The Intersection of cerebral cholesterol metabolism and Alzheimer's disease: Mechanisms and therapeutic prospects.

Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly, the exact pathogenesis of which remains incompletely understood, and effective preventive and therapeutic drugs are currently lacking. Cholesterol plays a vital role in cell membrane formation and neurotransmitter synthesis, and its abnormal metabolism is associated with the onset of AD. With the continuous advancement of imaging techniques and molecular biology methods, researchers can more accurately explore the relationship between cholesterol metabolism and AD. Elevated cholesterol levels may lead to vascular dysfunction, thereby affecting neuronal function. Additionally, abnormal cholesterol metabolism may affect the metabolism of ß-amyloid protein, thereby promoting the onset of AD. Brain cholesterol levels are regulated by multiple factors. This review aims to deepen the understanding of the subtle relationship between cholesterol homeostasis and AD, and to introduce the latest advances in cholesterol-regulating AD treatment strategies, thereby inspiring readers to contemplate deeply on this complex relationship. Although there are still many unresolved important issues regarding the risk of brain cholesterol and AD, and some studies may have opposite conclusions, further research is needed to enrich our understanding. However, these findings are expected to deepen our understanding of the pathogenesis of AD and provide important insights for the future development of AD treatment strategies targeting brain cholesterol homeostasis.

Decoding the impact of fiscal decentralization on urban pollution intensity in China: A spatial econometric analysis.

Utilizing city-level data from China, the paper employs a spatial econometric analysis to investigate the impact of fiscal decentralization on urban pollution. Empirical evidence indicates: (1) In the context of the emphasis of ecological civilization construction in China, an increase of fiscal autonomy for local governments is conducive to mitigating urban pollution intensity. Specifically, fiscal decentralization in one city not only promotes a reduction in local pollution intensity but alleviates environmental pollution problems in adjacent cities through spatial spillover effects. (2) Industrial structure upgrading and green technology progress become crucial measures for local governments to realize pollution reduction targets through fiscal expenditure. (3) Heterogeneity analysis reveals that the positive significance of decentralization is most prominent in the eastern China, while local governments with fiscal autonomy in central region tend to transfer pollution to neighboring cities. (4) There is a threshold characteristic for fiscal decentralization to promote a reduction in urban pollution intensity, and its marginal effect becomes more significant accompanied by continuous introduction of sophisticated foreign direct investment. Finally, the paper summarizes the potential significance of fiscal decentralization among Chinese local governments against the background of "Chinese-style decentralization" and proposes corresponding policy recommendations.

Discovery and genetic characterization of novel paramyxoviruses from small mammals in Hubei Province, Central China.

Paramyxoviruses are a group of single-stranded, negative-sense RNA viruses, some of which are responsible for acute human disease, including parainfluenza virus, measles virus, Nipah virus and Hendra virus. In recent years, a large number of novel paramyxoviruses, particularly members of the genus Jeilongvirus, have been discovered in wild mammals, suggesting that the diversity of paramyxoviruses may be underestimated. Here we used hemi-nested reverse transcription PCR to obtain 190 paramyxovirus sequences from 969 small mammals in Hubei Province, Central China. These newly identified paramyxoviruses were classified into four clades: genera Jeilongvirus, Morbillivirus, Henipavirus and Narmovirus, with most of them belonging to the genus Jeilongvirus. Using Illumina sequencing and Sanger sequencing, we successfully recovered six near-full-length genomes with different genomic organizations, revealing the more complex genome content of paramyxoviruses. Co-divergence analysis of jeilongviruses and their known hosts indicates that host-switching occurred more frequently in the evolutionary histories of the genus Jeilongvirus. Together, our findings demonstrate the high prevalence of paramyxoviruses in small mammals, especially jeilongviruses, and highlight the diversity of paramyxoviruses and their genome content, as well as the evolution of jeilongviruses.

Serum klotho associated with thyroid hormone in adults: A population-based cross-sectional research.

BACKGROUND AND STUDY AIM: The klotho protein, a multifunctional protein, has been shown to be associated with a wide range of endocrine diseases and has been linked to thyroid tumourigenesis. However, the relationship between serum klotho levels and thyroid hormones remains poorly understood. This study aimed to explore the correlation between serum klotho levels and thyroid hormones. METHODS: Data was obtained from the NHANES cycles 2007-2008, 2009-2010, and 2011-2012. A total of 4674 participants were recruited for this study. Statistical analysis was using multiple linear regression analyses, and restricted cubic spline plots (RCS) to investigate the association between serum klotho levels and serum levels of thyroid hormones. RESULTS: In the unadjusted covariate model, ln(klotho) significantly positively correlated with tT3, tT4, fT3, tT4/fT4, and tT3/fT3 (all P<0.01) and negatively correlated with TSH, tT4/tT3, and fT4/fT3 (all P<0.05). Furthermore, tT3, tT4, fT3and tT3/fT3 (P < 0.05) were still significant in the adjusted model. And it is worth noting that there is an approximately L-shaped nonlinear relationship between ln(klotho) and fT3,tT3 with a cut-off point of 6.697 (P-non-linear < 0.05). The stratification analysis showed gender and iodine level differences in the relationship between serum Klotho levels and thyroid hormones. CONCLUSION: There is an L-shaped nonlinear relationship between ln(klotho) and fT3, tT3, suggesting that klotho could be involved in the physiological regulation of thyroid function.

Effects of electroacupuncture on treatment-resistant chronic migraine with medication overuse headache: A 12-month follow-up case report.

Background: Medication overuse headache (MOH) is a secondary headache disorder that leads to pronounced disability and decreased quality of life. Available therapeutic options for MOH are limited, and many are only effective in a subset of individuals. Although the existing evidence is limited, acupuncture may be an effective treatment option for MOH. Case presentation: A 45-year-old Chinese woman presented to the Medical Acupuncture Department of Sanming Integrated Traditional Chinese and Western Medicine Hospital on April 11, 2022. Thirty-five years ago, she had episodic migraines. The frequency increased over time, however, and for the past 10 years she has had daily headaches. These headaches were characterized by daily persistent throbbing pain on the left side of the patient's head, accompanied by photophobia, phonophobia, neck stiffness, dizziness, and fatigue. Without painkillers, the patient rated her headache intensity as 9 out of 10 on a visual analog scale (0 = no pain, 10 = intolerable pain), and reported that the headaches lasted for up to 7 days or more. With painkillers, the headaches had a reduced intensity (5 of 10), but persisted. The patient had taken 1-3.5 compound aminopyrine phenacetin tablets daily for more than 5 years. Standard conservative therapy (patient education, medication withdrawal, and behavioral intervention) for MOH had failed to improve her symptoms. Before her visit, the patient had headache and engaged in short-term medication use on 30 days per month. The total monthly headache intensity score was 90. The patient's Migraine-Specific Quality of Life Questionnaire (MSQ) score was 33 points, her Hamilton Depression Scale (HAMD) score was 24 points, and her Hamilton Anxiety Scale (HAMA) score was 20 points. Results: After 48 acupuncture sessions over 24 weeks, the patient completely discontinued short-term analgesic use and the monthly number of headache days and headache intensity score were both reduced by 96.67 % (from 30 to 1 and 90 to 3, respectively), with no adverse effect. Compared with baseline, the MSQ, HAMD, and HAMA scores improved by 45, 17, and 16 points, respectively. At 12 months, the patient's condition remained stable and her MOH had not relapsed. Conclusion: In the context of the current literature and the present case, electroacupuncture shows promise for the long-term relief of chronic migraine with MOH when other treatments fail.

Classification and transfer learning of sleep spindles based on convolutional neural networks.

Background: Sleep plays a critical role in human physiological and psychological health, and electroencephalography (EEG), an effective sleep-monitoring method, is of great importance in revealing sleep characteristics and aiding the diagnosis of sleep disorders. Sleep spindles, which are a typical phenomenon in EEG, hold importance in sleep science. Methods: This paper proposes a novel convolutional neural network (CNN) model to classify sleep spindles. Transfer learning is employed to apply the model trained on the sleep spindles of healthy subjects to those of subjects with insomnia for classification. To analyze the effect of transfer learning, we discuss the classification results of both partially and fully transferred convolutional layers. Results: The classification accuracy for the healthy and insomnia subjects' spindles were 93.68% and 92.77%, respectively. During transfer learning, when transferring all convolutional layers, the classification accuracy for the insomnia subjects' spindles was 91.41% and transferring only the first four convolutional layers achieved a classification result of 92.80%. The experimental results demonstrate that the proposed CNN model can effectively classify sleep spindles. Furthermore, the features learned from the data of the normal subjects can be effectively applied to the data for subjects with insomnia, yielding desirable outcomes. Discussion: These outcomes underscore the efficacy of both the collected dataset and the proposed CNN model. The proposed model exhibits potential as a rapid and effective means to diagnose and treat sleep disorders, thereby improving the speed and quality of patient care.

Prognostic value of postoperative anti-thyroglobulin antibody in patients with differentiated thyroid cancer.

Purpose: Postoperative thyroglobulin (Tg) generally serves as a biomarker to monitor the recurrence or persistence of differentiated thyroid cancer (DTC), whereas it constrains to interference from anti-thyroglobulin antibody (TgAb). This study aimed to determine the value of postoperative TgAb as a surrogate for monitoring tumor status in DTCs with positive TgAb after successful radioactive iodine (RAI) remnant ablation. Methods: We retrospectively enrolled DTC patients with positive (≥40 IU/mL, Roche) postoperative TgAb measurements. An index of TgAb change (ΔTgAb) was defined to describe the TgAb decrease rate. DTC status was defined as either no evidence of disease (NED) or persistent/recurrent disease (PRD). Univariate and multivariate binary logistic analyses were used to identify the independent risk factors of PRD. Receiver operating characteristic (ROC) curves were performed to determine the optimal cutoff values of each risk factor, and DeLong's test was conducted to compare their predictive powers. Kaplan-Meier curves were used to assess the impact of different TgAb trends in the first year on progression-free survival. Results: Of the 232 patients enrolled, the median diagnosis age was 34 years (range, 18-62 years), with a male-to-female ratio of 1:4.66 (41/191). Among them, after a median follow-up of 44 months (range, 4-128 months),183 (78.87%) patients were evaluated as NED, while the other 49 (21.12%) had either persistent (n = 25) or recurrent disease (n = 24). Multivariate regression showed that ΔTgAb (P < 0.001) and lymph node metastasis (LNM) rate (P = 0.009) were independently relevant to the presence of PRD, with optimal cutoff values of 47.0% and 35.1%, respectively. It is important to note that there is a high negative predictive value (96.93%) of ΔTgAb with the cutoff of 47.0%. DeLong's test showed that ΔTgAb alone and the combination of ΔTgAb and LNM rate were significantly greater than the isolated LNM rate (both P < 0.001) in predicting NED, while there was no statistical difference of the predictive power between ΔTgAb and the combination (P = 0.203). Additionally, patients with ΔTgAb >47.0% had longer progression-free survival than those with ΔTgAb ≤47.0% (not reached vs. 50 months, P < 0.001), and those with ΔTgAb >47.0% or negative conversion within the first year after RAI ablation had longer progression-free survival. Conclusion: Our study suggested that ΔTgAb could serve as a valuable indicator of disease status in DTC patients with positive TgAb. A ΔTgAb of >47.0% is conducive to identify those with NED and may help to obviate their overtreatment. The decrease rate and negative conversion of TgAb in the first year were good predictors of disease-free survival in patients.

Associations between maternal exposure to multiple metals and metalloids and blood pressure in preschool children: A mixture-based approach.

BACKGROUND: Exposure to metals during pregnancy can potentially influence blood pressure (BP) in children, but few studies have examined the mixed effects of prenatal metal exposure on childhood BP. We aimed to assess the individual and combined effects of prenatal metal and metalloid exposure on BP in preschool children. METHODS: A total of 217 mother-child pairs were selected from the Zhuang Birth Cohort in Guangxi, China. The maternal plasma concentrations of 20 metals [e.g. lead (Pb), rubidium (Rb), cesium (Cs), and zinc (Zn)] in early pregnancy were measured by inductively coupled plasmamass spectrometry. Childhood BP was measured in August 2021. The effects of prenatal metal exposure on childhood BP were explored by generalized linear models, restricted cubic spline and Bayesian kernel machine regression (BKMR) models. RESULTS: In total children, each unit increase in the log10-transformed maternal Rb concentration was associated with a 10.82-mmHg decrease (95% CI: -19.40, -2.24) in childhood diastolic BP (DBP), and each unit increase in the log10-transformed maternal Cs and Zn concentrations was associated with a 9.67-mmHg (95% CI: -16.72, -2.61) and 4.37-mmHg (95% CI: -8.68, -0.062) decrease in childhood pulse pressure (PP), respectively. The log10-transformed Rb and Cs concentrations were linearly related to DBP (P nonlinear=0.603) and PP (P nonlinear=0.962), respectively. Furthermore, an inverse association was observed between the log10-transformed Cs concentration and PP (ß =-12.18; 95% CI: -22.82, -1.54) in girls, and between the log10-transformed Rb concentration and DBP (ß =-12.54; 95% CI: -23.87, -1.21) in boys, while there was an increasing association between the log10-transformed Pb concentration and DBP there was an increasing in boys (ß =6.06; 95% CI: 0.36, 11.77). Additionally, a U-shaped relationship was observed between the log10-transformed Pb concentration and SBP (P nonlinear=0.015) and DBP (P nonlinear=0.041) in boys. Although there was no statistically signiffcant difference, there was an inverse trend in the combined effect of maternal metal mixture exposure on childhood BP among both the total children and girls in BKMR. CONCLUSIONS: Prenatal exposure to both individual and mixtures of metals and metalloids influences BP in preschool children, potentially leading to nonlinear and sex-specific effects.

The impact of nursing interventions on the rehabilitation outcome of patients after lumbar spine surgery.

BACKGROUND: This study aimed to investigate the impact of nursing interventions on the rehabilitation outcomes of patients after lumbar spine surgery and to provide effective references for future postoperative care for patients undergoing lumbar spine surgery. METHODS: The study included two groups: a control group receiving routine care and an observation group receiving additional comprehensive nursing care. The comprehensive care encompassed postoperative rehabilitation, pain, psychological, dietary management, and discharge planning. The Visual Analogue Scale (VAS), Oswestry Disability Index (ODI), Short-Form 36 (SF-36) Health Survey, self-rating depression scale (SDS) and self-rating anxiety scale(SAS) were used to assess physiological and psychological recovery. Blood albumin, haemoglobin, neutrophil counts, white blood cell counts, red blood cell counts, inflammatory markers (IL-6, IL-10, and IFN-γ) were measured, and the incidence of postoperative adverse reactions was also recorded. RESULTS: Patients in the observation group exhibited significantly improved VAS, ODI, SF-36, SDS and SAS scores assessments post-intervention compared to the control group (P < 0.05). Moreover, levels of IL-6, IL-10, and IFN-γ were more favorable in the observation group post-intervention (P < 0.05), indicating a reduction in inflammatory response. There was no significant difference in the incidence of postoperative adverse reactions between the groups (P > 0.05), suggesting that the comprehensive nursing interventions did not increase the risk of adverse effects. CONCLUSION: Comprehensive nursing interventions have a significant impact on the postoperative recovery outcomes of patients with LSS, alleviating pain, reducing inflammation levels, and improving the overall quality of patient recovery without increasing the patient burden. Therefore, in clinical practice, it is important to focus on comprehensive nursing interventions for patients with LSS to improve their recovery outcomes and quality of life.

A Multi-Element Identification System Based on Deep Learning for the Visual Field of Percutaneous Endoscopic Spine Surgery.

Background: Lumbar disc herniation is a common degenerative lumbar disease with an increasing incidence. Percutaneous endoscopic lumbar discectomy can treat lumbar disc herniation safely and effectively with a minimally invasive procedure. However, the learning curve of this technology is steep, which means that initial learners are often not sufficiently proficient in endoscopic operations, which can easily lead to iatrogenic damage. At present, the application of computer deep learning technology to clinical diagnosis, treatment, and surgical navigation has achieved satisfactory results. Purpose: The objective of our team is to develop a multi-element identification system for the visual field of endoscopic spine surgery using deep learning algorithms and to evaluate the feasibility of this system. Method: We established an image database by collecting surgical videos of 48 patients diagnosed with lumbar disc herniation, which was labeled by two spinal surgeons. We selected 6000 images of the visual field of percutaneous endoscopic spine surgery (including various tissue structures and surgical instruments), divided into the training data, validation data, and test data according to 2:1:2. We developed convolutional neural network models based on instance segmentation-Solov2, CondInst, Mask R-CNN and Yolact, and set the four network model backbone as ResNet101 and ResNet50 respectively. Mean average precision (mAP) and frames per second (FPS) were used to measure the performance of each model for classification, localization and recognition in real time, and AP (average) is used to evaluate how easily an element is detected by neural networks based on computer deep learning. Result: Comprehensively comparing mAP and FSP of each model for bounding box test and segmentation task for the test set of images, we found that Solov2 (ResNet101) (mAP = 73.5%, FPS = 28.9), Mask R-CNN (ResNet101) (mAP = 72.8%, FPS = 28.5) models are the most stable, with higher precision and faster image processing speed. Combining the average precision of the elements in the bounding box test and segmentation tasks in each network, the AP(average) was highest for tool 3 (bbox-0.85, segm-0.89) and lowest for tool 5 (bbox-0.63, segm-0.72) in the instrumentation, whereas in the anatomical tissue elements, the fibrosus annulus (bbox-0.68, segm-0.69) and ligamentum flavum (bbox-0.65, segm-0.62) had higher AP(average),while extra-dural fat (bbox-0.42, segm-0.44) was lowest. Conclusion: Our team has developed a multi-element identification system for the visual field of percutaneous endoscopic spine surgery adapted to the interlaminar and foraminal approaches, which can identify and track anatomical tissue (nerve, ligamentum flavum, nucleus pulposus, etc.) and surgical instruments (endoscopic forceps, an high-speed diamond burr, etc.), which can be used in the future as a virtual educational tool or applied to the intraoperative real-time assistance system for spinal endoscopic operation.

Effects of N application methods on cotton yield and fertilizer N recovery efficiency in salinity fields with drip irrigation under mulch film using 15N tracing technique.

Introduction: Drip irrigation under mulch film promotes a non-uniform salinity distribution in salt fields. The effect of different N application methods on the growth and yield of cotton under drip irrigation under mulch film conditions in eastern coastal saline-alkaline soils in China remain remained unclear. Methods: A randomized complete block design was used in the experiment. Three N application methods were assigned: N applied under mulch film (low-salinity area; UM), N applied between mulch films (high-salinity area; BM), and half N applied under mulch film and half between mulch films (HUHB). Results: Plant height, photosynthesis, Chl content, boll load, biomass, boll weight and boll density under UM were all significantly higher than those under the other two treatments. The N absorption of UM was higher than in the other two treatments, which might be attributed to the expression of GHNRT1.5 and GHNRT2.1. The net NO3- influx in the roots in UM increased significantly compared with that in BM. The yield and FNRE of UM were 3.9% and 9.1%, respectively, and were 26.52% and 90.36% higher than under HUHB and BM treatments. Discussion: UM not only improved cotton yield but also alleviated the pollution of N residue on drip irrigation under mulch film conditions in salt areas.

Lithium-Doped Titanium Dioxide-Based Multilayer Hierarchical Structure for Accelerating Nerve-Induced Bone Regeneration.

Despite considerable advances in artificial bone tissues, the absence of neural network reconstruction in their design often leads to delayed or ineffective bone healing. Hence, we propose a multilayer hierarchical lithium (Li)-doped titanium dioxide structure, constructed through microarc oxidation combined with alkaline heat treatment. This structure can induce the sustained release of Li ions, mimicking the environment of neurogenic osteogenesis characterized by high brain-derived neurotrophic factor (BDNF) expression. During in vitro experiments, the structure enhanced the differentiation of Schwann cells (SCs) and the growth of human umbilical vein endothelial cells (HUVECs) and mouse embryo osteoblast progenitor cells (MC3T3-E1). Additionally, in a coculture system, the SC-conditioned media markedly increased alkaline phosphatase expression and the formation of calcium nodules, demonstrating the excellent potential of the material for nerve-induced bone regeneration. In an in vivo experiment based on a rat distal femoral lesion model, the structure substantially enhanced bone healing by increasing the density of the neural network in the tissue around the implant. In conclusion, this study elucidates the neuromodulatory pathways involved in bone regeneration, providing a promising method for addressing bone deformities.

Distinguishing Kikuchi-Fujimoto disease from lymphoma in patients by clinical and PET/CT features.

To develop a scheme for distinguishing Kikuchi-Fujimoto disease (KFD) from lymphoma in patients presenting enlarged lymph nodes (LNs) predominantly on the upper side of the diaphragm. From November 2015 to August 2023, 32 KFD patients and 38 lymphoma patients were pathologically confirmed and enrolled in this retrospectively study. Clinical and 18F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) features were collected. When comparing those PET/CT parameters, we set 5 models with different research objects: (1) all affected LNs; (2) the 5 largest affected LNs in terms of maximum diameter; (3) the 5 largest affected LNs in terms of maximum standard uptake values (SUVmax); (4) the largest affected LNs in terms of maximum diameter; (5) the largest affected LNs in terms of SUVmax. Compared to lymphoma patients, KFD patients were younger; and with higher incidence of fever, arthralgia, abnormal serum white blood cell, lactate dehydrogenase (LDH) and splenomegaly; lower incidence of affected LNs perinodal infiltration, necrosis and conglomeration; more affected LNs in Head and Neck nodes (particularly in level II) and Axillary in KFD (P ˂ .05). PET/CT parameters presented as various difference in each model. Finally, 11 clinical and PET/CT features (age ≤ 34, with fever, arthralgia, abnormal white blood cell, abnormal LDH, and without node necrosis and node conglomeration have a score of 2 each; splenomegaly, perinodal infiltration, median maximum diameter ≤ 20.5 and median SUVmax ≤ 7.1 of affected LNs in model 2 have score of 1 each) were selected as scheme items for distinguishing KFD from lymphoma. Individuals who have a total score > 8, meet the criteria for KFD. Sensitivity and specificity were high: 86.8% (95% CI: 71.9%, 95.5%) and 96.9% (95% CI: 83.7%, 99.5%), AUC = 0.975 (95% CI: 90.5%, 99.6%), respectively. It can effectively distinguish KFD from lymphoma by clinical and PET/CT parameters.

MicroRNA-298 determines the radio-resistance of colorectal cancer cells by directly targeting human dual-specificity tyrosine(Y)-regulated kinase 1A.

BACKGROUND: Radiotherapy stands as a promising therapeutic modality for colorectal cancer (CRC); yet, the formidable challenge posed by radio-resistance significantly undermines its efficacy in achieving CRC remission. AIM: To elucidate the role played by microRNA-298 (miR-298) in CRC radio-resistance. METHODS: To establish a radio-resistant CRC cell line, HT-29 cells underwent exposure to 5 gray ionizing radiation that was followed by a 7-d recovery period. The quantification of miR-298 levels within CRC cells was conducted through quantitative RT-PCR, and protein expression determination was realized through Western blotting. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and proliferation by clonogenic assay. Radio-induced apoptosis was discerned through flow cytometry analysis. RESULTS: We observed a marked upregulation of miR-298 in radio-resistant CRC cells. MiR-298 emerged as a key determinant of cell survival following radiation exposure, as its overexpression led to a notable reduction in radiation-induced apoptosis. Intriguingly, miR-298 expression exhibited a strong correlation with CRC cell viability. Further investigation unveiled human dual-specificity tyrosine(Y)-regulated kinase 1A (DYRK1A) as miR-298's direct target. CONCLUSION: Taken together, our findings underline the role played by miR-298 in bolstering radio-resistance in CRC cells by means of DYRK1A downregulation, thereby positioning miR-298 as a promising candidate for mitigating radio-resistance in CRC.

Construction of Co1-xZnxFe2xGa2-2xO4 (02 Reduction by H2O Vapour.

Solid solutions are garnering substantial attention in the realm of solar energy utilization due to their tunable electronic properties, encompassing band edge positions and charge-carrier mobilities. In this study, we designed and synthesized Co1-xZnxFe2xGa2-2xO4 (0

Invasive pneumococcal diseases in Chinese children: a multicentre hospital-based active surveillance from 2019 to 2021.

This study aimed to provide data for the clinical features of invasive pneumococcal disease (IPD) and the molecular characteristics of Streptococcus pneumoniae isolates from paediatric patients in China. We conducted a multi-centre prospective study for IPD in 19 hospitals across China from January 2019 to December 2021. Data of demographic characteristics, risk factors for IPD, death, and disability was collected and analysed. Serotypes, antibiotic susceptibility, and multi-locus sequence typing (MLST) of pneumococcal isolates were also detected. A total of 478 IPD cases and 355 pneumococcal isolates were enrolled. Among the patients, 260 were male, and the median age was 35 months (interquartile range, 12-46 months). Septicaemia (37.7%), meningitis (32.4%), and pneumonia (27.8%) were common disease types, and 46 (9.6%) patients died from IPD. Thirty-four serotypes were detected, 19F (24.2%), 14 (17.7%), 23F (14.9%), 6B (10.4%) and 19A (9.6%) were common serotypes. Pneumococcal isolates were highly resistant to macrolides (98.3%), tetracycline (94.1%), and trimethoprim/sulfamethoxazole (70.7%). Non-sensitive rates of penicillin were 6.2% and 83.3% in non-meningitis and meningitis isolates. 19F-ST271, 19A-ST320 and 14-ST876 showed high resistance to antibiotics. This multi-centre study reports the clinical features of IPD and demonstrates serotype distribution and antibiotic resistance of pneumococcal isolates in Chinese children. There exists the potential to reduce IPD by improved uptake of pneumococcal vaccination, and continued surveillance is warranted.

Metabolic Regulation-Mediated Reversion of the Tumor Immunosuppressive Microenvironment for Potentiating Cooperative Metabolic Therapy and Immunotherapy.

Tumor cells exhibit heightened glucose (Glu) consumption and increased lactic acid (LA) production, resulting in the formation of an immunosuppressive tumor microenvironment (TME) that facilitates malignant proliferation and metastasis. In this study, we meticulously engineer an antitumor nanoplatform, denoted as ZLGCR, by incorporating glucose oxidase, LA oxidase, and CpG oligodeoxynucleotide into zeolitic imidazolate framework-8 that is camouflaged with a red blood cell membrane. Significantly, ZLGCR-mediated consumption of Glu and LA not only amplifies the effectiveness of metabolic therapy but also reverses the immunosuppressive TME, thereby enhancing the therapeutic outcomes of CpG-mediated antitumor immunotherapy. It is particularly important that the synergistic effect of metabolic therapy and immunotherapy is further augmented when combined with immune checkpoint blockade therapy. Consequently, this engineered antitumor nanoplatform will achieve a cooperative tumor-suppressive outcome through the modulation of metabolism and immune responses within the TME.

PTPLAD1 Regulates PHB-Raf Interaction to Orchestrate Epithelial-Mesenchymal and Mitofusion-Fission Transitions in Colorectal Cancer.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide. The poor prognosis of this malignancy is attributed mainly to the persistent activation of cancer signaling for metastasis. Here, we showed that protein tyrosine phosphatase-like A domain containing 1 (PTPLAD1) is down-regulated in highly metastatic CRC cells and negatively associated with poor survival of CRC patients. Systematic analysis reveals that epithelial-to-mesenchymal transition (EMT) and mitochondrial fusion-to-fission (MFT) transition are two critical features for CRC patients with low expression of PTPLAD1. PTPLAD1 overexpression suppresses the metastasis of CRC in vivo and in vitro by inhibiting the Raf/ERK signaling-mediated EMT and mitofission. Mechanically, PTPLAD1 binds with PHB via its middle fragment (141-178 amino acids) and induces dephosphorylation of PHB-Y259 to disrupt the interaction of PHB-Raf, resulting in the inactivation of Raf/ERK signaling. Our results unveil a novel mechanism in which Raf/ERK signaling activated in metastatic CRC induces EMT and mitochondrial fission simultaneously, which can be suppressed by PTPLAD1. This finding may provide a new paradigm for developing more effective treatment strategies for CRC.

Microbiological Distribution, Antimicrobial Susceptibility and Risk Factors of Polymicrobial Infections in Diabetic Foot.

BACKGROUND: Diabetic foot infection (DFI) leads to poor prognosis and polymicrobial infections are usually the main cause. The study is to explore the microbiological distribution, antimicrobial drug susceptibility, and risk factors of polymicrobial infections in hospitalized patients with DFI. METHODS: This retrospective study included 160 patients with DFI in Wagner's grades 2, 3, and 4. Deep necrotic tissue was used to acquire specimens for microbiological culture. VITEK-2 system and MALDI-TOF mass spectrometry were used to identify the bacterial isolates. The Kirby Bauer method was used for drug susceptibility tests. RESULTS: A total of 202 pathogens were isolated. The proportion of gram-negative bacilli (GNB, 62.4%, 126 of 202) was higher than that of gram-positive cocci (GPC, 37.6%, 76 of 202). The most prevalent GPC was Staphylococcus aureus in every Wagner grade, while the most common GNB varied in different Wagner grades. Linezolid was the most effective antibiotic for GPC in different Wagner grades. Imipenem was the most effective antibiotic for GNB in Wagner grade 2. Amikacin was the most effective antibiotic for GNB in Wagner grades 3 and 4. Polymicrobial infections existed only in Wagner grades 3 and 4 and increased the risk of amputation (p < 0.01). History of antibiotics, duration of diabetic foot, CRP, and lower extremity arterial disease were the independent risk factors of polymicrobial infections (p < 0.05). CONCLUSIONS: Clinicians should adjust the antibiotic as needed based on the results of drug susceptibility and clinical treatment effect among different Wagner grades. Particular attention should be given to the treatment of polymicrobial infections.