Federal Impacts on Buprenorphine Prescribing in Washington State, 2012 to 2022.

Objectives. To evaluate changes in monthly buprenorphine dispensation associated with federal prescribing policies in Washington State from 2012 to 2022. Methods. We conducted an interrupted time series analysis comparing monthly buprenorphine prescriptions dispensed per 1000 population after the Comprehensive Addiction and Recovery Act (CARA), Substance Use-Disorder Prevention That Promotes Opioid Recovery and Treatment for Patients and Communities Act (SUPPORT), and new prescribing rules during the COVID-19 pandemic. Buprenorphine formulated for opioid use disorder was included from the Washington State Prescription Monitoring Program. A log-linear autoregressive model measured linear trend changes. Results. Physician prescribing increased by 1.63% (95% confidence interval [CI] = 1.41%, 1.85%) per month after CARA with sustained declines after SUPPORT. Nurse practitioner (NP) prescribing increased by 19.48% (95% CI = 18.8%, 20.16%) per month after CARA with physician assistants (PAs) showing similar trends. Following the implementation of SUPPORT, NP and PA trends continued to increase at a reduced growth rate of 3.96% (95% CI = 2.01%, 5.94%) and 1.87% (95% CI = 0.56%, 3.19%), respectively. No prescribers experienced increases during the COVID-19 pandemic. Conclusions. CARA nearly tripled the buprenorphine prescribing rate. The SUPPORT Act initiated sustained declines for physician prescribing, and the COVID-19 period reversed gains for PAs and NPs. The current opioid crisis requires expanded efforts in Washington State. (Am J Public Health. Published online ahead of print May 2, 2024:e1-e9. https://doi.org/10.2105/AJPH.2024.307649).

Biomarker-driven targeted therapy in patients with recurrent platinum-resistant epithelial ovarian cancer (BRIGHT): protocol for an open-label, multicenter, umbrella study.

BACKGROUND: Platinum-resistant, recurrent ovarian cancer has an abysmal prognosis with limited treatment options. Poly-(ADP-ribose)-polymerase (PARP), angiogenesis, and immune checkpoint inhibitors might improve the outcomes of platinum-resistant, recurrent ovarian cancer, but accurate patient selections for those therapies remain a significant clinical challenge. PRIMARY OBJECTIVE: To evaluate the efficacy and safety of biomarker-driven combinatorial therapies of pamiparib, tislelizumab, bevacizumab, and nab-paclitaxel in platinum-resistant, recurrent ovarian cancer. STUDY HYPOTHESIS: A precision medicine combination of PARP inhibitors, anti-angiogenic therapy, immunotherapy, and chemotherapy will improve disease outcomes of platinum-resistant, recurrent ovarian cancer by accounting for genomic and immunologic features. TRIAL DESIGN: The BRIGHT Trial is a prospective, open-label, multicenter, phase II, umbrella study planning to enroll 160 patients with serous, endometrioid, or clear cell platinum-resistant, recurrent ovarian cancer from 11 clinical centers in China. Patients are assigned to one of three experimental arms based on biomarkers. Patients with BRCA1/2 mutations will receive pamiparib plus bevacizumab (arm 1, n=40) regardless of CD8+ tumor-infiltrating lymphocytes count. Patients with wild-type BRCA1/2 (BRCAwt) and ≥3 CD8+ tumor-infiltrating lymphocytes count will receive the combination of tislelizumab, bevacizumab, and nab-paclitaxel (arm 2, n=50), while BRCAwt patients with <3 CD8+ tumor-infiltrating lymphocytes count will receive bevacizumab plus dose-dense nab-paclitaxel (arm 3, n=50). After completing patient enrollment in arm 2, another 20 BRCAwt patients with ≥3 CD8+ tumor-infiltrating lymphocytes count will be included as an arm 2 expansion. Treatment will continue until disease progression or intolerable toxicity, and all adverse events will be recorded. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients include those aged ≥18 with serous, endometrioid, or clear cell ovarian cancer, platinum-resistant recurrence, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. PRIMARY ENDPOINT: Objective response rate (ORR) assessed by the investigators by the RECIST 1.1 criteria. SAMPLE SIZE: 160 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Recruitment is estimated to be completed by 2024 and results may be published by 2027. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05044871.

Advances in environmental DNA monitoring: standardization, automation, and emerging technologies in aquatic ecosystems.

Environmental DNA (eDNA) monitoring, a rapidly advancing technique for assessing biodiversity and ecosystem health, offers a noninvasive approach for detecting and quantifying species from various environmental samples. In this review, a comprehensive overview of current eDNA collection and detection technologies is provided, emphasizing the necessity for standardization and automation in aquatic ecological monitoring. Furthermore, the intricacies of water bodies, from streams to the deep sea, and the associated challenges they pose for eDNA capture and analysis are explored. The paper delineates three primary eDNA survey methods, namely, bringing back water, bringing back filters, and bringing back data, each with specific advantages and constraints in terms of labor, transport, and data acquisition. Additionally, innovations in eDNA sampling equipment, including autonomous drones, subsurface samplers, and in-situ filtration devices, and their applications in monitoring diverse taxa are discussed. Moreover, recent advancements in species-specific detection and eDNA metabarcoding are addressed, highlighting the integration of novel techniques such as CRISPR-Cas and nanopore sequencing that enable precise and rapid detection of biodiversity. The implications of environmental RNA and epigenetic modifications are considered for future applications in providing nuanced ecological data. Lastly, the review stresses the critical role of standardization and automation in enhancing data consistency and comparability for robust long-term biomonitoring. We propose that the amalgamation of these technologies represents a paradigm shift in ecological monitoring, aligning with the urgent call for biodiversity conservation and sustainable management of aquatic ecosystems.

Development and validation of an artificial intelligence mobile application for predicting 30-day mortality in critically ill patients with orthopaedic trauma.

BACKGROUND: Given the intricate and grave nature of trauma-related injuries in ICU settings, it is imperative to develop and deploy reliable predictive tools that can aid in the early identification of high-risk patients who are at risk of early death. The objective of this study is to create and validate an artificial intelligence (AI) model that can accurately predict early mortality among critical fracture patients. METHODS: A total of 2662 critically ill patients with orthopaedic trauma were included from the MIMIC III database. Early mortality was defined as death within 30 days in this study. The patients were randomly divided into a model training cohort and a model validation cohort. Various algorithms, including logistic regression (LR), extreme gradient boosting machine (eXGBM), decision tree (DT), support vector machine (SVM), random forest (RF), and neural network (NN), were employed. Evaluation metrics, including discrimination and calibration, were used to develop a comprehensive scoring system ranging from 0 to 60, with higher scores indicating better prediction performance. Furthermore, external validation was carried out using 131 patients. The optimal model was deployed as an internet-based AI tool. RESULTS: Among all models, the eXGBM demonstrated the highest area under the curve (AUC) value (0.974, 95%CI: 0.959-0.983), followed by the RF model (0.951, 95%CI: 0.935-0.967) and the NN model (0.922, 95%CI: 0.905-0.941). Additionally, the eXGBM model outperformed other models in terms of accuracy (0.915), precision (0.906), recall (0.926), F1 score (0.916), Brier score (0.062), log loss (0.210), and discrimination slope (0.767). Based on the scoring system, the eXGBM model achieved the highest score (53), followed by RF (42) and NN (39). The LR, DT, and SVM models obtained scores of 28, 18, and 32, respectively. Decision curve analysis further confirmed the superior clinical net benefits of the eXGBM model. External validation of the model achieved an AUC value of 0.913 (95%CI: 0.878-0.948). Consequently, the model was deployed on the Internet at https://30-daymortalityincriticallyillpatients-fnfsynbpbp6rgineaspuim.streamlit.app/, allowing users to input patient features and obtain predicted risks of early mortality among critical fracture patients. Furthermore, the AI model successfully stratified patients into low or high risk of early mortality based on a predefined threshold and provided recommendations for appropriate therapeutic interventions. CONCLUSION: This study successfully develops and validates an AI model, with the eXGBM algorithm demonstrating the highest predictive performance for early mortality in critical fracture patients. By deploying the model as a web-based AI application, healthcare professionals can easily access the tool, enabling them to predict 30-day mortality and aiding in the identification and management of high-risk patients among those critically ill with orthopedic trauma.

Ginkgo biloba extract ameliorates hyperglycaemia-induced enteric glial cell injury via regulation of the TLR2-related pathway.

BACKGROUND: Diabetic gastrointestinal dysfunction (DGD) is a common complication in diabetic patients, and enteric glial cells (EGCs) found in the gastrointestinal tract have been shown to play an essential role in gastrointestinal dysfunction. Thus, targeting EGCs may be helpful for the control of DGD. This study aimed to evaluate the protective effect of Ginkgo biloba extract (GBE) from G. biloba dropping pills against hyperglycaemic stress-induced EGCs injury and its underlying mechanism. METHODS: In vitro, the protective effect of GBE on CRL-2690 cells was evaluated by MTT assay and TUNEL assay. The expression of related markers was evaluated by RNA sequencing and validated by using western blotting. In vivo, STZ-induced C57BL/6J WT mice were used as models to evaluate the effects of GBE on blood glucose, body weight, and EGCs' activity and relevant signalling pathways were validated by immunofluorescence. RESULTS: The results showed that GBE (25 µg/ml) treatment significantly attenuated hyperglycaemic stress-induced cytotoxicity and cell apoptosis in CRL-2690 cells, which was verified in an STZ-induced (100 mg/kg, 3 days) diabetic mouse model with continuous GBE administration (25/100 mg/kg/day, 6/12 weeks). Further mechanistic study based on transcriptomic data revealed that GBE exerted its beneficial effect by regulating immune-related pathways, and TLR2/BTK/NF-κB/IL-1α/IL-10 comprised the main targets of this drug. CONCLUSIONS: This study demonstrates the protective effect of GBE against hyperglycaemic stress-induced EGCs injury using both in vitro and in vivo models and further reveals that the effect was achieved by targeting TLR2 and its downstream molecules BTK/NF-κB/IL-1α/IL-10. This study may be helpful for expanding the clinical application of GBE in treating DGD.

Ultrasound characteristics of the cervical vagus nerve in patients with type 2 diabetes and diabetic peripheral neuropathy.

INTRODUCTION: Diabetic peripheral neuropathy (DPN) and autonomic neuropathy are commonly coexistent in patients with type 2 diabetes mellitus (T2DM). Current assessment tools for diabetic neuropathy remain complicated and limited. We aimed to investigate the sonographic changes of the cervical vagus nerve in DPN patients with T2DM. MATERIAL AND METHODS: Patients with T2DM were divided into a DPN group (DPN, n = 44) and non-DPN controls (NDPN, n = 43) based on electromyogram results. Another 43 healthy controls (CON) were included. High-frequency ultrasound (HFU) of the vagus nerve was performed in all participants. RESULTS: Compared with controls, the honeycomb structure of the vagus nerve in patients with T2DM decreased, p < 0.001. The DPN group had higher cross-sectional area (CSA) of the right vagus nerve than the NDPN group (1.60 ± 0.52 vs. 2.00 ± 0.57 mm2, p =0.001). Logistic regression showed that right vagus nerve CSA was a risk factor of DPN (odds ratio [OR] = 3.924, p = 0.002). Right vagus nerve CSA was positively correlated with diabetes duration (p = 0.003), and negatively correlated with the motor conduction velocity (MCV) of the ulnar, median, and common peroneal nerves (p < 0.001 for all), as well as the sensor conduction velocity (SCV) of the ulnar and median nerve (both p < 0.005). CONCLUSION: HFU shows thickening of the cervical vagus nerve in patients with DPN, which is a potential diagnostic feature of diabetic neuropathy.

Effect of Electroacupuncture with Different Current Intensities on the Serum Metabolomics of Functional Constipation.

Objective: The aim of the study is to investigate the serum metabolomics of electroacupuncture (EA) with different current intensities in the treatment of functional constipation (FC). Methods: The total number of FC patients was 19, (7, 6, 6, in the low current intensity group (LCI), high current intensity group (HCI), and mosapride citrate tablet control group (MC), respectively). Patients in the EA groups received 16 sessions of acupuncture treatments. Patients in the MC group were orally administered 5 mg mosapride citrate tablets 3 times daily, and serum samples were collected from the patients before and after treatment. Orthogonal partial least square-discriminant analysis (OPLS-DA) was used to assess the metabolic data. The significant differences before and after FC treatment are shown in the OPLS-DA score plot. Variable importance plots (VIPs) and T tests were used to identify significant metabolites. Results: Among the three groups, the number of metabolites with VIP > 1 was 11, 7, and 21 (in LCI, HCI and MC groups, respectively). Compared with those before treatment, the serum metabolites of patients were characterized by increased levels of L-ornithine (p < 0.05) and glyceric acid in the LCI group (p < 0.05), increased levels of vanillic acid in the MC group (p < 0.05), and decreased levels of arabinonic acid in the MC group (p < 0.05). Conclusions: The effects of EA treatment on the serum metabolomics of FC may involve fatty acid and amino acid metabolism.

Generation of Tunable Terahertz Waves from Tailored Versatile Spintronic Meta-Antenna Arrays.

Broadband spintronic terahertz (THz) radiation can be efficiently generated by spin-to-charge current conversion in a ferromagnetic/nonmagnetic heterostructure. There had been many studies on realizing the enhancement or the modulation of spintronic terahertz waves. However, reported devices so far focus on implementing certain specific modulation methods, either related to the spintronic stacks or related to the metamaterial structures. In this study, a set of femtosecond laser-driven versatile spintronic terahertz devices are proposed by integrating meta-antenna structures with W/CoFeB/Pt nanolayer stacks. These monolithic integrated devices exhibit spintronic terahertz wave emission, spectral modulation, and polarization manipulation simultaneously. The terahertz pulses are generated within the ferromagnetic heterostructure interfaces and transmitted along the metallic structures, leading to the modulation of the spintronic terahertz waves. Results have shown that the center-frequency shift is up to 140 GHz and the value of ellipticity can reach 0.6, demonstrating a set of integrated and efficient spintronic terahertz devices to modulate the emitted wave. In addition, compared with the slotline antenna, the maximum peak value of the bandpass band is enhanced up to 1.63 times by carefully designing the metamaterial structure. The spintronic meta-antenna array proposed here paves an integrated way for the manipulation of spintronic terahertz optoelectronic devices.

Highly thermal conductive shape-stabilized composite phase change materials based on boron nitride and expanded graphite for solar thermal applications.

Phase change heat storage technology is a good way to solve the problem that the temperature of solar hot water outlet is affected by the time domain. A stearic acid (SA)-benzamide (BA) eutectic mixture is a potential phase change material (PCM), but it still has the disadvantages of low thermal conductivity and liquid leakage. In this work, a new high thermal conductive shape-stabilized composite PCM was prepared by adding boron nitride (BN) and expanded graphite (EG) to a melted SA-BA eutectic mixture using an ultrasonic and melt adsorption method, and its phase change temperature, latent heat, crystal structure, morphology, thermal conductivity, chemical stability, thermal stability, cycle stability and leakage characteristics were characterized. The results indicates that the addition of BN and EG significantly improved the thermal conductivity of the SA-BA eutectic mixture, and they efficiently adsorbed the melted SA-BA eutectic mixture. Besides, when the mass fractions of BN and EG are 15 wt% and 20 wt%, respectively, the 15BN20EG composite has almost no liquid phase leakage. When the melting enthalpy and temperature of 15BN20EG are 132.35 J g-1 and 65.21 °C, respectively, the thermal conductivity of the 15BN20EG is 6.990 W m-1 K-1, which is 20.601 times that of the SA-BA eutectic mixture. Moreover, 15BN20EG shows good thermal stability after 100 cycles and good chemical stability below 100 °C. Therefore, the 15BN20EG composite is considered as a potential candidate for solar thermal applications.

Effect of oral pre-emptive analgesia on pain management after total knee arthroplasty: a protocol for systematic review and meta-analysis.

INTRODUCTION: Total knee arthroplasty (TKA) is currently regarded as an effective treatment for knee osteoarthritis, relieving patients' pain and significantly enhancing their quality of life and activity levels, allowing them to return to work and daily life after surgery. However, some TKA patients suffer from varying degrees of postoperative residual pain and opioid abuse, which negatively impacts their recovery and quality of life. It has been reported that preoperative treatment with multimodal analgesics improves postoperative pain and reduces opioid consumption. However, there is no conclusive evidence that pre-emptive analgesia provides the same benefits in TKA. In order to inform future research, this protocol focuses on the efficacy and safety of oral analgesics used in TKA pre-emptive analgesia. METHODS AND ANALYSIS: We will search the literature on the involvement of pre-emptive analgesia in the management of pain in TKA from the PubMed, EMBASE, MEDLINE, the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews, from their inception to 1 February 2023. Additionally, clinical registry platforms will be investigated to collect data for ongoing studies. Using the Cochrane Risk of Bias Tool, the quality assessment will be conducted. RevMan V.5.4 will be used for the meta-analysis. The statistic I 2 will be used to measure the percentage of total variability due to heterogeneity between studies. Where appropriate, subgroup and sensitivity analyses, assessment of evidence quality and publication bias will be conducted. ETHICS AND DISSEMINATION: No ethical approval and consent is required for this systematic review. Moreover, the results of this systematic review will be disseminated through peer-reviewed publications and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42022380782.

A machine learning-Based model to predict early death among bone metastatic breast cancer patients: A large cohort of 16,189 patients.

Purpose: This study aims to develop a prediction model to categorize the risk of early death among breast cancer patients with bone metastases using machine learning models. Methods: This study examined 16,189 bone metastatic breast cancer patients between 2010 and 2019 from a large oncological database in the United States. The patients were divided into two groups at random in a 90:10 ratio. The majority of patients (n = 14,582, 90%) were served as the training group to train and optimize prediction models, whereas patients in the validation group (n = 1,607, 10%) were utilized to validate the prediction models. Four models were introduced in the study: the logistic regression model, gradient boosting tree model, decision tree model, and random forest model. Results: Early death accounted for 17.4% of all included patients. Multivariate analysis demonstrated that older age; a separated, divorced, or widowed marital status; nonmetropolitan counties; brain metastasis; liver metastasis; lung metastasis; and histologic type of unspecified neoplasms were significantly associated with more early death, whereas a lower grade, a positive estrogen receptor (ER) status, cancer-directed surgery, radiation, and chemotherapy were significantly the protective factors. For the purpose of developing prediction models, the 12 variables were used. Among all the four models, the gradient boosting tree had the greatest AUC [0.829, 95% confident interval (CI): 0.802-0.856], and the random forest (0.828, 95% CI: 0.801-0.855) and logistic regression (0.819, 95% CI: 0.791-0.847) models came in second and third, respectively. The discrimination slopes for the three models were 0.258, 0.223, and 0.240, respectively, and the corresponding accuracy rates were 0.801, 0.770, and 0.762, respectively. The Brier score of gradient boosting tree was the lowest (0.109), followed by the random forest (0.111) and logistic regression (0.112) models. Risk stratification showed that patients in the high-risk group (46.31%) had a greater six-fold chance of early death than those in the low-risk group (7.50%). Conclusion: The gradient boosting tree model demonstrates promising performance with favorable discrimination and calibration in the study, and this model can stratify the risk probability of early death among bone metastatic breast cancer patients.

Oral Chinese patent medicines for acute myocardial infarction after percutaneous coronary intervention: A protocol for systematic review and network meta-analysis.

BACKGROUND: Acute myocardial infarction (AMI) is a serious and fatal heart disease with one of the highest mortality rates in the world. In some countries, percutaneous coronary intervention (PCI) is the preferred reperfusion strategy after AMI, but it cannot achieve safe and effective treatment of AMI after PCI remains a challenging clinical problem. The potential of oral Chinese patent medicines to treat AMI after PCI has been demonstrated, but which type of oral Chinese patent medicines may be preferred remains controversial. The aim of this network meta-analysis was to investigate the efficacy and safety of multiple oral Chinese patent medicines in the treatment of AMI after PCI. METHODS: We will conduct a literature search from China National Knowledge Infrastructure, formerly Chinese Biomedical Database (SinoMed), Wanfang Data, Chongqing VIP, PubMed, Embase, Web of Science and Cochrane Library (The Cochrane Database of Systematic Reviews) from their inception until to November 1, 2022, with language restricted to Chinese and English. Then, the study selection process will follow the Preferred Reporting Items for Meta-Analyses guideline, and the quality assessment will be conducted with Cochrane Collaboration's tool. Pairwise and network meta-analysis will be conducted using the WinBUGS V.1.4.3.37 and STATA V.13. Additionally, sensitivity analysis, subgroup analysis, quality assessment, Small-study effects and publication bias will be performed. ETHICS AND DISSEMINATION: This work is based on published research and therefore does not require ethical approval. This review will be published in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42020188065.

Characteristics of clinical trials related to hip fractures and factors associated with completion.

BACKGROUND: This study aimed at investigating the characteristics of clinical trials related to hip fractures that were registered at ClinicalTrials.gov. It also aimed to identify potential risk factors associated with completion. MAIN BODY: We obtained 733 clinical studies related to hip fractures from the ClinicalTrials.gov database and included 470 studies in the analysis. These clinical trials were divided into behavioral, drug/biological, device, procedure, and other categories based on intervention types. Clinical trials investigating drugs or biologics were categorized based on the specific agents administered in each trial. Multiple logistic and Cox regression models were used to test the ability of 24 potential risk factors in predicting recruitment status and completion time, respectively. Among the included clinical trials, 44.89% (211/470) had complete recruitment status. The overall median completion time was 931.00 days (95% confidence interval [CI]: 822.56-1039.44 days). The results of only 8.94% (42/470) of clinical trials were presented on the ClinicalTrials.gov website. Bupivacaine (a local anesthetic) was most commonly investigated (in 25 clinical trials); this was followed by ropivacaine (another local anesthetic, 23 clinical trials) and tranexamic acid (a hemostatic, 21 clinical trials). Multivariate analysis showed that trials including children (P = 0.03) and having National Institutes of Health funds (P < 0.01) had significantly higher rates of complete recruitment. Higher enrollment (P < 0.01), National Institutes of Health funding (P < 0.01), location in the United States (P = 0.04), and location in Europe (P = 0.03) predisposed to longer completion time, while studies involving drugs/biologics (P < 0.01) had shorter completion times. CONCLUSIONS: A considerable proportion of clinical trials related to hip fractures were completed, but the results of only a small fraction were presented on the ClinicalTrials.gov website. The commonly investigated drugs focused on anesthesia, pain relief, and hemostasis. Several independent risk factors that affect recruitment status and completion time were identified. These factors may guide the design of clinical trials relating to hip fractures.

The Progress of Research into Flexible Sensors in the Field of Smart Wearables.

In modern society, technology associated with smart sensors made from flexible materials is rapidly evolving. As a core component in the field of wearable smart devices (or 'smart wearables'), flexible sensors have the advantages of excellent flexibility, ductility, free folding properties, and more. When choosing materials for the development of sensors, reduced weight, elasticity, and wearer's convenience are considered as advantages, and are suitable for electronic skin, monitoring of health-related issues, biomedicine, human-computer interactions, and other fields of biotechnology. The idea behind wearable sensory devices is to enable their easy integration into everyday life. This review discusses the concepts of sensory mechanism, detected object, and contact form of flexible sensors, and expounds the preparation materials and their applicability. This is with the purpose of providing a reference for the further development of flexible sensors suitable for wearable devices.

Clinical significance and correlation of PD-L1, B7-H3, B7-H4, and TILs in pancreatic cancer.

BACKGROUND: B7 molecules play significant roles in regulating tumor immunity, but their expression patterns and immuno-biological correlations in pancreatic cancer (PaCa) have not been fully discussed. METHODS: RNA-sequencing data of B7 molecules of PaCa samples in the Cancer Genome Atlas (TCGA) dataset was downloaded from the UCSC Xena to assess the expression, correlation, and mutation of the B7 family in PaCa. Next, two PaCa tissue microarrays (TMAs, Cat. HPanA150CS02 and HPanA120Su02) were obtained from Outdo BioTech (Shanghai, China). To detect the expression levels of PD-L1, B7-H3 and B7-H4, immunohistochemistry (IHC) staining was performed on these TMAs. RESULTS: Most B7 molecules, including B7-1, B7-2, PD-L1, B7-DC, B7-H2, and B7-H5 exhibited similar expression patterns, but B7-H3, B7-H4, B7-H6, and B7-H7 showed outlier expression patterns compared with other B7 molecules. Besides, B7 molecules were genetically stable and exhibited low alteration frequency. IHC staining indicated PD-L1, B7-H3, and B7-H4 were up-regulated in PaCa tissues and showed uncorrelated expression patterns. Furthermore, high expression of PD-L1 and B7-H3 indicated poor-differentiated grades in PaCa. PD-L1 was positively, but B7-H4 was negatively correlated with CD8+ TILs infiltration in PaCa. Moreover, combined PD-L1 and B7-H4 expression was a novel subtyping strategy in PaCa, namely patients with both high PD-L1 and B7-H4 expression exhibited decreased CD8+ TILs infiltration in tumor tissues. CONCLUSION: Overall, we systemically analyzed the expression patterns of B7 molecules and proposed a novel subtyping strategy in PaCa. Patients with both high PD-L1 and B7-H4 expression exhibited the immuno-cold phenotype, which may be not suitable for immunotherapy.

Effects of Schyzocotyle acheilognathi (Yamaguti, 1934) infection on the intestinal microbiota, growth and immune reactions of grass carp (Ctenopharyngodon idella).

Our understanding of interactions among intestinal helminths, gut microbiota and host is still in its infancy in fish. In this study, the effects of Schyzocotyle acheilognathi infection on the intestinal microbiota, growth and immune reactions of grass carp were explored under laboratory conditions. 16S rDNA amplification sequencing results showed that S. acheilognathi infection altered the composition of intestinal microbiota only at the genus level, with a significant increase in the relative abundance of Turicibacter and Ruminococcus (P < 0.05) and a significant decrease in the relative abundance of Gordonia, Mycobacterium and Pseudocanthomonas (P < 0.05). Schyzocotyle acheilognathi infection had no significant effect (P > 0.05) on the alpha diversity indices (including Chao1, ACE, Shannon, Simpson index) of intestinal microbiota in grass carp, but PERMANOVA analysis showed that microbial structure significantly (P < 0.01) differed between hindgut and foregut. PICRUST prediction showed that some metabolism-related pathways were significantly changed after S. acheilognathi infection. The relative abundance of Turicibacter was positively correlated with the fresh weight of tapeworm (foregut: r = 0.48, P = 0.044; hindgut: r = 0.63, P = 0.005). There was no significant difference in the body condition of grass carp between the S. acheilognathi infected group and the uninfected group (P > 0.05). Intestinal tissue section with HE staining showed that S. acheilognathi infection severely damaged the intestinal villi, causing serious degeneration, necrosis and shedding of intestinal epithelial cells. The real-time fluorescent quantitative PCR results showed that S. acheilognathi infection upregulated the mRNA expression of the immune-related genes: Gal1-L2, TGF-ß1 and IgM.

The Role of Intestinal Microbiota in Regulating the Metabolism of Bile Acids Is Conserved Across Vertebrates.

In mammals, bile acid (BA) concentrations are regulated largely by the gut microbiota, and a study has shown that some metabolic responses to the gut microbiota are conserved between zebrafish and mice. However, it remains unknown whether the influence of specific intestinal microbes on BA metabolism is conserved between higher and lower vertebrates (i.e., mammals and fish). In the present study, Citrobacter freundii GC01 isolated from the grass carp (Ctenopharyngodon idella) intestine was supplemented to the fish and mice feed. We found the changes in the bile acid profile, especially significant changes in secondary BAs in both grass carp and mice fed on C. freundii. Also, lipid metabolism was significantly affected by C. freundii. Analysis of liver transcriptome sequencing data and validation by RT-qPCR revealed that the CYP7A1 gene was significantly up-regulated in both grass carp and mice. In addition, the overexpression of HNF4B from grass carp resulted in a significant increase in the expression level of CYP7A1. Generally, our results suggest that the metabolism of BAs by intestinal microbiota is conserved across vertebrates. Furthermore, specific intestinal bacteria may regulate the bile salt synthesis through CYP7A1 and that HNF4B might be an important regulator of BA metabolism in fish.

[Association of phthalate and polycyclic aromatic hydrocarbon exposure during early pregnancy with premature delivery: A cohort study].

OBJECTIVE: To explore the relationship of the exposure to phthalate esters (PAE) and polycyclic aromatic hydrocarbons (PAH) with clinical premature delivery during early pregnancy. METHODS: We conducted a baseline questionnaire survey among 821 pregnant women undergoing prenatal examination in Hubei Provincial Maternal and Child Health Care Hospital, collected their morning urine samples and followed them up to the outcomes of pregnancy. We quantitatively analyzed 10 PAE and 10 PAH metabolites in the urine samples, followed by Mann-Whitney U test, chi-square test, and logistic regression analysis. RESULTS: The detection rate of the 5 factors exposed to was >80% while that of phthalic acid monobenzyl ester (MBzP) was <50% in PAEs; that of the 5 factors exposed to was >80%, that of 3-hydroxyphene (3-OHPHE) was 86.91% while that of 4-hydroxyphene (4-OHPHE) was <50% in PAHs. Logistic regression analysis showed that the risk of premature delivery was higher in the high MBzP- than in the low MBzP-exposure group (aOR = 2.26, 95% CI: 1.17－4.39). CONCLUSION: High MBzP-exposure may be a risk factor for premature delivery.

Predicting the Survival of Cancer Patients With Multimodal Graph Neural Network.

In recent years, cancer patients survival prediction holds important significance for worldwide health problems, and has gained many researchers attention in medical information communities. Cancer patients survival prediction can be seen the classification work which is a meaningful and challenging task. Nevertheless, research in this field is still limited. In this work, we design a novel Multimodal Graph Neural Network (MGNN)framework for predicting cancer survival, which explores the features of real-world multimodal data such as gene expression, copy number alteration and clinical data in a unified framework. Specifically, we first construct the bipartite graphs between patients and multimodal data to explore the inherent relation. Subsequently, the embedding of each patient on different bipartite graphs is obtained with graph neural network. Finally, a multimodal fusion neural layer is proposed to fuse the medical features from different modality data. Comprehensive experiments have been conducted on real-world datasets, which demonstrate the superiority of our modal with significant improvements against state-of-the-arts. Furthermore, the proposed MGNN is validated to be more robust on other four cancer datasets.

Crosstalks between NOD1 and Histone H2A Contribute to Host Defense against Streptococcus agalactiae Infection in Zebrafish.

Correlation studies about NOD1 and histones have not been reported. In the present study, we report the functional correlation between NOD1 and the histone H2A variant in response to Streptococcus agalactiae infection. In zebrafish, NOD1 deficiency significantly promoted S. agalactiae proliferation and decreased larval survival. Transcriptome analysis revealed that the significantly enriched pathways in NOD1-/- adult zebrafish were mainly involved in immune and metabolism. Among 719 immunity-associated DEGs at 48 hpi, 74 DEGs regulated by NOD1 deficiency were histone variants. Weighted gene co-expression network analysis identified that H2A, H2B, and H3 had significant associations with NOD1 deficiency. Above all, S. agalactiae infection could induce the expression of intracellular histone H2A, as well as NOD1 colocalized with histone H2A, both in the cytoplasm and cell nucleus in the case of S. agalactiae infection. The overexpression of H2A variants such as zfH2A-6 protected against S. agalactiae infection and could improve cell survival in NOD1-deficient cells. Furthermore, NOD1 could interact with zfH2A-6 and cooperate with zfH2A-6 to inhibit the proliferation of S. agalactiae. NOD1 also showed a synergetic effect in inducing the expression of many antibacterial genes, especially antibacterial pattern recognition receptors PGRP2, PGRP5, and PGRP6. Collectively, these results firstly highlight the roles of NOD1 deficiency in the regulation of immune-related and metabolic pathways, and the correlation between zebrafish NOD1 and histone H2A variant in the defense against S. agalactiae infection.