Neurobrucellosis: laboratory features, clinical characteristics, antibiotic treatment, and clinical outcomes of 21 patients.

BACKGROUND: Neurobrucellosis (NB) is a rare and serious complication of brucellosis. Its clinical manifestations vary, with no obvious specificity. At present, there is no clear clinical diagnosis or treatment for reference. In this study, we retrospectively analyzed the clinical data for 21 patients with NB to provide reference data for its further study. METHODS: We analyzed the epidemiological and clinical manifestations, laboratory tests, imaging examinations, cerebrospinal fluid, and treatment plans of 21 patients diagnosed with NB in the Department of Neurology, Xuanwu Hospital, Capital Medical University Beijing, China. RESULTS: The ages of the patients ranged from 15 to 60 years old (mean age 40.1 ± 13.33 years), the male: female ratio was 4.25:1. Thirteen patients had a history of animal (sheep, cattle) contact, three had no history of animal contact, and the contact status of four was unknown. Brucella can invade various systems of the body and show multi-system symptoms, the main general manifestations were fever (66.67%), fatigue (57.14%) and functional urination or defecation disturbance (42.86%). The main nervous system manifestations were limb weakness (52.38%) and hearing loss (47.62%).The main positive signs of the nervous system included positive pathological signs (71.43%), sensory abnormalities (52.38%), limb paralysis (42.86%). Nervous system lesions mainly included spinal cord damage (66.67%), cranial nerve involvement (61.90%), central demyelination (28.57%) and meningitis (28.57%). In patients with cranial nerve involvement, 69.23% of auditory nerve, 15.38% of optic nerve and 15.38% of oculomotor nerve were involved. The blood of eight patients was cultured for Brucella, and three (37.5%) cultures were positive and five (63.5%) negative. The cerebrospinal fluid (CSF) of eight patients was cultured for Brucella, and two (25.00%) cultures were positive and six (75.00%) negative. Nineteen of the patients underwent a serum agglutination test (SAT), 18 (94.74%) of whom were positive and one (5.26%) of whom were negative. A biochemical analysis of the CSF was performed in 21 patients, and the results were all abnormal. Nineteen patients underwent magnetic resonance imaging (MRI). Twenty-one patients were treated with doxycycline and/or rifampicin, combined with ceftriaxone, quinolone, aminoglycoside, or minocycline. After hospitalization, 15 patients improved (71.43%), two patients did not recover, and the status of four patients was unknown. CONCLUSIONS: The clinical manifestations, CSF parameters, and neurological imaging data for patients with NB show no significant specificity or correlations. When patients with unexplained neurological symptoms accompanied by fever, fatigue, and other systemic manifestations in a brucellosis epidemic area or with a history of contact with cattle, sheep, animals, or raw food are encountered in clinical practice, the possibility of NB should be considered. Treatment is based on the principles of an early, combined, and long course of treatment, and the general prognosis is good.

Relationship between plasma brain-derived neurotrophic factor levels and neurological disorders: An investigation using Mendelian randomisation.

Background: Altered brain-derived neurotrophic factor (BDNF) concentrations have been detected in the central nervous system tissues and peripheral blood. These alterations are associated with a series of neurological disorders. Objective: To investigate the potential causal relationships between genetically determined plasma BDNF levels and various neurological diseases using a two-sample Mendelian randomisation study. Methods: We selected single nucleotide polymorphisms strongly related to plasma BDNF levels as instrumental variables. Within the Mendelian randomisation framework, we used summary-level statistics for exposure (plasma BDNF levels) and outcomes (neurological disorders). Results: We observed suggestive evidence of a relation between higher plasma BDNF levels and less risk of nontraumatic intracranial haemorrhage (nITH) (odds ratio [OR] = 0.861, 95 % confidence interval [CI]: 0.774-0.958, P = 0.006, PFDR = 0.078), epilepsy (OR = 0.927, 95 % CI: 0.880-0.976, P = 0.004, PFDR = 0.078), focal epilepsy (OR = 0.928, 95 % CI: 0.874-0.986, P = 0.016, PFDR = 0.139), and non-lesional focal epilepsy (OR = 0.981, 95 % CI: 0.964-0.999, P = 0.041, PFDR = 0.267). Combined with the UK Biobank dataset, the association of plasma BDNF levels with nITH remained significant (OR = 0.88, 95 % CI: 0.81-0.96, P < 0.01). The combined analysis of three consortium datasets demonstrated a considerable impact of plasma BDNF on epilepsy (OR = 0.94, 95 % CI: 0.90-0.98, P < 0.01) and a suggestive impact on focal epilepsy (OR = 0.94, 95 % CI: 0.89-0.99, P = 0.02). However, there was no apparent correlation between plasma BDNF levels and other neurological disorders or related subtypes. Conclusions: Our study supports a possible causal relationship between elevated plasma BDNF levels and a reduced risk of nITH, epilepsy, and focal epilepsy.

Immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma (CHANCE2201): a target trial emulation study.

Background: The role of transarterial chemoembolization (TACE) in the treatment of advanced hepatocellular carcinoma (HCC) is unconfirmed. This study aimed to assess the efficacy and safety of immune checkpoint inhibitors (ICIs) plus anti-vascular endothelial growth factor (anti-VEGF) antibody/tyrosine kinase inhibitors (TKIs) with or without TACE as first-line treatment for advanced HCC. Methods: This nationwide, multicenter, retrospective cohort study included advanced HCC patients receiving either TACE with ICIs plus anti-VEGF antibody/TKIs (TACE-ICI-VEGF) or only ICIs plus anti-VEGF antibody/TKIs (ICI-VEGF) from January 2018 to December 2022. The study design followed the target trial emulation framework with stabilized inverse probability of treatment weighting (sIPTW) to minimize biases. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and safety. The study is registered with ClinicalTrials.gov, NCT05332821. Findings: Among 1244 patients included in the analysis, 802 (64.5%) patients received TACE-ICI-VEGF treatment, and 442 (35.5%) patients received ICI-VEGF treatment. The median follow-up time was 21.1 months and 20.6 months, respectively. Post-application of sIPTW, baseline characteristics were well-balanced between the two groups. TACE-ICI-VEGF group exhibited a significantly improved median OS (22.6 months [95% CI: 21.2-23.9] vs 15.9 months [14.9-17.8]; P < 0.0001; adjusted hazard ratio [aHR] 0.63 [95% CI: 0.53-0.75]). Median PFS was also longer in TACE-ICI-VEGF group (9.9 months [9.1-10.6] vs 7.4 months [6.7-8.5]; P < 0.0001; aHR 0.74 [0.65-0.85]) per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. A higher ORR was observed in TACE-ICI-VEGF group, by either RECIST v1.1 or modified RECIST (41.2% vs 22.9%, P < 0.0001; 47.3% vs 29.7%, P < 0.0001). Grade ≥3 adverse events occurred in 178 patients (22.2%) in TACE-ICI-VEGF group and 80 patients (18.1%) in ICI-VEGF group. Interpretation: This multicenter study supports the use of TACE combined with ICIs and anti-VEGF antibody/TKIs as first-line treatment for advanced HCC, demonstrating an acceptable safety profile. Funding: National Natural Science Foundation of China, National Key Research and Development Program of China, Jiangsu Provincial Medical Innovation Center, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, and Nanjing Life Health Science and Technology Project.

Comprehensive Toxicological Assessment of Halobenzoquinones in Drinking Water at Environmentally Relevant Concentration.

Halobenzoquinones (HBQs), an emerging unregulated category of disinfection byproduct (DBP) in drinking water, have aroused an increasing concern over their potential health risks. However, the chronic toxicity of HBQs at environmentally relevant concentrations remains largely unknown. Here, the occurrence and concentrations of 13 HBQs in drinking water from a northern megacity in China were examined using ultrahigh performance liquid chromatography coupled with triple-quadrupole tandem mass spectrometry (UHPLC-MS/MS). Four HBQs, including 2,6-dichloro-1,4-benzoquinone (2,6-DCBQ), 2,6-dibromo-1,4-benzoquinone (2,6-DBBQ), 2,3,6-trichloro-1,4-benzoquinone (TriCBQ), and 2,5-dibromo-1,4-benzoquinone (2,5-DBBQ), were detected beyond 50% occurrence frequency and at median concentrations from 4 to 50 ng/L. The chronic toxicity of these four HBQs to normal human colon and liver cells (FHC and THLE-2) was investigated at these concentrations. After 90 days of exposure, 2,5-DBBQ and 2,6-DCBQ induced the highest levels of oxidative stress and deoxyribonucleic acid (DNA) damage in colon and liver cells, respectively. Moreover, 2,5-DBBQ and 2,6-DCBQ were also found to induce epithelial-mesenchymal transition (EMT) in normal human liver cells via the extracellular signal regulated kinase (ERK) signaling pathway. Importantly, heating to 100 °C (boiling) was found to efficiently reduce the levels of these four HBQs in drinking water. These results suggested that environmentally relevant concentrations of HBQs could induce cytotoxicity and genotoxicity in normal human cells, and boiling is a highly efficient way of detoxification for HBQs.

Effect of Tocilizumab plus Corticosteroid on Clinical Outcome in Patients Hospitalized with Severe Fever with Thrombocytopenia Syndrome: A Randomized Clinical Trial.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral hemorrhagic fever with high fatality rates. The blockade of pro-inflammatory cytokines presents a promising therapeutic strategy. METHODS: We conducted a randomized clinical trial at the 154th hospital, Xinyang, Henan Province. Eligible patients with severe SFTS disease were randomly assigned in a 1:2 ratio to receive either a single intravenous infusion of tocilizumab plus usual care; or usual care only. The primary outcome was the clinical status of death/survival at day 14, while secondary outcomes included improvement from baseline in liver and kidney damage and time required for hospital discharge. The efficacy of tocilizumab plus corticosteroid was compared to those receiving corticosteroid alone. The trial is registered with the Chinese Clinical Trial Registry website (ChiCTR2300076317). RESULTS: 63 eligible patients were assigned to the tocilizumab group and 126 to the control group. The addition of tocilizumab to usual care was associated with a reduced death rate (9.5%) compared to those received only usual care (23.0%), with an adjusted hazard ratio (aHR) of 0.37 (95% confidence interval [CI], 0.15 to 0.91, P=0.029). Combination therapy of tocilizumab and corticosteroids was associated with a significantly reduced fatality (aHR, 0.21; 95% CI, 0.08 to 0.56; P =0.002) compared to those receiving corticosteroid alone. CONCLUSIONS: A significant benefit of reducing fatality in severe SFTS patients was observed by using tocilizumab. A combined therapy of tocilizumab plus corticosteroids was recommended for the therapy of severe SFTS.

Improvements in the health-related quality-of-life benefit of cancer drugs approved in China, 2005-2020: an observational study.

Background: Health-related quality of life (HRQoL), along with overall survival (OS), is a critical study endpoint for measuring the clinical benefits of cancer drugs. Previous studies have examined the OS benefit of new cancer drugs approved in China. However, their HRQoL benefits have not been systematically evaluated. We aimed to characterise the measurement and improvement of HRQoL associated with cancer drugs approved in China. Methods: This mixed-methods study comprises of a literature review and a cross-sectional study, including all antineoplastic agents approved in China between January 1, 2005 and December 31, 2020. A systematic search was conducted on December 31, 2023 to extract HRQoL information of identified drugs. We extracted information on the characteristics of HRQoL assessment and statistically significant HRQoL gains compared with the control treatment. Findings: A total of 64 novel cancer drugs, corresponding to 115 cancer indications, supported by randomised clinical trials were approved in China between 2005 and 2020. Among the indications, 78 (67.8%) used HRQoL as an endpoint in the pivotal trial. By December 31, 2023, after a median follow-up of 5.3 (range, 3.0-18.8) years from approval, HRQoL information was available for more than half of the indications (75, 65.2%). Thirty-three indications (28.7%) reported statistically significant improvement in HRQoL, with 22 (19.1%) also having documented OS benefit. Approximately one-third of the indications (39, 33.9%) showed no difference in HRQoL, with 21 (18.3%) having documented OS gains. Three indications (2.6%) reported worsening HRQoL. The most commonly used HRQoL measurements were individual disease-specific instruments (62 of 75, 82.7%) while the most frequently employed analysis metric was the mean change scores from baseline (56 of 75, 74.7%). Interpretation: Fewer than one-third of cancer indications approved in China had shown HRQoL improvements. There was considerable heterogeneity in the analysis and reporting of HRQoL benefits associated with new cancer drugs approved in China. These findings emphasise the important role of HRQoL evaluation and analysis in clinical research and the necessity of improving the standardization of HRQoL assessment. Funding: National Natural Science Foundation of China (72274004).

MicroRNA-375-3p Alleviates Salicylate-Induced Neuronal Injury by Targeting ELAVL4 in Tinnitus.

Purpose Tinnitus is a phantom perception of sound in the absence of acoustic source. Previous evidence has indicated that miR-375-3p is downregulated in rats with tinnitus in comparison to the controls. Nevertheless, its molecular mechanism underlying tinnitus pathogenesis is unclarified. Methods SH-SY5Y cells were differentiated into neuronlike cells and stimulated with salicylate to mimic tinnitus in vitro. Immunofluorescence staining was utilized for measuring expression of NR2B (glutamate ionotropic receptor NMDA type subunit 2B). Intracellular reactive oxygen species (ROS) level was determined using DCFH-DA assay kit. Real-time quantitative polymerase chain reaction as well as western blotting was utilized for examining RNA and protein levels. Luciferase reporter assay was implemented for verifying the interaction between miR-375-3p and ELAVL4 (ELAV-like RNA-binding protein 4). Results Salicylate treatment enhanced levels of NR2B and the early immediate gene ARC as well as ROS production. miR-375-3p was downregulated in salicylate-treated group. Overexpressing miR-375-3p attenuated the effects induced by salicylate in SH-SY5Y cells. miR-375-3p targeted ELAVL4 and upregulating ELAVL4 reversed miR-375-3p upregulation-triggered effects on SH-SY5Y cells under salicylate treatment. Conclusion miR-375-3p mitigates salicylate-triggered neuronal injury in SH-SY5Y cells by regulating ELAVL4 expression.

Tetrahydroxy stilbene glucoside rejuvenates aging hematopoietic stem cells with predilection for lymphoid differentiation via AMPK and Tet2.

INTRODUCTION: Aging of hematopoietic stem cells (HSCs) has emerged as an important challenge to human health. Recent advances have raised the prospect of rejuvenating aging HSCs via specific medical interventions, including pharmacological treatments. Nonetheless, efforts to develop such drugs are still in infancy until now. OBJECTIVES: We aimed to screen the prospective agents that can rejuvenate aging HSCs and explore the potential mechanisms. METHODS: We screened a set of natural anti-aging compounds through oral administration to sub-lethally irradiated mice, and identified 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (TSG) as a potent rejuvenating agent for aging HSCs. Then naturally aged mice were used for the follow-up assessment to determine the HSC rejuvenating potential of TSG. Finally, based on the transcriptome and DNA methylation analysis, we validated the role of the AMP-activated protein kinase (AMPK)-ten-eleven-translocation 2 (Tet2) axis (the AMPK-Tet2 axis) as the underlying mechanisms of TSG for ameliorating HSCs aging. RESULTS: TSG treatment not only significantly increased the absolute number of common lymphoid progenitors (CLPs) along with B lymphocytes, but also boosted the HSCs/CLPs repopulation potential of aging mice. Further elaborated mechanism research demonstrated that TSG supplementation restored the stemness of aging HSCs, as well as promoted an epigenetic reprograming that was associated with an improved regenerative capacity and an increased rate of lymphopoiesis. Such effects were diminished when the mice were co-treated with an AMPK inhibitor, or when it was performed in Tet2 knockout mice as well as senescent cells assay. CONCLUSION: TSG is effective in rejuvenating aging HSCs by modulating the AMPK- Tet2 axis and thus represents a potential candidate for developing effective HSC rejuvenating therapies.

The pattern of tumor progression on first-line immune checkpoint inhibitor-based systemic therapy for Chinese advanced hepatocellular carcinoma -CLEAP 004 study.

Background: For decades, stratification criteria for first-line clinical studies have been highly uniform. However, there is no principle or consensus for restratification after systemic treatment progression based on immune checkpoint inhibitors (ICIs). The aim of this study was to assess the patterns of disease progression in patients with advanced hepatocellular carcinoma (HCC) who are not eligible for surgical intervention, following the use of immune checkpoint inhibitors. Methods: This is a retrospective study that involved patients with inoperable China liver stage (CNLC) IIIa and/or IIIb. The patients were treated at eight centers across China between January 2017 and October 2022. All patients received at least two cycles of first-line treatment containing immune checkpoint inhibitors. The patterns of disease progression were assessed using RECIST criteria 1.1. Different progression modes have been identified based on the characteristics of imaging progress. The study's main outcome measures were post-progression survival (PPS) and overall survival (OS). Survival curves were plotted using the Kaplan-Meier method to compare the difference among the four groups. Subgroup analysis was conducted to compare the efficacy of different immunotherapy combinations. Variations in the efficacy of immunotherapy have also been noted across patient groups exhibiting alpha-fetoprotein (AFP) levels equal to or exceeding 400ng/mL, in contrast to those with AFP levels below 400ng/mL. Results: The study has identified four distinct patterns of progress, namely p-IIb, p-IIIa, p-IIIb, and p-IIIc. Diverse patterns of progress demonstrate notable variations in both PPS and OS. The group p-IIb had the longest PPS of 12.7m (95% 9.3-16.1) and OS 19.6m (95% 15.6-23.5), the remaining groups exhibited p-IIIb at PPS 10.5 months (95%CI: 7.9-13.1) and OS 19.2 months (95%CI 15.1-23.3). Similarly, p-IIIc at PPS 5.7 months (95%CI: 4.2-7.2) and OS 11.0 months (95%CI 9.0-12.9), while p-IIIa at PPS 3.4 months (95%CI: 2.7-4.1) and OS 8.2 months (95%CI 6.8-9.5) were also seen. Additional stratified analysis was conducted and showed there were no differences of immunotherapy alone or in combination in OS (HR= 0.92, 95%CI: 0.59-1.43, P=0.68) and PPS (HR= 0.88, 95%CI: 0.57-1.36, P=0.54); there was no significant difference in PPS (HR=0.79, 95% CI: 0.55-1.12, P=0.15) and OS (HR=0.86, 95% CI: 0.61-1.24, P=0.39) for patients with AFP levels at or over 400ng/mL. However, it was observed that patients with AFP levels above 400ng/mL experienced a shorter median progression of PPS (8.0 months vs. 5.0 months) after undergoing immunotherapy. Conclusion: In this investigation of advanced hepatocellular carcinoma among Chinese patients treated with immune checkpoint inhibitors, we identified four distinct progression patterns (p-IIb, p-IIIa, p-IIIb and p-IIIc) that showed significant differences in PPS and OS. These findings demonstrate the heterogeneity of disease progression and prognosis after immunotherapy failure. Further validation in large cohorts is necessary to develop prognostic models that integrate distinct progression patterns to guide subsequent treatment decisions. Additionally, post-immunotherapy progression in patients with AFP levels ≥400ng/mL indicates a shortened median PPS. These findings provide valuable insights for future personalized treatment decisions.

Flexible filament winding strategy to prepare COF@polyionic liquid-coated fibers for non-selective exclusion of macromolecules in electro-enhanced solid-phase microextraction.

BACKGROUND: Accurate quantitative analysis of small molecule metabolites in biological samples is of great significance. Hydroxypolycyclic aromatic hydrocarbons (OH-PAHs) are metabolic derivatives of emerging pollutants, reflecting exposure to polycyclic aromatic hydrocarbons (PAHs). Macromolecules such as proteins and enzymes in biological samples will interfere with the accurate quantification of OH-PAHs, making direct analysis impossible, requiring a series of complex treatments such as enzymatic hydrolysis. Therefore, the development of matrix-compatible fiber coatings that can exclude macromolecules is of great significance to improve the ability of solid-phase microextraction (SPME) technology to selectively quantify small molecules in complex matrices and achieve rapid and direct analysis. RESULTS: We have developed an innovative coating with a stable macromolecular barrier using electrospinning and flexible filament winding (FW) technologies. This coating, referred to as the hollow fibrous covalent organic framework@polyionic liquid (F-COF@polyILs), demonstrates outstanding conductivity and stability. It accelerates the adsorption equilibrium time (25 min) for polar OH-PAHs through electrically enhanced solid-phase microextraction (EE-SPME) technology. Compared to the powder form, F-COF@polyILs coating displays effective non-selective large-size molecular sieving. Combining gas chromatography-tandem triple quadrupole mass spectrometry (GC-MS/MS), we have established a simple, efficient quantitative analysis method for OH-PAHs with a low detection limit (0.008-0.05 ng L-1), wide linear range (0.02-1000 ng L-1), and good repeatability (1.0%-7.3 %). Experimental results show that the coated fiber exhibits good resistance to matrix interference (2.5%-16.7 %) in complex biological matrices, and has been successfully used for OH-PAHs analysis in human urine and plasma. SIGNIFICANCE: FW technology realizes the transformation of the traditional powder form of COF in SPME coating to a uniform non-powder coating, giving its ability to exclude large molecules in complex biological matrices. A method for quantitatively detecting OH-PAHs in real biological samples was also developed. Therefore, the filament winding preparation method for F-COF@polyILs coated fibers, along with fibrous COFs' morphology control, has substantial implications for efficiently extracting target compounds from complex matrices.

A physiologically based pharmacokinetic/pharmacodynamic model to determine dosage regimens and withdrawal intervals of aditoprim against Streptococcus suis.

Introduction: Streptococcus suis (S. suis) is a zoonotic pathogen threatening public health. Aditoprim (ADP), a novel veterinary medicine, exhibits an antibacterial effect against S. suis. In this study, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model was used to determine the dosage regimens of ADP against S. suis and withdrawal intervals. Methods: The PBPK model of ADP injection can predict drug concentrations in plasma, liver, kidney, muscle, and fat. A semi-mechanistic pharmacodynamic (PD) model, including susceptible subpopulation and resistant subpopulation, is successfully developed by a nonlinear mixed-effect model to evaluate antibacterial effects. An integrated PBPK/PD model is conducted to predict the time-course of bacterial count change and resistance development under different ADP dosages. Results: ADP injection, administrated at 20 mg/kg with 12 intervals for 3 consecutive days, can exert an excellent antibacterial effect while avoiding resistance emergence. The withdrawal interval at the recommended dosage regimen is determined as 18 days to ensure food safety. Discussion: This study suggests that the PBPK/PD model can be applied as an effective tool for the antibacterial effect and safety evaluation of novel veterinary drugs.

[99mTc]Tc-labeled cyc-DX600-HYNIC as a SPECT probe for ACE2-specific pancreatic cancer imaging.

As a regulator in renin-angiotensin-aldosterone system, angiotensin-converting enzyme 2 (ACE2) closely correlated with tumor progression of pancreatic cancer, meantime, was easily affected by a variety of factors. [99mTc]Tc-cyc-DX600 SPECT was established as an ACE2-specific imaging protocol to figure out the ACE2 status in pancreatic tumor. BALB/C-NU mice were used to prepare the subcutaneous cell derived xenograft (CDX) models with HEK-293T or HEK-293T/hACE2 cells to validate ACE2 specificity of [99mTc]Tc-cyc-DX600 SPECT and establish SPECT imaging protocol. On the basis of [99mTc]Tc-cyc-DX600 SPECT and [18F]F-FDG PET/CT, ACE2-dependence on tumor size and tumor metabolism were further verified on orthotopic pancreatic cancer model with KPC cells. Immunohistochemical analysis was used to demonstrate the findings on ACE2 SPECT. [99mTc]Tc-cyc-DX600 was of superior tumor uptake in HEK-293T/hACE2 CDX than wild type (6.74 ± 0.31 %ID/mL vs 1.83 ± 0.26 %ID/mL at 1.5 h post injection (p.i.); 3.14 ± 0.31 %ID/mL vs 1.16 ± 0.15 %ID/mL at 4.5 h p.i.). For the CDX models with PANC-1 cells, a significant negative correlation between the slope of tumor volume and tumor uptake was observed (r = -0.382 for the 1-4th day; r = -0.146 for the 1-5th day; r = -0.114 for the 1-6th day; r = -0.152 for the 1-7th day; but P > 0.05 for all). For orthotopic pancreatic cancer model, the linear correlation between FDG PET and ACE2 SPECT of the pancreatic lesions was negative (r = -0.878), the quantitative values of ACE2 SPCET was positively correlated with the volume of primary lesions (r = 0.752) and also positively correlated with the quantitative values of ACE2 immunohistochemical analysis (r = 0.991). Conclusively, [99mTc]Tc-cyc-DX600 SPECT is an ACE2-specific imaging protocol with clinical translational potential, adding multidimensional information on the disease progression of pancreatic cancer.

Contingency management for substance use disorders in the U.S. Veterans Health Administration: 2018-2022.

INTRODUCTION: Contingency management (CM) is one of the most effective interventions for substance use disorders (SUDs), including stimulant use disorder. In the United States, the Veterans Health Administration (VHA) led the largest-scale rollout of CM in the US to date, but little is known about characteristics of patients treated and CM clinical practices. METHODS: In this retrospective cohort study, we used VHA electronic health records data to descriptively examine CM treatment course (e.g., number of visits, time between visits, duration of treatment episode) and characteristics of patients receiving CM for SUDs from 2018 to 2022. RESULTS: From January 2018 to September 2022, 2844 patients received CM at 90 VA Health Systems (including 98 VA Medical Center, 7 community-based outpatient clinics, and 15 other sites). The median number of CM visits was 8 (mean = 10.17, SD = 8.12) visits over the course of 1.5 months (median = 45 days, mean = 57.46 days, SD = 62.65). The target substance was stimulants in 86.42 % of visits. Average age of patients was 52.29 years (SD = 12.10), with 55.06 % of patients experiencing homelessness or housing instability, and 97.50 % of patients diagnosed with more than one SUD. Compared to the year prior to the COVID-19 pandemic (03/2019-02/2020; mean = 957.33, SD = 157.71 visits/month), CM visits declined by 83.20 % in the year following the pandemic (03/2020-02/2021; mean = 160.83, SD = 164.14), and have yet to return to pre-pandemic levels. CONCLUSIONS: The CM rollout has been markedly successful in the VHA, with adoption across multiple VHA sites within a complex patient population, indicating the potential for effective, more widespread CM implementation. At the same time, there was a considerable reduction in CM care during the COVID-19 pandemic and CM has not yet returned to pre-pandemic levels. Moreover, only a small minority of VA patients with stimulant use disorder have received CM. Given increasing rates of overdose, including stimulant-involved overdose, it is important to increase CM provision in VHA and non-VHA settings.

Profiling the Gut Microbiota in Obese Children with Formula Feeding in Early Life and Selecting Strains against Obesity.

Formula feeding, obesity and the gut microbiota are closely related. The present investigation explored the profiles of the intestinal microbiota in obese children over 5 years old with formula feeding in early life. We identified functional bacteria with anti-obesity potential through in vitro and in vivo experiments, elucidating their mechanisms. The results indicated that, in the group of children over 5 years old who were fed formula in early life, obese children exhibited distinct gut microbiota, which were characterized by diminished species diversity and reduced Bifidobacterium levels compared to normal-weight children. As a result, Lactobacillus acidophilus H-68 (H-68) was isolated from the feces of the N-FF group and recognized as a promising candidate. H-68 demonstrated the ability to stimulate cholecystokinin (CCK) secretion in STC-1 cells and produce bile salt hydrolase. In vivo, H-68 promoted CCK secretion, suppressing food intake, and regulated bile acid enterohepatic circulation, leading to increased deoxycholic acid and lithocholic acid levels in the ileum and liver. This regulation effectively inhibited the diet-induced body weight and body fat gain, along with the liver fat deposition. In conclusion, H-68 was recognized for its prospective anti-obesity impact, signifying an auspicious pathway for forthcoming interventions targeted at averting pediatric obesity in formula-fed children.

Psychometric properties of the Chinese version of the oncology nurses health behaviors determinants scale: a cross-sectional study.

Objective: To test the validity and reliability of the Oncology Nurses Health Behaviors Determinants Scale (HBDS-ON) in oncology nurses, the Chinese version was developed. Methods: The Brislin double translation-back translation approach was employed to forward translation, back translation, synthesis, cross-cultural adaptation, and pre-survey, resulting in the first Chinese version of the Oncology Nurses Health Behaviors Determinants Scale (HBDS-ON). A convenience sample technique was used to select 350 study participants in Liaoning, Shandong, and Jiangsu, China, who satisfied the inclusion and exclusion criteria, to assess the validity and reliability of the scale. Results: The Chinese version of the Oncology Nurses Health Behaviors Determinants Scale (HBDS-ON) had six subscales (perceived threat, perceived benefits, perceived barriers, self-efficacy, cues to action, and personal protective equipment availability and accessibility), including 29 items. The average scale level was 0.931, and the content validity level of the items varied from 0.857 to 1.000. Each Cronbach's α coefficient had an acceptable internal consistency reliability range of 0.806 to 0.902. X2/df = 1.667, RMSEA = 0.044, RMR = 0.018, CFI = 0.959, NFI = 0.905, TLI = 0.954, and IFI = 0.960 were the model fit outcomes in the validation factor analysis. All of the model fit markers fell within reasonable bounds. Conclusion: The Chinese version of the Oncology Nurses Health Behaviors Determinants Scale (HBDS-ON) has good reliability and validity and can be used as a tool to assess the influencing factors of chemotherapy exposure for oncology nurses in China.

Targeting the Cdc2-like kinase 2 for overcoming platinum resistance in ovarian cancer.

Platinum resistance represents a major barrier to the survival of patients with ovarian cancer (OC). Cdc2-like kinase 2 (CLK2) is a major protein kinase associated with oncogenic phenotype and development in some solid tumors. However, the exact role and underlying mechanism of CLK2 in the progression of OC is currently unknown. Using microarray gene expression profiling and immunostaining on OC tissues, we found that CLK2 was upregulated in OC tissues and was associated with a short platinum-free interval in patients. Functional assays showed that CLK2 protected OC cells from platinum-induced apoptosis and allowed tumor xenografts to be more resistant to platinum. Mechanistically, CLK2 phosphorylated breast cancer gene 1 (BRCA1) at serine 1423 (Ser1423) to enhance DNA damage repair, resulting in platinum resistance in OC cells. Meanwhile, in OC cells treated with platinum, p38 stabilized CLK2 protein through phosphorylating at threonine 343 of CLK2. Consequently, the combination of CLK2 and poly ADP-ribose polymerase inhibitors achieved synergistic lethal effect to overcome platinum resistance in patient-derived xenografts, especially those with wild-type BRCA1. These findings provide evidence for a potential strategy to overcome platinum resistance in OC patients by targeting CLK2.

VLPs generated by the fusion of RSV-F or hMPV-F glycoprotein to HIV-Gag show improved immunogenicity and neutralizing response in mice.

Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) vaccines have been long overdue. Structure-based vaccine design created a new momentum in the last decade, and the first RSV vaccines have finally been approved in older adults and pregnant individuals. These vaccines are based on recombinant stabilized pre-fusion F glycoproteins administered as soluble proteins. Multimeric antigenic display could markedly improve immunogenicity and should be evaluated in the next generations of vaccines. Here we tested a new virus like particles-based vaccine platform which utilizes the direct fusion of an immunogen of interest to the structural human immunodeficient virus (HIV) protein Gag to increase its surface density and immunogenicity. We compared, in mice, the immunogenicity of RSV-F or hMPV-F based immunogens delivered either as soluble proteins or displayed on the surface of our VLPs. VLP associated F-proteins showed better immunogenicity and induced superior neutralizing responses. Moreover, when combining both VLP associated and soluble immunogens in a heterologous regimen, VLP-associated immunogens provided added benefits when administered as the prime immunization.

A new TROP2-targeting antibody-drug conjugate shows potent antitumor efficacy in breast and lung cancers.

Trophoblast cell surface antigen 2 (Trop2) is considered to be an attractive therapeutic target in cancer treatments. We previously generated a new humanized anti-Trop2 antibody named hIMB1636, and designated it as an ideal targeting carrier for cancer therapy. Lidamycin (LDM) is a new antitumor antibiotic, containing an active enediyne chromophore (AE) and a noncovalently bound apoprotein (LDP). AE and LDP can be separated and reassembled, and the reassembled LDM possesses cytotoxicity similar to that of native LDM; this has made LDM attractive in the preparation of gene-engineering drugs. We herein firstly prepared a new fusion protein hIMB1636-LDP composed of hIMB1636 and LDP by genetic engineering. This construct showed potent binding activities to recombinant antigen with a KD value of 4.57 nM, exhibited binding to Trop2-positive cancer cells and internalization and transport to lysosomes, and demonstrated powerful tumor-targeting ability in vivo. We then obtained the antibody-drug conjugate (ADC) hIMB1636-LDP-AE by molecular reconstitution. In vitro, hIMB1636-LDP-AE inhibited the proliferation, migration, and tumorsphere formation of tumor cells with half-maximal inhibitory concentration (IC50) values at the sub-nanomolar level. Mechanistically, hIMB1636-LDP-AE induced apoptosis and cell-cycle arrest. In vivo, hIMB1636-LDP-AE also inhibited the growth of breast and lung cancers in xenograft models. Moreover, compared to sacituzumab govitecan, hIMB1636-LDP-AE showed more potent antitumor activity and significantly lower myelotoxicity in tumors with moderate Trop2 expression. This study fully revealed the potent antitumor efficacy of hIMB1636-LDP-AE, and also provided a new preparation method for LDM-based ADC, as well as a promising candidate for breast cancer and lung cancer therapeutics.

Fungal-Bacterial Mutualism: Species and Strain-Dependent Simultaneous Modulation of Branched-Chain Esters and Indole Derivatives in Fermented Sausages through Metabolite Cross-Feeding.

The precise impact of species and strain diversity on fungal-bacterial interactions and the overall community functioning has remained unclear. First, our study revealed how Debaryomyces hansenii influences diverse bacteria to accumulate key metabolites in a simulated fermented food system. For flavor, D. hansenii promoted the accumulation of branched-chain esters in Staphylococcus xylosus by promoting growth and facilitating the precursor branched-chain acids transformations but hindered the accumulation of Staphylococcus equorum. Furthermore, fungal-bacterial interactions displayed diversity among S. equorum strains. For bioactive compounds, species and strain diversity of lactic acid bacteria (LAB) also influences the production of indole derivatives. Then, we investigated specific metabolic exchanges under reciprocal interaction. Amino acids, rather than vitamins, were identified as the primary drivers of the bacterial growth promotion. Moreover, precursor transformations by D. hansenii played a significant role in branched-chain esters production. Finally, a synthetic community capable of producing high concentrations of branched-chain esters and indole derivatives was successfully constructed. These results provide valuable insights into understanding and designing synthetic communities for fermented sausages.

[Energy-saving and Emission Reduction Path for Road Traffic in Key Coastal Cities of Guangdong, Fujian and Zhejiang].

The rapid development of society and economy has resulted in a substantial increase in energy consumption, consequently exacerbating pollution issues. Current research predominantly focuses on energy-saving and emission reduction in road transportation within individual cities or the three major economic regions of China:the Yangtze River Delta, the Pearl River Delta, and the Beijing-Tianjin-Hebei Region. However, there is a dearth of studies addressing the southeastern coastal economic region. Located at the heart of China's southeastern coastal economic development, the provinces of Guangdong, Fujian, and Zhejiang unavoidably face challenges associated with energy consumption and emissions while pursuing economic growth. To address these challenges, this study employed a LEAP model to construct various scenarios for road transportation in the key coastal cities of Guangdong, Fujian, and Zhejiang from 2015 to 2035. These scenarios included a baseline scenario (BAU), an existing policy scenario (EPS), and an improved policy scenario (MPS). The MPS and EPS encompassed vehicle structure optimization (VSO), improved fuel economy (IFE), and reduced annual average mileage (RDM). By simulating and evaluating these scenarios, the energy-saving and emission reduction potentials of road transportation in the key coastal cities were assessed. The results indicated that, in the primary scenario, the MPS exhibited the most significant improvements in energy-saving, carbon reduction, and pollutant reduction effects. By 2035, the MPS achieved a remarkable 75% energy-saving rate compared to that in the baseline scenario, accompanied by reductions of 68%, 59%, 66%, 70%, and 64% in CO2, CO, NOx, PM2.5, and SO2 emissions, respectively. In the secondary scenario, the improved scenario of enhancing fuel economy achieved a notable 30% reduction in energy consumption. Additionally, the scenarios involving vehicle structure adjustment (yielding reductions of 36%, 30%, 36%, 26%, and 40%) and annual average mileage reduction (resulting in reductions of 37%, 37%, 36%, 37%, and 36%) demonstrated significant reductions in CO2, CO, NOx, PM2.5, and SO2 emissions.