU in a Caucasian British population. To determine the causal effect of bilirubin level on JIAU, we constructed strong instrumental variables using 47 and 80 single‐nucleotide polymorphisms (SNPs) specific to direct bilirubin and total bilirubin levels, respectively. For reverse causal inference, seven SNPs associated with JIAU were included in our study. Multiple complementary methods were further performed to evaluate the robustness of MR estimates. Results The inverse‐variance weighted estimate did not show any significant causal associations of genetically predicted serum direct or total bilirubin level with the risk of JIAU (odds ratio [OR]: 1.010, 95% confidence interval [CI]: 0.750–1.359, p = 0.947; OR: 0.867, 95% CI: 0.688–1.093; p = 0.227, respectively). MR–Egger and weighted median methods also obtained similar associations. Additionally, the results of reverse MR analyses using JIAU as exposure showed no associations of genetically predicted risk of JIAU with serum bilirubin levels (p > 0.05). In sensitivity analysis, the causal estimate between serum bilirubin levels and JIAU did not differ when SNPs associated with possible confounders were omitted. Conclusion Genetic evidence from our bidirectional analysis did not support a causal association between serum bilirubin levels and JIAU risk in the Caucasian British population. Future large‐scale studies should be conducted to validate these findings and explore any causal effects on the disease process.

Introduction Postoperative sleep disturbances significantly impair postoperative recovery. The administration of intravenous esketamine has been shown to potentially improve postoperative sleep quality. However, the effectiveness of epidural esketamine in improving postoperative sleep quality remains to be elucidated. This study aims to explore the impact of both intraoperative and postoperative use of epidural esketamine on the postoperative sleep quality of patients undergoing minimally invasive lower abdominal surgeries.Methods and analysis This randomised, double-blind, parallel-group, placebo-controlled trial will be conducted at the Fudan University Shanghai Cancer Centre. A total of 128 adults undergoing minimally invasive lower abdominal surgeries will be randomly allocated in a 1:1 ratio to either the esketamine group or the placebo group. In the esketamine group, epidural esketamine will be administered intraoperatively (0.2 mg/kg) and postoperatively (25 mg). Postoperatively, all patients will receive epidural analgesia. The primary outcome of the study is the incidence of poor sleep quality on the third day after surgery. The sleep quality assessment will be conducted using the Pittsburgh Sleep Quality Index and a Numeric Rating Scale of sleep. The main secondary outcomes include postoperative pain and anxiety and depression scores. The postoperative pain, both rest pain and movement pain, will be assessed using a Numerical Rating Scale within 5 days after surgery. Anxiety and depression scores will be evaluated using the Hospital Anxiety and Depression Scale both before and after the surgery. Safety outcomes will include delirium, fidgeting, hallucinations, dizziness and nightmares. The analyses will be performed in accordance with intention-to-treat principleEthics and dissemination Ethics approval has been obtained from the Ethics Committee of the Shanghai Cancer Centre (2309281-9). Prior to participation, all patients will provide written informed consent. The results of the trial are intended to be published in a peer-reviewed journal.Trial registration number ChiCTR2300076862.

Background Chronic post-surgical pain (CPSP) is one of the important causes of poor postoperative outcomes, the activation of microglia in the spinal cord is closely related to the generation, transmission and maintenance of CPSP. Xenon (Xe), an anesthetic gas, has been reported to be able to significantly reduce intraoperative analgesia and postoperative pain sensation at low doses. However, the mechanism of the regulatory effect of xenon on activated microglia after CPSP remains unclear. Methods In this study, CPSP model rats were treated with 50% Xe inhalation for 1 h following skin/muscle incision and retraction (SMIR), once a day for 5 consecutive days, and then the painbehavioraltests (pain behavior indexes paw withdrawal mechanical threshold, PWMT and thermal withdrawal latency, TWL), microglial activation, oxidative stress-related indexes (malondialdehyde, MDA; superoxide dismutase, SOD; hydrogen peroxide, H2O2; and catalase, CAT), mitophagy and PINK1/Parkin pathway were examined. Results The present results showed that a single dose of Xe treatment in SMIR rat model could significantly improve PWMT and TWL in the short-term at a single treatment and long-term at multiple treatments. Xe treatment inhibited microglia activation and oxidative stress in the spinal dorsal horn of SMIR rats, as indicated by the decrease of Iba1 and MDA/H2O2 levels and the increase of SOD/CAT levels. Compared with the control group, Xe further increased the CPSP promoted Mito-Tracker (a mitochondrial marker) and LC3 (an autophagy marker) co-localization positive spots and PINK1/Parkin/ATG5/BECN1 (autophagy-related proteins) protein expression levels, and inhibited the Mito-SOX (a mitochondrial reactive oxygen species marker) positive signal, indicating that Xe promoted microglia mitophagy and inhibited oxidative stress in CPSP. Mechanistically, we verified that Xe promoted PINK1/Parkin signaling pathway activation. Conclusion Xe plays a role in ameliorating chronic post-surgical pain by regulating the PINK1/Parkin pathway mediated microglial mitophagy and provide new ideas and targets for the prevention and treatment of CPSP.

BackgroundThe increasing prevalence of nonalcoholic fatty liver disease (NAFLD) in China presents a significant public health concern. Traditional ultrasound, commonly used for fatty liver screening, often lacks the ability to accurately quantify steatosis, leading to insufficient follow-up for patients with moderate-to-severe steatosis. Transient elastography (TE) provides a more quantitative diagnosis of steatosis and fibrosis, closely aligning with biopsy results. Moreover, machine learning (ML) technology holds promise for developing more precise diagnostic models for NAFLD using a variety of laboratory indicators. ObjectiveThis study aims to develop a novel ML-based diagnostic model leveraging TE results for staging hepatic steatosis. The objective was to streamline the model’s input features, creating a cost-effective and user-friendly tool to distinguish patients with NAFLD requiring follow-up. This innovative approach merges TE and ML to enhance diagnostic accuracy and efficiency in NAFLD assessment. MethodsThe study involved a comprehensive analysis of health examination records from Suzhou Municipal Hospital, spanning from March to May 2023. Patient data and questionnaire responses were meticulously inputted into Microsoft Excel 2019, followed by thorough data cleaning and model development using Python 3.7, with libraries scikit-learn and numpy to ensure data accuracy. A cohort comprising 978 residents with complete medical records and TE results was included for analysis. Various classification models, including logistic regression (LR), k-nearest neighbor (KNN), support vector machine (SVM), random forest (RF), light gradient boosting machine (LightGBM), and extreme gradient boosting (XGBoost), were constructed and evaluated based on the area under the receiver operating characteristic curve (AUROC). ResultsAmong the 916 patients included in the study, 273 were diagnosed with moderate-to-severe NAFLD. The concordance rate between traditional ultrasound and TE for detecting moderate-to-severe NAFLD was 84.6% (231/273). The AUROC values for the RF, LightGBM, XGBoost, SVM, KNN, and LR models were 0.91, 0.86, 0.83, 0.88, 0.77, and 0.81, respectively. These models achieved accuracy rates of 84%, 81%, 78%, 81%, 76%, and 77%, respectively. Notably, the RF model exhibited the best performance. A simplified RF model was developed with an AUROC of 0.88, featuring 62% sensitivity and 90% specificity. This simplified model used 6 key features: waist circumference, BMI, fasting plasma glucose, uric acid, total bilirubin, and high-sensitivity C-reactive protein. This approach offers a cost-effective and user-friendly tool while streamlining feature acquisition for training purposes. ConclusionsThe study introduces a groundbreaking, cost-effective ML algorithm that leverages health examination data for identifying moderate-to-severe NAFLD. This model has the potential to significantly impact public health by enabling targeted investigations and interventions for NAFLD. By integrating TE and ML technologies, the study showcases innovative approaches to advancing NAFLD diagnostics.

Background. An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic occurred throughout China from December 2022 to January 2023, and the vast majority of those infected individuals were mild. The symptom characteristics of mildly infected individuals in this epidemic wave of the Omicron variant have not been well described. Methods. We conducted a nationwide survey of symptomatic characteristics of nonhospitalized individuals with mild Omicron infection through a WeChat app. Results. Respondents (68.6% female) were aged 18–87 years (42.6 ± 13.1 years), of whom 79.8% were diagnosed by SARS-CoV-2 PCR or antigen test. Of the 19 symptoms predefined in the questionnaire, an average of 7.8 symptoms was reported. The most common symptoms included cough (81.2%), fever (79.9%), fatigue (73.8%), muscle soreness (62.2%), headache (59.2%), and phlegm (55.1%). Painful swallowing was present in 38.3% of the participants and was one of the most severe symptoms perceived by the participants. Also, we found that young people were more likely to have symptoms such as fever, painful swallowing, and headache compared to the elderly population. 36.9% of respondents graded their symptoms as severe, and the severity of symptoms was higher in young people than in older adults, with fever, cough, painful swallowing, fatigue, and headache being the most severe. In addition, women experienced a significantly higher prevalence of symptoms than men, but there was no significant difference in the severity of most symptoms. The presence of comorbidities did not increase the incidence or severity of symptoms in those with mildly infected individuals. Conclusions. The symptom profile of mild COVID-19 cases in the nationwide Omicron wave in China was markedly different from previous reports, featuring a high incidence of symptoms, multiple symptoms, and heavy symptoms. The symptoms of mild Omicron infection cases are not mild and are more pronounced in young people.

Genike, the imatinib (IM)-alpha form is widely used in the treatment of gastrointestinal stromal tumor (GIST) patients in China. We wanted to investigate whether there are differences in IM plasma concentrations, adverse events, health-related quality of life (QOL) and outcomes between patients treated with Genike and Glivec. Thirty included GIST patients receiving IM treatment were matched to either Genike or Glivec according to gastrectomy, body weight, body surface area and sex. There was no statistically significant difference in IM trough plasma levels between the two groups. There were no significant differences in very common adverse events of IM between the Genike and Glivec groups. IM was well tolerated, although it was associated with a significant change in cognitive function (P < 0.001), fatigue (P = 0.015), pain (P = 0.015), nausea/vomiting (P = 0.029), insomnia (P = 0.019), diarrhea (P = 0.003) and financial difficulties (P < 0.001). Physical functioning, financial burden and insomnia were significantly different between the two groups (P = 0.026). Until Aug. 2022, there was no significant difference in time to imatinib treatment failure (TTF) between the two groups. In conclusion, there was no difference in IM plasma concentration and adverse events between Genike and Glivec. Both Genike and Glivec could partially decrease the QOL of GIST patients. Physical functioning was worse in Genike group than in Glivec group, while the economic burden and symptoms of insomnia in Glivec patients were worse. There was no significant difference in TTF between the two groups.

BackgroundNonalcoholic fatty liver disease (NAFLD) is strongly associated with type 2 diabetes mellitus (T2DM). Lifestyle intervention remains a preferred treatment modality for NAFLD. The glucagon-like peptide (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been developed as new glucose-lowering drugs, which can improve fatty liver via an insulin-independent glucose-lowering effect. However, studies exploring the efficacy of GLP-1 receptor agonists combined with SGLT-2 inhibitors in patients with NAFLD and T2DM are scanty. Thus, the present randomised controlled trial aims at comparing the efficacy and safety of semaglutide plus empagliflozin with each treatment alone in patients with NAFLD and T2DM.MethodsThis 52-week double-blinded, randomised, parallel-group, active-controlled trial evaluates the effects of semaglutide, empagliflozin and semaglutide + empagliflozin in 105 eligible overweight/obese subjects with NAFLD and T2DM. The primary outcome will be a change from baseline to week 52 in the controlled attenuation parameter, free fatty acid and glucagon. Secondary endpoints include changes in liver stiffness measurement, liver enzymes, blood glucose, lipid levels, renal function, electrolyte balances, minerals and bone metabolism, cytokines, high-sensitivity C-reactive protein, ferritin, anthropometric indicators, nonalcoholic fatty liver fibrosis score, fibrosis 4 score and homeostatic model assessment for insulin resistance. In addition, intention-to-treat, interim analysis and safety analysis will be performed.DiscussionThis double-blinded, randomised, clinical trial involves a multi-disciplinary approach and aims to explore the synergistic effects of the combination of semaglutide and empagliflozin. The results can provide important insights into mechanisms of GLP-1 receptor agonists and/or SGLT-2 inhibitors in patients with NAFLD and T2DM.Trial registrationThis study has been registered with Chinese Clinical Trial Registry (ChiCTR2300070674).

Objectives To depict the seasonality and age variations of community-acquired pneumonia (CAP) incidence in the context of the COVID-19 impact.Design Retrospective cohort study.Participants The observational cohort study was conducted at Soochow University Affiliated Children’s Hospital from January 2017 to June 2021 and involved 132 797 children born in 2017 or 2018. They were followed and identified CAP episodes by screening on the Health Information Systems of outpatients and inpatients in the same hospital.Outcome The CAP episodes were defined when the diagnoses coded as J09–J18 or J20–J22. The incidence of CAP was estimated stratified by age, sex, birth year, health status group, season and month, and the rate ratio was calculated and adjusted by a quasi-Poisson regression model. Stratified analysis of incidence of CAP by birth month was conducted to understand the age and seasonal variation.Results The overall incidence of CAP among children aged ≤5 years was 130.08 per 1000 person years. Children aged ≤24 months have a higher CAP incidence than those aged >24 months (176.84 vs 72.04 per 1000 person years, p