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Min Chai,1,* Patajiang Yusufu,2,* Yixin Chen,1 Jiannan Chai,3 Xinran Yang,1 Yuqi Xiao,1 Hongwei Long,4 Dilimulat Maimaiti,2 Dahai Xu1 1Department of Emergency Medicine, The First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 2Department of Emergency Medicine, Seventh Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China; 3Department of Laboratory, The First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 4Department of Neurosurgery, Meihekou Central Hospital, Changchun, Jilin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dahai Xu, Department of Emergency Medicine, The First Hospital of Jilin University, No. 1 Xinmin Street, Chaoyang District, Changchun, Jilin, People’s Republic of China, Tel +8615043032548, Email xudahai0319@jlu.edu.cn Dilimulat Maimaiti, Department of Emergency Medicine, Seventh Affiliated Hospital of Xinjiang Medical University, No. 1986, Qidaowan Road, Shuimogou District, Urumqi City, Xinjiang, People’s Republic of China, Tel +8617704972862, Email 3090760383@qq.comAbstract: Peptoniphilus asaccharolyticus is a gram-positive anaerobic coccus that can cause infections in immunocompromised individuals. P. asaccharolyticus causing empyema has not been reported earlier. Here, we present a novel case of empyema caused by P. asaccharolyticus. A 72-year-old male had a constant fever with difficulty breathing. A chest computed tomography scan revealed infiltration in the right lower lobe and pleural effusion. Following hospital admission, pleural fluid drainage was conducted, and the culture isolated P. asaccharolyticus. Initially treated with piperacillin/tazobactam, the patient experienced excessive thick sputum production, prompting a tracheostomy. Subsequent sputum cultures identified Acinetobacter baumannii. After transitioning to cefoperazone/sulbactam for antibiotic treatment and continued pleural effusion drainage, recovery was achieved. Empyema can be caused by P. asaccharolyticus and further complicated by a secondary infection with A. baumannii. Management should include appropriate antibiotic therapy, pleural drainage, vigilant monitoring, and supportive care. We aim to raise clinicians’ awareness of the potential for P. asaccharolyticus to cause empyema in immunocompromised patients and to provide early treatments, thereby improving morbidity and mortality.Keywords: Peptoniphilus asaccharolyticus, empyema, Acinetobacter baumannii, case report

Ziyan Zhong,1,* Jian Liu,2,* Yan Luo,1 Mei Wu,1 Feng Qiu,1 Hongqing Zhao,1 Yang Liu,1 Yajing Wang,3 Hongping Long,2 Lei Zhao,4 Yuhong Wang,1 Yuanshan Han,2 Pan Meng1 1Science & Technology Innovation Center, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, People’s Republic of China; 2The First Hospital, Hunan University of Chinese Medicine, Changsha, Hunan, 410007, People’s Republic of China; 3Office of Science & Technology, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, People’s Republic of China; 4School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuanshan Han, The First Hospital, Hunan University of Chinese Medicine, Changsha, Hunan, 410007, People’s Republic of China, Email 121983755@qq.com Pan Meng, Science & Technology Innovation Center, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, People’s Republic of China, Email 004181@hnucm.edu.cnBackground: Depression, a leading cause of disability worldwide, is characterized by dysfunction of immature neurons, resulting in dysregulated calcium homeostasis and impaired structural plasticity. Jujuboside A (JuA), a biologically active compound derived from Semen Ziziphi Spinosae, has demonstrated anti-anxiety and anti-insomnia properties. Recent studies suggest that JuA may be a promising antidepressant, but its underlying mechanisms remain unclear.Methods: Sprague-Dawley rats were subjected to chronic unpredictable mild stress (CUMS) to induce a depression model. JuA (12.5 mg/kg, 25 mg/kg, 50 mg/kg) was administered orally for 4 weeks. Emotional and cognitive function were assessed. Monoamine neurotransmitter levels were measured using enzyme-linked immunosorbent assay (ELISA). The number of immature neurons and calcium homeostasis were evaluated by immunofluorescence. Western blotting and immunofluorescence were employed to detect the expression of Sonic hedgehog (Shh) signaling proteins. Additionally, lentiviral vector expressing Shh shRNA (LV-Shh-RNAi) were infused intracerebrally to investigate the role of Shh in JuA’s antidepressant effects.Results: JuA significantly ameliorated depressive-like behavior and cognitive dysfunction in CUMS rats, increased monoamine neurotransmitter levels in serum and hippocampal tissue, reduced the number of BrdU/DCX (bromodeoxyuridine/doublecortin)-positive immature neurons, and attenuated calcium ion (Ca2+) concentration and Ca2+/calmodulin-dependent protein kinase II (CaMKII) levels in immature neurons. JuA also markedly elevated synaptic density and prominence complexity, upregulated Shh, Gli family zinc finger 1 and 2 (Gli1/2), synaptophysin (Syn) and postsynaptic density protein-95 (PSD-95) expression in the ventral dentate gyrus (vDG). However, knockdown of Shh in the vDG counteracted JuA’s therapeutic effects.Conclusion: These findings collectively suggest that JuA improves depressive-like behavior in CUMS rats by modulating calcium homeostasis and synaptic structural plasticity in immature neurons through the Shh signaling pathway.Keywords: Jujuboside A, Sonic hedgehog, Immature neuron, Calcium homeostasis, Depression

Tran Quoc Hoa,1 Nguyen Ngoc Cuong,2 Nguyen Cong Hoan,3 Nguyen Quang Trung,2 Thieu Thi Tra My,4 Nguyen Ngoc Anh,5 Hoang Long1 1Surgery Urology, Hanoi Medical University Hospital, Hanoi Medical University, Hanoi, Vietnam; 2Radiology Center Hanoi Medical University Hospital, Hanoi Medical University, Hanoi, Vietnam; 3Outpatient department, Hanoi medical university hospital, Hanoi medical university, Hanoi, Vietnam; 4Radiology Department, Vinmec Times city Interational Hospital, Hanoi, Vietnam; 5Anatomy Department, Hanoi Medical University, Hanoi, VietnamCorrespondence: Nguyen Ngoc Cuong, Radiology center, Hanoi medical university hospital, No. 1, Ton That Tung Street, Dong Da District, Hanoi, Viet Nam, Tel +84965131314, Email cuongcdha@gmail.comPurpose: Chyluria is a rare condition primarily prevalent in developing countries in tropical regions. In chyluria, there exists the communication between lymphatic vessels and the urinary tract, but the specific mechanism of this communication remains undocumented. The objective of this study was to assess the morphology of the main lymphatic vessels including the uro-lymphatic fistula, the thoracic duct using Magnetic Resonance Lymphangiography (MRL) and Intranodal Lymphangiography (IL).Materials and Methods: A retrospective study spanning five years, from January 2020 to January 2024, included 43 patients diagnosed with chyluria through cystoscopy and quantitative urine testing for triglycerides. These patients underwent MRL and then IL for uro-lymphatic fistula embolization.Results: The study involved 43 patients with an average age of 66.1 ± 19.5 years, with a male-to-female ratio of 1:2. Uro-lymphatic fistula occurred predominantly in the left kidney (72.1%), followed by the right kidney (20.9%), and both sides (7%). MRL imaging showed the thoracic duct in 100% of cases but visualized only 84.5% of the uro-lymphatic fistulas. In contrast, IL imaging showed the thoracic duct in 51.5% of patients but visualized uro-lymphatic fistulas in 100% of cases. In the procedure of IL, the average visualization time of the thoracic duct was 45 minutes, with a range of 35 to 69 minutes.Conclusion: MRL and IL complement each other in diagnosing the main lymphatic vessels in chyluria patients. The observed circulatory stasis in the thoracic duct supports the hypothesis that it contributes to increased pressure in the thoracic duct and the formation uro-lymphatic fistula as collateral circulations.Keywords: chyluria, MR lymphangiography, intranodal lymphangiography, uro-lymphatic fistula

Lixia Wang,1,* Yilai Pei,2,* Yuanfei Zhu,1 Haiying Long,3 Weiguo Pang4 1Shanghai Teacher Institute, Shanghai, People’s Republic of China; 2China Institute of Education and Social Development, Beijing Normal University, Beijing, People’s Republic of China; 3Department of Educational Psychology, University of Kansas, Lawrence, KS, USA; 4School of Psychology and Cognitive Science, East China Normal University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haiying Long; Weiguo Pang, Email hlong@ku.edu; wgpang@psy.ecnu.edu.cnIntroduction: The schizotypy-creativity link has been studied from different perspectives over the past few decades, yet the results of this relationship are inconsistent in the literature. Previous studies have suggested that two basic motivational systems—Behavioral Inhibition System (BIS, avoidance motivation) and Behavioral Activation System (BAS, approach motivation)—underlie the relationship between schizotypy and creativity. Few empirical studies, however, have examined how the relationship interacts with other variables. This study fills these gaps and explores the role of the approach and avoidance motivation assessed by trait behavioral activation and inhibition in the link between schizotypy as a dimensional personality trait and creative ideational behavior as a measure of creativity.Method: Undergraduate students (N = 388) completed questionnaires including the Schizotypal Personality Questionnaire (SPQ) measuring 3 dimensions of schizotypy, Runco Ideational Behavior Scale (RIBS) measuring creative ideational behavior, and BIS/BAS Scales measuring trait behavioral motivation. Bivariate Pearson correlation was computed, and hierarchical linear regression was performed to explore the effects of schizotypy, BIS/BAS, and their interaction on creative ideational behavior. The conditional effect of schizotypy based on different levels of the moderator was further tested.Results: The total score, positive dimension and disorganized dimension of SPQ were all positively correlated with RIBS, BAS, and BIS. Negative dimension of SPQ was not significantly correlated with the RIBS score but was positively correlated with BIS. Additionally, after controlling gender and age, BAS significantly moderated the relationship between the positive and disorganized dimensions of schizotypy and creative ideational behavior measured by RIBS. However, BIS was not a significant moderator.Discussion: The findings of this study regarding the relationships between different dimensions of schizotypy, two motivational systems, and creative ideational behavior were mostly consistent with previous findings. The significant moderated effect of BAS on the relationship between two dimensions of schizotypy and creative ideational behavior made significant contributions to the understanding of the relationship between schizotypy and creativity.Keywords: schizotypy, creativity, creative ideational behavior, motivation

Abstract The etiopathogenesis of diverticulitis, among the most common gastrointestinal diagnoses, remains largely unknown. By leveraging stool collected within a large prospective cohort, we performed shotgun metagenomic sequencing and untargeted metabolomics profiling among 121 women diagnosed with diverticulitis requiring antibiotics or hospitalizations (cases), matched to 121 women without diverticulitis (controls) according to age and race. Overall microbial community structure and metabolomic profiles differed in diverticulitis cases compared to controls, including enrichment of pro-inflammatory Ruminococcus gnavus, 1,7-dimethyluric acid, and histidine-related metabolites, and depletion of butyrate-producing bacteria and anti-inflammatory ceramides. Through integrated multi-omic analysis, we detected covarying microbial and metabolic features, such as Bilophila wadsworthia and bile acids, specific to diverticulitis. Additionally, we observed that microbial composition modulated the protective association between a prudent fiber-rich diet and diverticulitis. Our findings offer insights into the perturbations in inflammation-related microbial and metabolic signatures associated with diverticulitis, supporting the potential of microbial-based diagnostics and therapeutic targets.

Lujie Wei,1,&ast; Pingyang Li,2,&ast; Xiaofeng Liu,1 Yuxia Wang,1 Zhengping Tang,1 Hang Zhao,1 Lu Yu,3 Kaixiu Li,1 Jianping Li,1 Min Du,4 Xinzhu Chen,2 Xin Zheng,2 Yixiong Zheng,5 Yao Luo,2 Jing Chen,5 Xiamin Jiang,6 Xiaobing Chen,7 Huaicong Long1 1Geriatric Intensive Care Unit, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, People’s Republic of China; 2Medical College, University of Electronic Science and Technology of China, Chengdu, Sichuan, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, Nanbu County People’s Hospital, Nanbu, Sichuan, People’s Republic of China; 5College of Medicine and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China; 6Clinical College, North Sichuan Medical College, Nanchong, Sichuan, People’s Republic of China; 7Department of Respiratory and Critical Care Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huaicong Long, Geriatric Intensive Care Unit, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610000, People’s Republic of China, Tel +86 18981838105, Fax +86-28-8779 5585, Email longhc69@163.comBackground: Chronic obstructive pulmonary disease (COPD) is closely associated with frailty, and prevention of acute exacerbations is important for disease management. Moreover, COPD patients with frailty experience a higher risk of acute exacerbations. However, the frailty instruments that can better predict acute exacerbations remain unclear.Purpose: (1) To explore the factors influencing frailty and acute exacerbations in stable COPD patients, and (2) quantify the ability of multidimensional frailty instruments to predict acute exacerbations within 1 year.Patients and methods: In this retrospective longitudinal study, stable COPD patients were recruited from the outpatient department of Sichuan Provincial People’s Hospital from July 2022 to June 2023. COPD patients reviewed their frailty one year ago and their acute exacerbations within one year using face-to-face interviews with a self-developed frailty questionnaire. Frailty status was assessed using the Frailty Index (FI), frailty questionnaire (FRAIL), and Clinical Frailty Scale (CFS). One-way logistic regression was used to explore the factors influencing frailty and acute exacerbations. Multivariate logistic regression was used to establish a prediction model for acute exacerbations, and the accuracy of the three frailty instruments was compared by measuring the area under the receiver operating characteristic curve (AUC).Results: A total of 120 individuals were included. Frailty incidence estimates using FI, FRAIL, and CFS were 23.3%, 11.7%, and 15.8%, respectively. The three frailty instruments showed consistency in COPD assessments (P< 0.05). After adjusting for covariates, frailty reflected by the FI and CFS score remained an independent risk factor for acute exacerbations. The CFS score was the best predictor of acute exacerbations (AUC, 0.764 (0.663– 0.866); sensitivity, 57.9%; specificity, 80.0%). Moreover, the combination of CFS plus FRAIL scores was a better predictor of acute exacerbations (AUC, 0.792 (0.693– 0.891); sensitivity, 86.3%; specificity, 60.0%).Conclusion: Multidimensional frailty assessments could improve the identification of COPD patients at high risk of acute exacerbations and facilitate targeted interventions to reduce acute exacerbations in these patients.Keywords: chronic obstructive pulmonary disease, frailty, acute exacerbations

The elemental mercury (Hg0) release characteristics from the Hg-contaminated soil applied with Humic acid fertilizer (HAF) in the greenhouse were identified. The adsorption features of mercuric ion (Hg2+) on HAF under different reaction times and pH were investigated to elucidate the influencing mechanism of HAF on soil Hg0 release. Besides, the microstructure of HAF loading with Hg2+ was characterized by using Fourier transform infrared spectroscopy (FTIR) and scanning electron micrograph-energy dispersive spectrometry–EDS). The results showed that with the increasing HAF dosage, soil oxidation-reduction potential (Eh), and organic matter (SOM) content, as well as the decreasing soil pH, the soil Hg0 release fluxes showed a decreasing tendency. The soil pH, Eh, SOM, and total Hg content are the key factors that can affect the soil Hg0 release fluxes. The interior air temperature, light intensity, soil moisture, and soil temperature have little impact on soil Hg0 release fluxes when the greenhouse soil is applied with HAF. The HAF can immobilize Hg2+ and reduce its activity by surface precipitation and specific adsorption, then affecting the soil Hg0 release fluxes. The results of this study provide a basis for the application of HAF to reduce soil Hg0 release fluxes in the greenhouse of Hg-contaminated areas.

Yiqin Xia,1– 3 Hongyu Long,4 Qiang Lai,1– 3 Yiwu Zhou1– 3 1Emergency Department, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Laboratory of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Disaster Medical Center, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 4Department of Critical Care Medicine, Chengdu First People’s Hospital, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Yiwu Zhou, Emergency Department, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China, Email 456zyw@163.comObjective: Acute pancreatitis (AP) progresses to septic shock can be fatal. Early identification of high-risk patients and timely intervention can prevent and interrupt septic shock. By analyzing the clinical characteristics of AP with sepsis, this study uses machine learning (ML) to build a model for early prediction of septic shock within 28 days of admission, which guided emergency physicians in resource allocation and medical decision-making.Methods: This retrospective cohort study collected data from the emergency departments (EDs) of three tertiary care hospitals in China. The dataset was randomly divided into a training dataset (70%) and a testing dataset (30%). Ten ML classifiers were utilized to analyze characteristics of AP with sepsis in the training dataset upon admission. Results were evaluated through cross-validation analysis. The optimal model was then tested on the testing dataset without any parameter modifications. The ML model was evaluated using the receiver operating characteristic curve (ROC) and compared to scoring systems through the DeLong test.Results: A total of 604 AP patients with sepsis were included in this study. The auto-encoder (AE) model based on mean normalization, Pearson correlation coefficient (PCC), and recursive feature elimination (RFE) selection, achieved the highest Area Under the Curve (AUC) on the validation dataset (AUC 0.900, accuracy 0.868), with the AUC of 0.879 and accuracy of 0.790 on the testing dataset. Compared to the Sequential Organ Failure Assessment (AUC 0.741), quick Sequential Organ Failure Assessment (AUC 0.727), Acute Physiology and Chronic Health Evaluation II (AUC 0.778), and Bedside Index of Severity in Acute Pancreatitis (AUC 0.691), the AE model showed superior performance.Conclusion: The AE model outperforms traditional scoring systems in predicting septic shock in AP patients with sepsis within 28 days of admission. This assists emergency physicians in identifying high-risk patients early and making timely medical decisions.Keywords: machine learning, acute pancreatitis, sepsis, septic shock

Abstract The analysis of ceramide (Cer) and sphingomyelin (SM) lipid species using liquid chromatography–tandem mass spectrometry (LC–MS/MS) continues to present challenges as their precursor mass and fragmentation can correspond to multiple molecular arrangements. To address this constraint, we developed ReTimeML, a freeware that automates the expected retention times (RTs) for Cer and SM lipid profiles from complex chromatograms. ReTimeML works on the principle that LC–MS/MS experiments have pre-determined RTs from internal standards, calibrators or quality controls used throughout the analysis. Employed as reference RTs, ReTimeML subsequently extrapolates the RTs of unknowns using its machine-learned regression library of mass-to-charge (m/z) versus RT profiles, which does not require model retraining for adaptability on different LC–MS/MS pipelines. We validated ReTimeML RT estimations for various Cer and SM structures across different biologicals, tissues and LC–MS/MS setups, exhibiting a mean variance between 0.23 and 2.43% compared to user annotations. ReTimeML also aided the disambiguation of SM identities from isobar distributions in paired serum-cerebrospinal fluid from healthy volunteers, allowing us to identify a series of non-canonical SMs associated between the two biofluids comprised of a polyunsaturated structure that confers increased stability against catabolic clearance.

Domain adaptation in neural machine translation (NMT) tasks often involves working with datasets that have a different distribution from the training data. In such scenarios, k-nearest-neighbor machine translation (kNN-MT) has been shown to be effective in retrieving relevant information from large datastores. However, the high-dimensional context vectors of large neural machine translation model result in high computational costs for distance computation and storage. To address this issue, index optimization techniques have been proposed, including the use of inverted file index (IVF) and product vector quantization (PQ), called IVFPQ. In this paper, we explore the recent index techniques for efficient machine translation domain adaptation and combine multiple index structures to improve the efficiency of nearest-neighbor search in domain adaptation datasets for machine translation task. Specifically, we evaluate the effectiveness when combining optimized product quantization (OPQ) and hierarchical navigable small-world (HNSW) indexing with IVFPQ. Our study aims to provide insights into the most suitable composite index methods for efficient nearest-neighbor search in domain adaptation datasets, with a focus on improving both accuracy and speed.

Miao Wan,1,&ast; Xiangrong Xu,2,&ast; Xiaojiao Zhao,1 Xia You,1 Guiying Zhang,3 Hai Long,3 Ping He,1 Jian Long,1 Jianjian Zhu1 1Department of Dermatovenerology of the First People’s Hospital of Changde City, Changde Hospital Affiliated to Xiangya School of Medicine of Central South University, Changde, 415000, People’s Republic of China; 2Department of Plastic Surgery of the First People’s Hospital of Changde City, Changde Hospital Affiliated to Xiangya School of Medicine of Central South University, Changde, 415000, People’s Republic of China; 3Department of Dermatovenerology of the Second Xiangya Hospital of Central South University, Changsha, 410000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianjian Zhu, No. 388, Renmin East Road, Changde, Hunan Province, People’s Republic of China, Tel +15873658886, Email lidocute@163.comAbstract: Necrotizing fasciitis is a rare, severe, rapidly progressing disease with a high mortality rate. We report a case of a 72-year female with erythematous pemphigus who developed erythema, swelling and ulceration on right vulva, groin, and thigh. The early clinical manifestations of the patient were nonspecific and easily misdiagnosed as cellulitis. However, upon the occurrence of ulceration and necrosis, deep fungal infection, pyoderma gangrenosum or lymphoproliferative disorders were considered. The pathology suggested IgG4-related diseases, plasmacytoma et al. But at last, surgical exploration and postoperative pathology confirmed the diagnosis of necrotizing fasciitis. The patient recovered after multiple aggressive surgical debridement procedures and antibiotic therapy and the patient has been followed up for 2 years without recurrence. Clinicians should be vigilant about the possibility of necrotizing fasciitis in patients with erythema, pain, rapid ulceration of skin and soft tissue, particularly in immunocompromised individuals with long-term use of immunosuppressive agents. It is crucial for saving life by early multi-disciplinary consultation, prompt diagnosis, and aggressive treatment.Keywords: debridement, infection, multidisciplinary consultation, necrotizing fasciitis, pemphigus

Weibing Xu,1 Yuxin Di,1 Shengjing Chu,1 Zixuan Wang,1 Haitao Long,1 Lumei Pu,1 Runtian Ma,1 Yanwei Wang2 1College of Science, Gansu Agricultural University, Lanzhou, 730000, People’s Republic of China; 2Department of Chemical and Materials Engineering, School of Engineering and Digital Sciences, Nazarbayev University, Astana, 010000, KazakhstanCorrespondence: Weibing Xu, College of Science, Gansu Agricultural University, No. 1 Yingmen Village, Anning District, Lanzhou, 730000, People’s Republic of China, Tel/Fax +86 931 7631212, Email xuwb@gsau.edu.cnBackground: Combination therapy employing multiple drugs has been shown to enhance the efficacy of cancer treatment. Chlorambucil (Chl) and 6-mercaptopurine (6MP) are the first-line medicines for chronic lymphocytic leukemia and ovarian cancer. However, both were limited by their short half-life of disintegration, unsatisfactory water solubility, and adverse reactions.Methods: In this work, the drug Chl and 6MP were introduced into the polymerized N-(2-hydroxypropyl) methacrylamide (polyHPMA) by pH and glutathione responsive linker to construct the polymer nanodrug delivery system for effective co-delivery.Results: The drug load capacities, release, morphology, and cytotoxicity of the pro-drug were systematic. The two drugs showed satisfactory synergism with a combination index of 0.81, and a better ability to induce apoptosis. In and ex vivo fluorescence imaging showed a rapid systemic distribution of the conjugate within mice, majorly metabolized by liver and kidneys and eliminated after 24 hr. No significant pathological damage was observed in the major organs. This polymeric prodrug system holds promise for improved therapeutic efficiency and reduced side effects through the synergistic delivery of various chemotherapeutics.Conclusion: The introduction of HPMA as a carrier not only enhanced the solubility and biocompatibilities of Chl and 6 MP but also improved their drug effect. This strategy might be a promising alternative for constructing multi-drug-release system. Keywords: polymer prodrug, co-delivery, chlorambucil, mercaptopurine, fluorescence images, cancer treatment

Preoperative risk biomarkers for delirium may aid in identifying high-risk patients and developing intervention therapies, which would minimize the health and economic burden of postoperative delirium. Previous studies have typically used single omics approaches to identify such biomarkers. Preoperative cerebrospinal fluid (CSF) from the Healthier Postoperative Recovery study of adults ≥ 63 years old undergoing elective major orthopedic surgery was used in a matched pair delirium case–no delirium control design. We performed metabolomics and lipidomics, which were combined with our previously reported proteomics results on the same samples. Differential expression, clustering, classification, and systems biology analyses were applied to individual and combined omics datasets. Probabilistic graph models were used to identify an integrated multi-omics interaction network, which included clusters of heterogeneous omics interactions among lipids, metabolites, and proteins. The combined multi-omics signature of 25 molecules attained an AUC of 0.96 [95% CI: 0.85–1.00], showing improvement over individual omics-based classification. We conclude that multi-omics integration of preoperative CSF identifies potential risk markers for delirium and generates new insights into the complex pathways associated with delirium. With future validation, this hypotheses-generating study may serve to build robust biomarkers for delirium and improve our understanding of its pathophysiology.